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WO2024238591A2 - Methods of treating anti-aav seropositive hemophilia patients - Google Patents

Methods of treating anti-aav seropositive hemophilia patients Download PDF

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Publication number
WO2024238591A2
WO2024238591A2 PCT/US2024/029349 US2024029349W WO2024238591A2 WO 2024238591 A2 WO2024238591 A2 WO 2024238591A2 US 2024029349 W US2024029349 W US 2024029349W WO 2024238591 A2 WO2024238591 A2 WO 2024238591A2
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aav
administration
fviii
subject
aav vector
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WO2024238591A3 (en
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Christian Vettermann
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Biomarin Pharmaceutical Inc
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Biomarin Pharmaceutical Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/37—Factors VIII
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0083—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the administration regime
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the disclosure relates to methods of treating hemophilia patients with Factor VIII (FVIII) adeno-associated virus (AAV), wherein the patients have pre-existing AAV antibodies or require re-administration or redosing of a gene therapy vector.
  • the disclosure also provides for methods of treating hemophilia patients with active FVIII inhibitors or patients that have undergone seroconversion to AAV capsid proteins.
  • FVIII Factor VIII
  • AAV-based vectors are promising tools for gene therapy applications, in part because AAVs have no known human pathologies, and vector genomes generally persist in an epi-chromosomal state that drive long-term transgene expression with little or no integration into the host genome.
  • Neutralizing antibodies can be present in the blood of a patient prior to AAV treatment due to naturally acquired infections with the wild type AAV (pre-existing NAbs) or acquired NAbs as a result of prior treatment with an AAV vector.
  • Literature regarding the impact of pre-existing or antibodies elicited after administration of adenoviral vectors on transduction efficiency has been well documented (Scallan et al.2006; Zaiss and Muruve 2008; Wang et al. 2011, Mingozzi and High 2017; Fitzpatrick et al.2018; Long et al.2019).
  • a detailed understanding of the interaction of AAV vectors with the immune system is of great importance for the safety and success of gene therapy applications.
  • the current practice in the clinic with regard to pre-existing immunity involves the screening of human patients for exclusion should patients have neutralizing antibodies against the AAV capsid (Brimble et al. Expert Opin Biol Ther 2016, 16(1):79-92 and Boutin et al. Hum Gene Ther 2010, 21:704-712).
  • Immunosuppressive regimens have been tried in order to reduce the formation of NAb upon first administration to allow for a second administration (Corti et al., Mol Ther-Meth Clin Dev (2014) 1, 14033; Mingozzi et al.
  • Valoctocogene roxaparvovec (ROCTAVIAN; BMN 270) is a gene therapy for severe hemophilia A using an adeno-associated virus serotype 5 (AAV5) capsid to deliver a B-domain- deleted (BDD) FVIII coding sequence controlled by a hepatocyte-selective promoter through a single infusion; it has been granted conditional marketing authorization by the European Medicines Agency (Bunting et al. Mol Ther 2018;26:496-509; Fong et al. Nat Med 2022;28:789- 97; Rangarajan et al. S. N Engl J Med 2017;377:2519-30; Pasi et al.
  • AAV5 adeno-associated virus serotype 5
  • AAV5 TAb positivity estimated to be applicable to approximately 30% of Hemophilia A patients globally (Klamroth et al. Hum Gene Ther.2022; 33:432-441), was incorporated as an exclusion criterion in BMN 270 clinical studies.
  • Interim results from the pivotal GENEr8-1 study have recapitulated findings from the NHP study, with median FVIII activity indicating gene therapy efficacy in TAb-negative but TI-positive subjects (Long et al.
  • the disclosure provides for methods of overcoming humoral immunity (i.e., antibodies) to AAV capsids, which may result from pre-existing exposure to the AAV or prior exposure to an AAV-based gene therapy vector, that can limit transduction efficiency and may pose safety concerns for AAV vectored gene therapy.
  • humoral immunity i.e., antibodies
  • the disclosure provides for methods of using therapeutic plasma exchange (TPE) or immuno-adsorption plasmapheresis (IAP) to transiently remove or reduce levels of immunoglobulins, including AAV5 capsid specific antibodies, from the plasma of individuals who had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy. Individuals are then administered a dose of AAV5 vector gene therapy shortly after plasmapheresis while AAV5 antibody levels are absent or low, circumventing any interference. Antibodies will naturally rebound within a few days after plasmapheresis treatment; therefore, several rounds of IAP are needed per session; wherein a “round” refers to the processing of 1 plasma volume.
  • TPE therapeutic plasma exchange
  • IAP immuno-adsorption plasmapheresis
  • the disclosure provides for methods of treating hemophilia in a subject comprising administering an AAV comprising a functionally active FVIII coding region wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV.
  • the disclosure provides for use of an adeno-associated virus (AAV) vector for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
  • AAV adeno-associated virus
  • the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1.
  • the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2.
  • the subject is suffering from hemophilia A.
  • the AAV is the gene therapy product referred to as FVIII-V3 which comprised the FVIII coding sequence of SEQ ID NO: 48.
  • the method further comprises subjecting the subject to at least one session of TPE or IAP prior to administration of the AAV.
  • the disclosure provides methods of using an IgG degrading enzyme prior to administration of the AAV to transiently remove or reduce levels of immunoglobulins, including AAV5 capsid specific antibodies, from the plasma of individuals who had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy. Individuals are then administered a dose of AAV5 vector gene therapy shortly after receiving the IgG degrading enzyme while AAV5 antibody levels are absent or low, circumventing any interference.
  • IgG degrading enzyme is Imlifidase (IdeS), which is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG.
  • IdeS Imlifidase
  • Other IgG degrading enzymes include IdeZ, IgdE (family) and IdeP, which all cleave IgG in the hinge region.
  • Another example are glycosidase EndoS and EndoS2, which hydrolyses the glycans on IgG Fc, thereby removing the majority of the glycans.
  • the disclosure provides for methods of treating hemophilia in a subject comprising administering an IgG degrading enzyme prior to treatment with an AAV comprising a functionally active FVIII coding region wherein the subject has antibodies specific for an AAV capsid protein.
  • the disclosure also provides for use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject has received a dose of the AAV vector prior to administration of the medicament, and wherein the AAV vector comprises a functionally active FVIII coding region.
  • compositions for use in treating hemophilia in a subject comprising an adeno-associated virus (AAV) vector comprising a functionally active FVIII coding region and wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector.
  • AAV adeno-associated virus
  • the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1.
  • the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48.
  • Antibodies specific for an AAV capsid refer to antibodies that specifically target or bind to a capsid protein of an AAV (also referred to as “anti-AAV antibodies”). These antibodies include anti-AAV neutralizing antibodies and pre-existing anti-AAV antibodies.
  • Neutralizing antibodies are antibodies which target or bind to viral epitopes that are critical for cellular entry, e,g. these antibodies reduce or inhibit virus infectivity. When anti-AAV antibodies target viral epitopes critical for cellular entry, they can block virus infectivity and are deemed neutralizing antibodies.
  • the anti-AAV antibodies are specific for or bind to a capsid protein from any AAV serotype or for a chimeric AAV capsid protein.
  • the anti-AAV antibodies specifically target or bind to a capsid protein from an AAV5, AAV6 or AAV8.
  • the anti-AAV antibodies may be caused by natural exposure to wild-type AAV, prior AAV infection or previous administration of AAV vector gene therapy.
  • the disclosure provides for methods of treating hemophilia in a subject comprising administering to a subject a second dose of an AAV comprising a functionally active FVIII coding region, wherein the subject has received a dose of the AAV prior to administration of the second dose of the AAV.
  • the disclosure also provides for use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject has received a dose of the AAV vector prior to administration of the medicament, and wherein the AAV vector comprises a functionally active FVIII coding region.
  • the disclosure provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises an AAV vector comprises a functionally active FVIII coding region and the subject has received a dose of the AAV vector prior to administration of the composition.
  • the method, use or composition further comprises subjecting the subject to at least one session of TPE or IAP prior to administration of the second dose of AAV.
  • the method, use or composition further comprises administering to the subject an IgG degrading enzyme prior to administration of the second dose of AAV.
  • the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48.
  • the subject is suffering from hemophilia A.
  • the disclosure also provides for methods of treating hemophilia in a subject comprising administering a corticosteroid and an AAV comprising a functionally active FVIII coding region to a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV.
  • the disclosure also provides for use of a corticosteroid and an AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV, and wherein the AAV comprises a functionally active FVIII coding region.
  • compositions for use in treating hemophilia in a subject wherein the composition comprises i) a corticosteroid and ii) an AAV comprising a functionally active FVIII coding region, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV.
  • the corticosteroid is administered on the day of AAV administration, or at least about 2 hours prior to administration of the AAV, or at least about 4 hours prior to administration of the AAV, or at least about 6 hours prior to administration of the AAV, or at least 12 hours prior to administration of the AAV, or at least 24 hours prior to administration of the AAV.
  • the methods further comprise the step of continuing administration of a corticosteroid once a day for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 8 weeks, or at least 16 weeks, or at least 19 weeks after administration of the AAV.
  • corticosteroid is administered orally.
  • the corticosteroid may be administered at a dose in the range of 20-60 mg/day.
  • the corticosteroid is administered for a set period of time and then gradually tapered off.
  • the corticosteroid is administered for 21 days, and the dose of therapeutic corticosteroid is gradually tapered off at day 22, optionally at day 22 the therapeutic corticosteroid is administered at 40mg/day for 28 days, and at day 29 the therapeutic corticosteroid is administered at 30 mg/day for 28 days.
  • a corticosteroid or a non- steroidal immunosuppressive agent may be used.
  • the corticosteroid is presnisone, prednisolone, dexamethasone, prednisone, fludrocortisone or hydrocortisone.
  • the disclosure provides for methods of treating hemophilia in a subject comprising administering an effective dose of AAV to a subject with pre- existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region.
  • the disclosure also provides for use of an effective dose of AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has pre-existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region.
  • the disclosure also provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises an effective dose of AAV ad wherein the subject has pre-existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region.
  • an effective dose of AAV-FVIII-SQ is administered to patients with severe hemophilia A having pre-existing antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers.
  • the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1.
  • the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48.
  • the subject is suffering from hemophilia A.
  • subjects are dosed based on the results of their AAV antibody titers as determined by a total antibody (TAb) assay.
  • the antibody titers are determined by an AAV5 TAb assay.
  • the titer cutoff for AAV treatment is ⁇ 100, ⁇ 200, ⁇ 500, or ⁇ 1000 using a proprietary AAV5 TAb screening assay.
  • an AAV5 TAb ⁇ 500 is used as a titer cutoff, reflecting the distribution of observed titer data for pre-existing antibodies to the AAV5 vector capsid.
  • the disclosure also provides for methods of treating hemophilia in a subject comprising administering an AAV to a subject having active FVIII inhibitors prior to or at the time of administration of the AAV, wherein the AAV comprises a functionally active FVIII coding region.
  • the disclosure also provides for use of a AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV, wherein the AAV comprises a functionally active FVIII coding region.
  • compositions for use in treating hemophilia comprising an AAV comprising a functionally active FVIII coding region and wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV.
  • the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1.
  • the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48.
  • the subject is suffering from hemophilia A.
  • FVIII inhibitors are molecules that interfere with FVIII replacement therapy and render the replacement therapy ineffective.
  • FVIII inhibitors may be antibodies that neutralize FVIII activity (anti-FVIII NAb) or non-antibody inhibitors.
  • Neutralizing anti-FVIII antibodies are alloantibodies that bind exogenous FVIII.
  • FVIII inhibitors interfere with the infused FVIII concentrates of the replacement therapy rendering them ineffective.
  • a subject with an “active FVIII inhibitor” is a subject having a titer of FVIII inhibitors, such as a high titer of FVIII inhibitors, a moderate titer of FVIII inhibitors or a low titer of FVIII inhibitors.
  • FVIII inhibitors are detected and quantified using the Bethesda assay or the Nijmegen Bethesda Assay (NBA).
  • NBA Nijmegen Bethesda Assay
  • 1 Bethesda unit (Bu) neutralizes about 50% of FVIII activity.
  • a subject having a titer of less than 0.6 BU is considered to be negative for FVIII inhibitors, while titers between 0.6 BU and 2.0 BU are considered low-titer FVIII inhibitors, titer between 2.1 BU to 5.0 BU are considered moderate-titer FVIII inhibitors and titers of > 5.0 BU are considered high-titer FVIII inhibitors.
  • the subject having active FVIII inhibitors has a titer of greater than about 5.0 Bu, or at least about 5.1 Bu, or at least about 5.2 Bu, or at least about 5.2 Bu, or at least about 5.3 Bu, or at least about 5.4 Bu, or at least about 5.5 Bu, or at least about 5.6 Bu, or at least about 5.7 Bu, or at least about 5.8 Bu, or at least about 5.9 Bu, or at least about 6.0 Bu, or at least about 6.5 Bu, at least about 7.0 Bu, at least about 7.5 Bu, at least about 8.0 Bu, at least about 8.5 Bu, or at least about 9.0 BU or at least about 9.5 Bu.
  • the subject has FVIII inhibitors ranging from about 5.1 BU to about 8.0 Bu, or ranging from about 5.2 BU to about 8.0 Bu, or ranging from about 5.5 BU to about 8.0 Bu, or ranging from about 5.7 BU to about 8.0 Bu, or about 6.0 BU to about 9.0 Bu, or ranging from about 6.2 BU to about 9.0 Bu, or ranging from about 6.5 BU to about 9.0 Bu, or ranging from about 6.7 BU to about 6.0 Bu, or about 7.1 BU to about 9.0 Bu, or ranging from about 7.2 BU to about 9.0 Bu, or ranging from about 7.5 BU to about 9.0 Bu, or ranging from about 7.7 BU to about 9.0 Bu, or about 5.1 BU to about 7.0 Bu, or ranging from about 5.1 BU to about 7.2 Bu, or ranging from about 5.1 BU to about 7.5 Bu, or ranging from about 5.1 BU to about 7.7 Bu, or about 5.1 BU to about 7.0 Bu, or ranging from
  • the subject has FVIII inhibitors ranging from about 3.0 BU to about 5.0 Bu, or ranging from about 3.2 BU to about 5.0 Bu, or ranging from about 3.5 BU to about 5.0 Bu, or ranging from about 3.7 BU to about 5.0 Bu, or about 4.0 BU to about 5.0 Bu, or ranging from about 4.2 BU to about 5.0 Bu, or ranging from about 4.5 BU to about 5.0 Bu, or ranging from about 4.7 BU to about 5.0 Bu, or about 2.1 BU to about 4.0 Bu, or ranging from about 2.2 BU to about 4.0 Bu, or ranging from about 2.5 BU to about 2.0 Bu, or ranging from about 2.7 BU to about 4.0 Bu, or about 2.1 BU to about 3.0 Bu, or ranging from about 2.1 BU to about 3.2 Bu, or ranging from about 2.1 BU to about 3.5 Bu, or ranging from about 2.1 BU to about 3.7 Bu.
  • the subject has FVIII inhibitors ranging from about 0.6 BU to about 2.0 Bu, or ranging from about 0.7 BU to about 2.0 Bu, or ranging from about 0.8 BU to about 2.0 Bu, or ranging from about 0.9 BU to about 2.0 Bu, or about 1.0 BU to about 2.0 Bu, or ranging from about 1.2 to about 2.0 Bu, or ranging from about 1.3 to about 2.0 BU or ranging from about 1.4 BU to about 2.0 Bu, or ranging from about 1.4 BU to about 2.0 Bu, or ranging from about 1.5 BU to about 2.0 Bu, or ranging from about 1.6 BU to about 2.0 Bu, or ranging from about 1.7 BU to about 2.0 Bu.
  • any of the disclosed methods, compositions or uses further comprise a step of subjecting the subject to TPE or IAP prior to administration of the AAV to remove the antibodies from the subject’s plasma.
  • the subject may be subjected to at least one session of TPE or IAP, or at least two sessions of TPE or IAP or at least three sessions of TPE or IAP.
  • any of the foregoing methods, compositions or uses further comprise the step of administering a corticosteroid or a non-steroidal immunosuppressive agent therapeutically after administration of the AAV.
  • the corticosteroid is presnisone, prednisolone, dexamethasone, prednisone, fludrocortisone or hydrocortisone.
  • the non-steroidal immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab, and optionally the immunosuppressive agent is administered systemically.
  • the therapeutic corticosteroid is administered to a subject having elevated alanine aminotransferase (ALT) levels after administration of the AAV compared to ALT level before administration of the AAV.
  • ALT alanine aminotransferase
  • the ALT level is at least 1.5x the ALT level prior to administration of the AAV vector, or at least 2x the ALT level prior to administration of the AAV vector, 2.5x the ALT level prior to administration of the AAV vector, or 3x the ALT level prior to administration of the AAV vector.
  • the AAV is administered intravenously.
  • the AAV is administered at a dose of 6E13 vg/kg.
  • the subject has a residual FVIII activity ⁇ 1 IU/dL prior to administration of AAV.
  • Figure 4 provides the results from one NHP as an example that multiple rounds of IAP over multiple days enabled up to 99% reduction of anti-AAV5 TAb titers.
  • Figure 5 provides a graph showing the mean reduction in AAV5 TAb titers per day in n- 2-10 NHPs that underwent variable days of IAP.
  • Figures 6A-6B provides the AAV total antibody (TAb) titer reduction following IAP. In Fig.6A, the black dotted lines mark the beginning of each day of IAP (before the first run) while the light dotted line marks the administration of AAV5-hFIX.
  • FIG. 10 provides a graph showing pre-existing immunity within the global populations and demonstrates that the pre-existing immunity titer are significantly lower than the treatment- emergent titers.
  • Figure 11 provides a graph showing seroprevalence of AAV5 TAb data.
  • Figures 12A provide a suggested schedule of prophylactic corticosteroid dosing in Part A of the study described in Example 6.
  • Figure 12B provides a suggested schedule of prophylactic corticosteroid dosing in Part B of the study described in Example 6.
  • Figures 13 A-13D provide data showing IdeS reduced pre-existing titers in an NHP pilot study and successful liver transduction.
  • Figures 14A-14B provide (A) a schematic of the rabbit model system to evaluate immunogenicity and AAV5 vectored gene therapy, and (B) a graph showing sensitized animals produced a range of NAb and TAb titers and were evenly distributed into IdeS and control groups.
  • Figures 15A-15C provide (A) a graph showing treatment with IdeS resulted in 99% reduction of TAb titer, and (B and C) provide graphs showing a single dose of IdeS enabled successful FIX transgene expression in sensitized rabbits.
  • Figure 16 provides a graph showing how a 99% decrease would reduce TAb titers to below a comparable CDx cutoff in hemophilia A patients.
  • Figure 17 provides the design of the study described in detail in Example 7 and the data provided in Example 8.
  • FIG. 18A-18B provide the data for participants having active FVIII inhibitors (part A).
  • ALT normal range was 5–48 U/L; ALT 1.5x baseline was 45 U/L (participant 1), 24 U/L (participant 2).
  • FVIII activity values ⁇ 1.5 IU/dL were imputed as 0 and FVIII antigen values ⁇ 4.7 ng/mL were imputed as 1.
  • ALT alanine aminotransferase
  • BU Bethesda units
  • CS corticosteroid
  • FVIII factor VIII
  • W week
  • Figures 19A-19B provide the data for participant having received prior FVIII inhibitors (part B).
  • ALT normal range was 5–48 U/L; ALT 1.5x baseline, 28.5 U/L (participant 1) or 27 U/L (participant 2).
  • Abbreviation for this figure are as follows: ALT (alanine aminotransferase); CS (corticosteroid); D (Day); FVIII (factor VIII); MMF (mycophenolate mofetil); W (week).
  • a single intravenous dose of this codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) was infused in nine men with severe hemophilia A. These subjects were enrolled sequentially into one of three dose cohorts (6e12 vector genomes vg/kg, 2e13 vg/kg, or 6e13 vg/kg) and followed for a planned 5 years following infusion.
  • AAV5-hFVIII-SQ B-domain-deleted human factor VIII
  • the objective of the first NHP study was to determine the pharmacodynamics of gene delivery and human FVIII-SQ expression following a single bolus injection of AAV-FVIII-SQ, an investigational AAV5-based gene therapy vector for the treatment of hemophilia A, to NHPS with varying pre-existing (naturally occurring) levels of AAV5 total binding antibodies (AAV5 TAb) and antibody or non-antibody inhibitors of transduction (AAV5 TI).
  • the objectives of the second study were to evaluate the impact of re-administration of an AAV5 vector to NHPs that had previously received the same serotype (AAV5) with high levels of antibodies generated due to intentional exposure to an AAV5 vector.
  • NHPs tolerated the second dose (re-dosing) of the vector AAV5-hFIX, showing no adverse clinical signs. Additionally, there were no clinical chemistry changes or histopathologic changes in the tissues at the end of the study. [61] Expression of human FIX was observed only in AAV5-hFIX animals (group 1) that were not previously sensitized to AAV5 prior to challenge dose administration. FIX plasma protein expression was not detected in group 2 animals (as expected the AAV5 NAbs elicited after the first vector administration prevented successful transduction of the second vector, AAV5-hFIX).
  • NHPs in these two studies received a single dose of AAV5-hFVIII-SQ at 6e13 vg/kg (study 1), while NHPs in the second study (study 2) received AAV5-cgb at 5e12 vg/kg (group 2) or a single dose of AAV5-hfix at 3e13 vg/kg (groups 1, 2).
  • NHPs in both studies were pre-screened specifically to include animals with pre-existing titers to AAV5 (study 1) or exclude animals with pre-existing titers to AAV5 (study 2).
  • a recent study reported severe toxicity after high vector doses (2e14 vg/kg) of an AAV9 variant (AAVhu68) were administered to young rhesus monkeys (14 months old) or piglets (7/30 day old).
  • AAVhu68 AAV9 variant
  • the piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection, all three animals exhibited proprioceptive deficits and ataxia, which profoundly impaired ambulation and necessitated euthanasia. (Hinderer et al.2018).
  • the acute toxicity in the latter study is likely due to an innate immune response rather than a humoral response to the viral capsid.
  • severe toxicity due to exacerbated innate immune response to viral vectors has been reported in the clinical setting as well (2018; Raper et al 2003).
  • a cytotoxic T-cell response directed against the AAV capsid, as well as the transgene product particularly at high doses (Mingozzi et al.2007, 2009 Basner-Tschakarjan et al., 2014).
  • a cytotoxic t-cell response is likely to be manifested by hepatic inflammation or hepatic injury, with concomitant increase in serum transaminases. Elevated transaminases (ALT or AST) were not observed in either study at any time point and with no histopathologic changes (at terminal necropsy).
  • FVIII activity an essential cofactor in the intrinsic coagulation pathway. Severe HA is classified as FVIII activity less than 1% of normal activity ( ⁇ 1 IU/dL), moderate disease comprises 1-5% of normal activity and the mild form is 5- 40% of normal activity.
  • the clinical manifestations of severe HA are frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially increased risk of death from hemorrhage when the brain is involved.
  • FVIII neutralizing antibodies inhibitors. Inhibitors arise in about 35% HA patients.
  • HA patients developing inhibitors express the clinical phenotype of severe ha, with residual FVIII activity ⁇ 1 IU/dL at the time of detected inhibitors.
  • these bleeds are difficult to manage since the usual method of achieving hemostasis through the use of FVIII infusions is rendered ineffective due to the presence of inhibitors.
  • Bypassing agents are available as alternative therapeutic options, but they are more burdensome to administer, less effective than replacement FVIII, and/or require more frequent infusions due to extremely short half-lives. Therefore, overall morbidity and mortality is worse in inhibitor patients, in conjunction with substantially increased health care costs due to the usage of expensive bypassing agents to manage bleeds (Walsh, 2016).
  • FVIII inhibitors may be antibodies that neutralize FVIII activity or non-antibody inhibitors.
  • Neutralizing antibodies are alloantibodies that bind exogenous FVIII.
  • FVIII inhibitors interfere with the infused factor concentrates rendering them ineffective and necessitating the use of more costly and less effective alternative hemostatic agents.
  • the FVIII inhibitor is a polyclonal high-affinity immunoglobulin G (IgG) that is directed against the FVIII protein, such as an IgG4 antibody.
  • the inhibitory antibodies may be directed to any against domain in the FVIII protein (FVIII contains three A domains (A1, A2, A3), one B domain and two C domains (C1, C2).
  • Exemplary inhibitors bind to the A2, A3 and C2 domains in FVIII. Antibodies in inhibitor patients can simultaneously target multiple FVIII epitopes and these epitope targets can change over time.
  • FVIII inhibitors are classified based on the kinetics and extent of inhibition of FVIII. Type I inhibitors follow second-order kinetics (dose-dependent linear inhibition) and completely inactivate FVIII. Type II inhibitors have complex kinetics and incompletely inactivate FVIII. Type I inhibitors are more common in severe hemophilia. Type II inhibitors are more common in inhibitor patients with mild hemophilia or in patients without hemophilia who develop an acquired FVIII inhibitor.
  • FVIII inhibitors are detected and quantified using the Bethesda assay or the Nijmegen Bethesda Assays (NBA). Both assays utilize serial dilutions of a patient’s plasma that is incubated with equal volumes of normal plasma for 2 h at 37 ° C. For the NBA, where 1 Bethesda unit (Bu) neutralizes about 50% of FVIII activity. Measurement of less than 0.6 BU is considered to be negative for inhibitors, while assessments between 0.6 and 5.0 Bus are considered low-titer inhibitors and > 5.0 Bus are considered high-titer inhibitors.
  • NBA Nijmegen Bethesda Assays
  • Inhibitors are most likely to develop in an HA patient during the first 20 exposure days (ed) to FVIII treatment – typically during childhood for patients with severe disease - after which, the risk decreases from 20 ed to 50 ed. After 50 ed, the risk decreases even further, reaching a very low steady- state rate of 2-5 per 1,000 patients per year after 150 ed (Hay, 2011). In later life, HA patients who have previously been stably managed with replacement FVIII products without any evidence of inhibitors may go on to subsequently develop inhibitors following periods of intensive FVIII exposure, such as may be required following major trauma or during surgical procedures.
  • the FVIII inhibitors are also classified as into low- or high-responding inhibitors based on a patient’s peak inhibitor titer after repeated FVIII exposure.
  • An inhibitor titer of 5 BU differentiates low- from high-responding inhibitors (White et al.2001).
  • An antibody titer that is persistently below 5 BU despite repeat challenges with factor VIII is considered a low- responding inhibitor.
  • a high-responsive inhibitor is applied if the assay has been greater than 5 BU at any time (White et al.2001).
  • APCC and FVIIIa are administered intravenously, with APCC requiring every other day dosing and FVIIIa requiring dosing from 2 times per day up to 2 times per week when used as prophylaxis; as a result, many HA patients with inhibitors require surgical implantation of central venous access devices, which are associated with risks of infection, bacteremia, thrombosis, device failure, and bleeding (Campbell, 2019).
  • Emicizumab a bi-specific monoclonal antibody that binds FIXa and FX and is administered subcutaneously, is unaffected by anti-FVIII antibodies and hence can be used to manage HA patients with inhibitors (Oldenburg 2017).
  • bpas and emicizumab both require chronic administrations and carry with them associated patient compliance issues.
  • the inability to manage hemostasis with replacement FVIII remains for HA patients with inhibitors on emicizumab, as these patients still need episodic treatment with bpas should they experience a bleed or undergo surgery.
  • hemostatic monitoring of bpas and emicizumab may be difficult or impossible using conventional clot-based assays.
  • ITI immune tolerance induction
  • Positive predictive parameters for successful ITI include historical peak inhibitor titer ⁇ 200 BU and pre- ITI inhibitor titer ⁇ 10 BU as well as patient compliance to the ITI regimen with uninterrupted treatment schedules.
  • Ha patients with inhibitors can experience improvement within 12 months of ITI initiation, but some patients can be on ITI for 2 or more years.
  • the high cost, requirement for access to large amounts of FVIII, and treatment burden make it challenging for some HA patients with inhibitors to pursue this treatment course and in countries with limited resources to offer ITI.
  • the liver is the body’s largest organ and is highly perfused with a rich supply of blood from the hepatic artery and hepatic portal vein containing microbial products and food antigens derived from the gut.
  • liver parenchymal tissue and other resident cell populations are highly competent to present antigens to effector cells of the immune system.
  • the liver serves as a waystation for the confluence of normally harmless antigens and immune effector cells that necessitates a mechanism by which unwarranted immune responses are suppressed (Morris, 2017; Tiegs 2010) to this end, the healthy liver represents a tolerogenic immune environment in which the default setting is an attenuated response to most gut derived molecules and immune suppression through the generation of antigen-specific regulatory t cells (t-regs). Consequently, liver directed gene therapy that results in efficient transgene expression in liver parenchyma cells, may reduce or eliminate immune responses specific for the transgene expressed protein.
  • liver directed gene therapy offers the opportunity to attenuate FVIII-specific immune responses and eradicate inhibitors in hemophilia A patients.
  • a single intravenous infusion of a vector encoding a functional FVIII gene can result in the formation of stable episomes leading to long-term endogenous production of FVIII in liver hepatocytes, and it is this stable, constant expression of FVIII protein that has the potential to induce immune tolerance.
  • Liver-directed gene therapy utilizing AAV vectors in animal models of hemophilia has been reported to induce immune tolerance to both FVIII and fix through induction of factor-specific T- regs (Finn, 2010; Markusic, 2013; Arruda, 2016).
  • cFVIII canine FVIII
  • inhibitor titers were observed to gradually decline as plasma cFVIII levels increased (Finn, 2010).
  • Expression of cFVIII in this system appeared to result in durable immune tolerance to FVIII with a decline in inhibitor titers to undetectable levels that did not rebound upon challenge with 500 u of recombinant cFVIII.
  • HA patients that have been able to successfully achieve immune tolerance with an ITI regimen can be re-established on a FVIII prophylaxis regimen. Additionally, there are some HA patients that only transiently express inhibitors, and these patients may also be treated with standard FVIII prophylaxis without issue. At present, these patients with a prior history of inhibitors have been excluded from clinical trials of gene therapy for ha, presumably due to concerns regarding the potential risk of a recurrence of the inhibitors, although this concern is primarily theoretical since there is no clear plausible mechanism as to why this patient group should re-develop inhibitors following gene therapy.
  • AAV-FVIII-SQ is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the control of a hybrid human liver-specific promoter ( Figure 1).
  • the codon- optimized FVIII encoding SQ sequence referred to herein as " FVIII-SQ" is set out as SEQ ID NO: 1.
  • AAV-FVIII-SQ is 4970 bases in length and comprises, from left to right, a modified AAV serotype 2 (AAV2) 5’ ITR, a 34 base human apolipoprotein e (ApoE)/c1 enhancer element, a 32 base human alpha anti-trypsin (AAT) promoter distal x region, a 186 base HAAT promoter, including 42 bases of 5’ untranslated region (UTR) sequence, a novel codon-optimized human FVIII sequence in which the FVIII b domain is replaced with the 14 amino acid SQ sequence, a 49 bases synthetic proudfoot polyadenylation sequence, and a modified AAV23’ITR.
  • AAV2 AAV2
  • ApoE apolipoprotein e
  • AAT alpha anti-trypsin
  • UTR untranslated region
  • novel codon-optimized human FVIII sequence in which the FVIII b domain is replaced with the 14 amino acid SQ sequence
  • AAV-FVIII-SQ is delivered by a single intravenous dose and is designed to achieve stable, durable expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue.
  • Exemplary doses of AAV-FVIII-SQ include 6e12 vg/kg, 2e13 vg/kg, 4e13 vg/kg, and 6e13 vg/kg.
  • AAV-FVIII-SQ has an acceptable safety and tolerability profile that supports a positive benefit-risk assessment. Single infusions have been generally well tolerated by treated subjects across all investigated doses.
  • Exemplary AAV FVIII Vectors [76] The exemplary recombinant AAV FVIII vector is described in detail in WO 2011/005968, published January 13, 2011, which is incorporated herein by reference in its entirety, and McIntosh et al. Blood 121:3335-3344, 2013, is an oversized, i.e., greater than 5.0 kb, AAV FVIII vector.
  • This AAV FVIII vector comprises, from left to right, the AAV serotype 2 (AAV2) 5’ ITR, wild-type AAV2-derived viral sequence, a 34 base human apolipoprotein E ApoE)/c1 enhancer element, a 32 base human alpha anti-trypsin (AAT) promoter distal x region, a 186 base human AAT (hAAT) promoter, including 42 bases of 5’ untranslated region (UTR) sequence, a codon- optimized human FVIII sequence in which the FVIII b domain is replaced with the 14 amino acid SQ sequence, a 49 bases synthetic proudfoot polyadenylation sequence, wild-type AAV2- derived viral sequence, and the AAV23’ ITR.
  • any of the disclosed methods may comprise the step of administering the following FVIII AAV: Proto1S (SEQ ID NO: 3), Proto 2S (SEQ ID NO: 4), Proto 3S (SEQ ID NO: 5), Proto 4 (SEQ ID NO: 6), Proto 5 (SEQ ID NO: 7), Proto 6 (SEQ ID NO: 8), Proto 7 (SEQ ID NO: 9), Construct 100ATG (SEQ ID NO: 10), Construct 100ATG bGH poly A (SEQ ID NO: 11), Construct 100ATG short bGH poly A (SEQ ID NO: 12), Construct 103ATG (SEQ ID NO: 13), Construct 103ATG short bGH poly A (SEQ ID NO: 14), Construct 105ATG short bGH poly A (SEQ ID NO: 15), Construct DC172AT
  • the AAV FVIII vector comprises a nucleotide sequence encoding for a functional factor VIII protein, wherein the portion of the nucleotide sequence encoding for the B domain of the factor VIII protein is between 90 and 111 base pairs in length and comprises a sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO: 47 and which encodes for six asparagine residues, such as the nucleotide sequence encoding for a functional FVIII protein comprising the nucleotide sequence of SEQ ID NO: 48.
  • AAV vectors are a standard abbreviation for adeno-associated virus.
  • Adeno-associated virus is a single-stranded DNA parvovirus that grows only in cells in which certain functions are provided by a co-infecting helper virus.
  • serotypes of AAV There are currently thirteen serotypes of AAV that have been characterized, as shown below in Table 1.
  • General information and reviews of AAV can be found in, for example, Carter, 1989, Handbook of Parvoviruses, Vol.1, pp.169-228, and Berns, 1990, Virology, pp.1743-1764, Raven Press, (New York).
  • An "AAV vector” as used herein refers to a vector comprising one or more polynucleotides of interest (or transgenes) that are flanked by one or more AAV terminal repeat sequences (ITRs) and operably linked to one or more expression control elements.
  • An "AAV virion” or "AAV viral particle” or “AAV vector particle” refers to a viral particle composed of at least one AAV capsid protein and an encapsidated polynucleotide AAV vector. If the particle comprises a heterologous polynucleotide (i.e. a polynucleotide other than a wild- type AAV genome such as a transgene to be delivered to a mammalian cell), it is typically referred to as an "AAV vector particle” or simply an "AAV vector”.
  • a heterologous polynucleotide i.e. a polynucleotide other than a wild- type AAV genome such as a transgene to be delivered to a mammalian cell
  • AAV vector particle necessarily includes production of AAV vector, as such a vector is contained within an AAV vector particle.
  • AAV "rep" and “cap” genes are genes encoding replication and encapsidation proteins, respectively.
  • AAV rep and cap genes have been found in all AAV serotypes examined to date, and are described herein and in the references cited. In wild-type AAV, the rep and cap genes are generally found adjacent to each other in the viral genome (i.e., they are “coupled” together as adjoining or overlapping transcriptional units), and they are generally conserved among AAV serotypes.
  • AAV rep and cap genes are also individually and collectively referred to as "AAV packaging genes.”
  • the AAV cap genes in accordance with the present invention encode Cap proteins which are capable of packaging AAV vectors in the presence of rep and adeno helper function and are capable of binding target cellular receptors.
  • the AAV cap gene encodes a capsid protein having an amino acid sequence derived from a particular AAV serotype, for example the serotypes shown in Table 1. Table 1.
  • AAV serotypes AAV Serotype Genbank Accession No.
  • the AAV sequences employed for the production of AAV can be derived from the genome of any AAV serotype.
  • the AAV serotypes have genomic sequences of significant homology at the amino acid and the nucleic acid levels, provide a similar set of genetic functions, produce virions which are essentially physically and functionally equivalent, and replicate and assemble by practically identical mechanisms.
  • genomic sequence of AAV serotypes and a discussion of the genomic similarities see, for example, GenBank Accession number U89790; GenBank Accession number J01901; GenBank Accession number AF043303; GenBank Accession number AF085716; Chiorini et al., J. Vir.71: 6823-33(1997); Srivastava et al., J. Vir.45:555-64 (1983); Chiorini et al., J.
  • AAV non-structural replication
  • VP structural proteins
  • the terminal 145 nt are self-complementary and are organized so that an energetically stable intramolecular duplex forming a T-shaped hairpin may be formed. These hairpin structures function as an origin for viral DNA replication, serving as primers for the cellular DNA polymerase complex.
  • the Rep genes encode the Rep proteins, Rep78, Rep68, Rep52, and Rep40. Rep78 and Rep68 are transcribed from the p5 promoter, and Rep 52 and Rep40 are transcribed from the p19 promoter.
  • the cap genes encode the VP proteins, VP1, VP2, and VP3. The cap genes are transcribed from the p40 promoter.
  • the ITRs employed in the vectors of the present invention may correspond to the same serotype as the associated cap genes, or may differ.
  • the ITRs employed in the vectors of the present invention correspond to an AAV2 serotype and the cap genes correspond to an AAV5 serotype.
  • a nucleic acid sequence encoding an AAV capsid protein is operably linked to expression control sequences for expression in a specific cell type, such as Sf9 or HEK cells. Techniques known to one skilled in the art for expressing foreign genes in insect host cells or mammalian host cells can be used to practice the invention. Methodology for molecular engineering and expression of polypeptides in insect cells is described, for example, in Summers and Smith.1986. A Manual of Methods for Baculovirus Vectors and Insect Culture Procedures, Texas Agricultural Experimental Station Bull.
  • a particularly suitable promoter for transcription of a nucleotide sequence encoding an AAV capsid protein is e.g. the polyhedron promoter.
  • promoters that are active in insect cells are known in the art, e.g. the p10, p35 or IE-1 promoters and further promoters described in the above references are also contemplated.
  • Use of insect cells for expression of heterologous proteins is well documented, as are methods of introducing nucleic acids, such as vectors, e.g., insect-cell compatible vectors, into such cells and methods of maintaining such cells in culture.
  • the nucleic acid construct encoding AAV in insect cells is an insect cell- compatible vector.
  • An "insect cell-compatible vector” or “vector” as used herein refers to a nucleic acid molecule capable of productive transformation or transfection of an insect or insect cell.
  • Exemplary biological vectors include plasmids, linear nucleic acid molecules, and recombinant viruses. Any vector can be employed as long as it is insect cell-compatible.
  • the vector may integrate into the insect cells genome but the presence of the vector in the insect cell need not be permanent and transient episomal vectors are also included.
  • the vectors can be introduced by any means known, for example by chemical treatment of the cells, electroporation, or infection.
  • the vector is a baculovirus, a viral vector, or a plasmid.
  • the vector is a baculovirus, i.e. the construct is a baculoviral vector. Baculoviral vectors and methods for their use are described in the above cited references on molecular engineering of insect cells.
  • Baculoviruses are enveloped DNA viruses of arthropods, two members of which are well known expression vectors for producing recombinant proteins in cell cultures. Baculoviruses have circular double-stranded genomes (80-200 kbp) which can be engineered to allow the delivery of large genomic content to specific cells. The viruses used as a vector are generally Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) or Bombyx mori (Bm)NPV) (Kato et al., 2010). [88] Baculoviruses are commonly used for the infection of insect cells for the expression of recombinant proteins.
  • heterologous genes in insects can be accomplished as described in for instance U.S. Pat. No.4,745,051; Friesen et al (1986); EP 127,839; EP 155,476; Vlak et al (1988); Miller et al (1988); Carbonell et al (1988); Maeda et al (1985); Lebacq-Verheyden et al (1988); Smith et al (1985); Miyajima et al (1987); and Martin et al (1988).
  • the present invention is directed to pharmaceutical formulations of FVIII AAV vectors/virions useful for administration to subjects suffering from hemophilia A.
  • the pharmaceutical formulations of the present invention are liquid formulations that comprise recombinant AAV FVIII virions produced from the vectors disclosed herein, wherein the concentration of recombinant AAV FVIII virions in the formulation may vary widely.
  • the concentration of recombinant AAV FVIII virion in the formulation may range from 1E12 vg/ml to 2E14 vg/ml. In a particularly preferred embodiment, the concentration of recombinant AAV FVIII virion in the formulation is about 2E13 vg/ml. In another preferred embodiment, the recombinant AAV FVIII virion present in the formulation is AAV5-FVIII-SQ derived from encapsidation of the Proto 1 vector shown schematically in Figure 1 in an AAV5 capsid.
  • the AAV FVIII pharmaceutical formulation of the invention comprises one or more pharmaceutically acceptable excipients to provide the formulation with advantageous properties for storage and/or administration to subjects for the treatment of hemophilia A.
  • the pharmaceutical formulations of the present invention are capable of being stored at ⁇ 65 o C for a period of at least 2 weeks, preferably at least 4 weeks, more preferably at least 6 weeks and yet more preferably at least about 8 weeks, without detectable change in stability.
  • stable means that the recombinant AAV FVIII virus present in the formulation essentially retains its physical stability, chemical stability and/or biological activity during storage.
  • the recombinant AAV FVIII virus present in the pharmaceutical formulation retains at least about 80% of its biological activity in a human patient during storage for a determined period of time at -65 o C, more preferably at least about 85%, 90%, 95%, 98% or 99% of its biological activity in a human patient.
  • the formulation comprising recombinant AAV FVIII virions further comprises one or more buffering agents.
  • the formulation of the present invention comprises sodium phosphate dibasic at a concentration of about 0.1 mg/ml to about 3 mg/ml, about 0.5 mg/ml to about 2.5 mg/ml, about 1 mg/ml to about 2 mg/ml, or about 1.4 mg/ml to about 1.6 mg/ml.
  • the AAV FVIII formulation of the present invention comprises about 1.42 mg/ml of sodium phosphate, dibasic (dried).
  • Another buffering agent that may find use in the recombinant AAV FVIII formulations of the present invention is sodium phosphate, monobasic which, in some embodiments, finds use at a concentration of from about 0.1 mg/ml to about 3 mg/ml, about 0.5 mg/ml to about 2.5 mg/ml, about 1 mg/ml to about 2 mg/ml, or about 1.3 mg/ml to about 1.5 mg/ml.
  • the AAV FVIII formulation of the present invention comprises about 1.38 mg/ml of sodium phosphate, monobasic.
  • the recombinant AAV FVIII formulation of the present invention comprises about 1.42 mg/ml of sodium phosphate, dibasic and about 1.38 mg/ml of sodium phosphate, monobasic.
  • the recombinant AAV FVIII formulation of the present invention may comprise one or more isotonicity agents, such as sodium chloride, preferably at a concentration of about 1 mg/ml to about 20 mg/ml, for example, about 1 mg/ml to about 10 mg/ml, about 5 mg/ml to about 15 mg/ml, or about 8 mg/ml to about 20 mg/ml.
  • the formulation of the present invention comprises about 8.18 mg/ml sodium chloride.
  • Other buffering agents and isotonicity agents known in the art are suitable and may be routinely employed for use in the formulations of the present disclosure.
  • the recombinant AAV FVIII formulations of the present invention may comprise one or more bulking agents.
  • Exemplary bulking agents include without limitation mannitol, sucrose, dextran, lactose, trehalose, and povidone (PVP K24).
  • the formulations of the present invention comprise mannitol, which may be present in an amount from about 5 mg/ml to about 40 mg/ml, or from about 10 mg/ml to about 30 mg/ml, or from about 15 mg/ml to about 25 mg/ml. In a particularly preferred embodiment, mannitol is present at a concentration of about 20 mg/ml.
  • the recombinant AAV FVIII formulations of the present invention may comprise one or more surfactants, which may be non-ionic surfactants. Exemplary surfactants include ionic surfactants, non-ionic surfactants, and combinations thereof.
  • the surfactant can be, without limitation, TWEEN 80 (also known as polysorbate 80, or its chemical name polyoxyethylene sorbitan monooleate), sodium dodecylsulfate, sodium stearate, ammonium lauryl sulfate, TRITON AG 98 (Rhone-Poulenc), poloxamer 407, poloxamer 188 and the like, and combinations thereof.
  • TWEEN 80 also known as polysorbate 80, or its chemical name polyoxyethylene sorbitan monooleate
  • sodium dodecylsulfate sodium stearate
  • ammonium lauryl sulfate sodium stearate
  • ammonium lauryl sulfate TRITON AG 98 (Rhone-Poulenc)
  • poloxamer 407 poloxamer 188 and the like, and combinations thereof.
  • the formulation of the present invention comprises poloxamer 188, which may be present at a concentration of from about 0.1 mg/ml to about 4 mg/ml, or from about 0.5 mg/ml to about 3 mg/ml, from about 1 mg/ml to about 3 mg/ml, about 1.5 mg/ml to about 2.5 mg/ml, or from about 1.8 mg/ml to about 2.2 mg/ml.
  • poloxamer 188 is present at a concentration of about 2.0 mg/ml.
  • the pharmaceutical formulation of the present invention comprises AAV5-FVIII-SQ formulated in a liquid solution that comprises about 1.42 mg/ml of sodium phosphate, dibasic, about 1.38 mg/ml of sodium phosphate, monobasic monohydrate, about 8.18 mg/ml sodium chloride, about 20 mg/ml mannitol and about 2 mg/ml poloxamer 188.
  • AAV5-FVIII-SQ formulated in a liquid solution that comprises about 1.42 mg/ml of sodium phosphate, dibasic, about 1.38 mg/ml of sodium phosphate, monobasic monohydrate, about 8.18 mg/ml sodium chloride, about 20 mg/ml mannitol and about 2 mg/ml poloxamer 188.
  • the formulation is stable at a temperature of about 5 o C (e.g., 2 o C to 8 o C) for at least 1 month, for example, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or more.
  • the formulation is stable at a temperature of less than or equal to about -20 o C for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more.
  • the formulation is stable at a temperature of less than or equal to about -40 o C for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more. In another aspect, the formulation is stable at a temperature of less than or equal to about -60 o C for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more.
  • the present invention is directed to methods for treating a subject suffering from hemophilia A comprising administering to that subject a therapeutically effective amount of an AAV FVIII vector, recombinant AAV FVIII virus or a pharmaceutical composition comprising the same.
  • the present invention is directed to methods for reducing bleeding time during a bleeding episode in a subject suffering from hemophilia A comprising administering to that subject a therapeutically effective amount of an AAV FVIII vector, recombinant AAV FVIII virus or a pharmaceutical composition comprising the same.
  • a "therapeutically effective amount”, in reference to the treatment of hemophilia A or for use in a method for reducing bleeding time during a bleeding episode in a subject suffering from hemophilia A refers to an amount capable of invoking one or more of the following effects: (1) reduction, inhibition, or prevention, to some extent, of one or more of the physiological symptoms of hemophilia A including, for example, bruising, joint pain or swelling, prolonged headache, vomiting or fatigue, (2) improvement in the capability to clot blood, (3) reduction of overall bleeding time during a bleeding episode, (4) administration resulting in a measurable increase in the concentration or activity of functional FVIII protein in the plasma of a subject, and/or (5) relief, to some extent, of one or more symptoms associated with the disorder.
  • a “therapeutically effective amount” of an AAV FVIII vector or virus or a pharmaceutical composition comprising the same for purposes of treatment as described herein may be determined empirically and in a routine manner. In certain embodiments, however, a "therapeutically effective amount" of recombinant AAV FVIII virus ranges from about 1E12 vg/kg body weight to about 1E14 vg/kg body weight, preferably from about 6E12 vg/kg body weight to about 6E13 vg/kg body weight. In a particularly preferred embodiment, a therapeutically effective amount of recombinant AAV FVIII virus is about 2E13 vg/kg body weight.
  • a therapeutically effective amount of recombinant AAV FVIII virus is about 6E13 vg/kg body weight.
  • Recombinant AAV FVIII vectors/virus of the present invention may be administered to a subject, preferably a mammalian subject, more preferably a human subject, through a variety of known administration techniques.
  • the recombinant AAV FVIII gene therapy virus is administered by intravenous injection either as a single bolus or over a prolonged time period, which may be at least about 1, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210 or 240 minutes, or more.
  • the recombinant AAV FVIII virus administered is AAV5-FVIII-SQ.
  • Administration of a recombinant AAV FVIII vector/virus, or pharmaceutical formulation comprising the same, of the present invention preferably results in an increase in functional FVIII protein activity in the plasma of the subject of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more IU/dl as compared to the amount of functional FVIII protein activity present in the plasma in the subject prior to administration.
  • administration of a recombinant AAV FVIII vector/virus, or pharmaceutical formulation comprising the same, of the present invention results in the expression of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more IU/dl of functional FVIII protein activity in the plasma of the subject.
  • IU or "international unit” in regards to FVIII activity is a well understood and accepted term, wherein 1 IU of FVIII activity is equivalent to the quantity of FVIII in one ml of normal human plasma.
  • FVIII activity in the plasma may be quantitatively determined by a number of well-known and accepted assays including, for example, the activated partial thromboplastin time (APPT) method (see, e.g., Miletich JP: Activated partial thromboplastin time.
  • APPT activated partial thromboplastin time
  • Miletich JP Activated partial thromboplastin time.
  • E Beutler, MA Lichtman, BA Coller, TJ Kipps. New York, McGraw-Hill, 1995 pp L85-86, Greaves and Preston, Approach to the bleeding patient.
  • Hemostasis and Thrombosis Basic Principles and Clinical Practice. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al.
  • bleeding time in a subject may be measured by well-known and accepted techniques including, for example, the Ivy method (see, e.g., Ivy et al., Surg. Gynec. Obstet.60:781 (1935) and Ivy et al., J. Lab. Clin.
  • a "bleeding episode" in a subject refers to an injury that results in bleeding in the subject, either externally or internally, and generally comprises the time period from injury to formation of a blood clot.
  • Administration of an AAV FVIII virus of the present invention may, in some cases, result in an observable degree of hepatotoxicity.
  • Hepatotoxicity may be measured by a variety of well- known and routinely used techniques for example, measuring concentrations of certain liver-associated enzyme(s) (e.g., alanine transaminase, ALT) in the bloodstream of a subject both prior to AAV FVIII administration (i.e., baseline) and after AAV FVIII administration.
  • concentrations of certain liver-associated enzyme(s) e.g., alanine transaminase, ALT
  • ALT alanine transaminase
  • the subject in addition to administration of a therapeutically effective amount of AAV FVIII virus, the subject may be treated either prophylactically, therapeutically, or both with a corticosteroid to prevent and/or treat any hepatotoxicity associated with administration of the AAV FVIII virus.
  • "Prophylactic" corticosteroid treatment refers to the administration of a corticosteroid to prevent hepatotoxicity and/or to prevent an increase in measured ALT levels in the subject.
  • prophylactic corticosteroid treatment is administered before hepatoxicity is detected in the subject or prior to an elevation of ALT levels, such as at the time of administration of the AAV FVIII.
  • prophylactic corticosteroid treatment refers to the administration of a corticosteroid to reduce hepatotoxicity caused by administration of an AVV FVIII virus and/or to reduce an elevated ALT concentration in the bloodstream of the subject caused by administration of an AAV FVIII virus.
  • prophylactic or therapeutic corticosteroid treatment may comprise administration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more mg/day of the corticosteroid to the subject.
  • prophylactic or therapeutic corticosteroid treatment of a subject may occur over a continuous period of at least about 3, 4, 5, 6, 7, 8, 9, 10 weeks, or more.
  • Corticosteroids that find use in the methods described herein include any known or routinely employed corticosteroid including, for example, dexamethasone, prednisone, fludrocortisone, hydrocortisone, and the like.
  • Seroconversion refers to the development of detectable antibodies in the serum of the subject, such as the subject develops antibodies to AAV capsid protein and/or antibodies to exogenous FVIII. To evaluate antibody level consistency over time, a re-test procedure will be requested at either 12 or 24 weeks ( ⁇ 2 weeks) after initial testing (baseline). This re-test will follow the same biospecimen collection procedures as the initial testing.
  • Seroprevalance refers to the number of persons in a population who test positive for a antibodies to a specific antigen.
  • the prospective patient Prior to administration of an AAV vector in a therapeutic regimen to a human patient as described above, the prospective patient may be assessed for the presence of anti-AAV capsid antibodies, AAV neutralizing antibodies and FVIII inhibitors that are capable of blocking cell transduction or otherwise reduce the overall efficiency of the therapeutic regimen.
  • anti-AAV capsid antibodies AAV neutralizing antibodies and FVIII inhibitors that are capable of blocking cell transduction or otherwise reduce the overall efficiency of the therapeutic regimen.
  • Such antibodies may be present in the serum of the prospective patient and may be directed against an AAV capsid of any serotype or FVIII produced by the AAV vector.
  • the serotype against which pre-existing antibodies are directed is AAV5.
  • the determination of the presence of anti-AAV may be determined utilizing an immunofluorescence assay, an immunohistochemical assay, a Western blot, a direct enzyme-linked immunosorbent assay (ELISA), an indirect ELISA, a sandwich ELISA, a competitive ELISA, a reverse ELISA, a chemiluminescence assay, a radioimmunoassay, or an immunoprecipitation assay.
  • ELISA direct enzyme-linked immunosorbent assay
  • an indirect ELISA a sandwich ELISA
  • a competitive ELISA a competitive ELISA
  • a reverse ELISA a chemiluminescence assay
  • radioimmunoassay a radioimmunoassay
  • TI assays cell-based in vitro transduction inhibition (TI) assays, in vivo (e.g., in mice) TI assays, and ELISA-based detection of total anti-capsid antibodies (TAb)
  • TI assays may employ host cells into which an AAV-inducible reporter vector has been previously introduced.
  • the reporter vector may comprise an inducible reporter gene such as GFP, etc.
  • TAb assays to detect anti-AAV antibodies may employ solid-phase-bound AAV capsid as a "capture agent" over which human serum is passed, thereby allowing anti-capsid antibodies present in the serum to bind to the solid-phase-bound capsid "capture agent".
  • a "detection agent” may be employed to detect the presence of anti-AAV antibodies bound to the capture agent.
  • the detection agent may be an antibody, an AAV capsid, or the like, and may be detectably labeled to aid in detection and quantitation of bound anti-capsid antibody.
  • the detection agent is labeled with ruthenium or a ruthenium-complex that may be detected using electrochemiluminescence techniques and equipment. [108] The same above-described methodology may be employed to assess and detect the generation of an anti-AAV immune response in a patient previously treated with a therapeutic AAV virus of interest.
  • Therapeutic apheresis refers to the process of separating the cellular and soluble components of blood, such as removing plasma based on specific gravity.
  • therapeutic apheresis is therapeutic plasma exchange (TPE) or plasmapheresis.
  • TPE is an extracorporal blood purification technique designed to remove high molecular weight substances, such as antibodies.
  • whole blood is removed via vascular access and subsequently spun through a centrifuge within the apheresis machine, where the plasma (antibodies) is removed.
  • the whole blood is removed using highly permeable membranes.
  • Red blood cells are delivered back along with a replacement fluid (Human Albumin) for maintenance fluid for the subject, e.g. a plasma surrogate such as 3% albumin solution.
  • a plasma surrogate such as 3% albumin solution.
  • the amount of plasma to be exchanged in a TPE session is determined in relation to the subject’s estimated plasma volume (EPV).
  • EPV estimated plasma volume
  • a number of formulas may be used to calculate the EPV (see, e.g. Inkley et al., J. Lab Clin. Med.45:841-850, 1955, Retzlaff et al., Blood 33: 649-887, 1969, Feldschuh et al., Circulation 56: 605-612, 1977).
  • An exemplary method of estimating the EPV is calculated using the subject’s weight and hematocrit according to the following formula which is described in Kaplan et al. Kidney Intl.38:160-166, 1990, which is incorporated by reference herein in its entirety.
  • the TPE is carried out with techniques incorporating blood bank procedures using selective cell removal (cytopheresis) as described in Gurland et al., Int. J. Artif Organs 7:35-38, 1984, or using membrane plasma separation (MPS) which uses a highly permeable filter and dialysis equipment as described in Gurland et al., Nephron 36:173-182, 1984. Additional methods of carrying out TPE are described in Sowada et al. (Available removal systems: state of the art. In Nydegger UE, editor. Therapeuitc Hemapheresis in the 1990s. Current Studies in Hematology and Blood Transfusions, Vol 57. Basal Switzerland: Karger.1990 pp.57-113).
  • cytopheresis selective cell removal
  • MPS membrane plasma separation
  • methods of subjecting a subject’s plasma to TPE removes at least about 50% of anti-AAV antibodies within the intravascular space of the subject, or removes at least about 55% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 60% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 70% of anti-AAV antibodies or FVIII inhibitors or removes at least about 80% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 90% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 95% of anti-AAV antibodies or FVIII inhibitors in the plasma of the subject or removes at least about 99% of anti-AAV antibodies or FVIII inhibitors in the plasma of the subject.
  • the disclosed methods comprising subjecting the subject’s plasma to at least one TPE session, or at least two TPE sessions, or at least three TPE sessions, or at least four TPE sessions.
  • the TPE sessions are carried out once a day over about 1 to 5 days, or about 1 to 10 days, or about 5 to 10 days, or about 5 to 7 days or about 7 to 10 days.
  • Immunoadsorption plasmapheresis is an autologous plasma exchange, which separates plasma from blood cells as described about for TPE. However, in IAP antibodies are selectively removed from the plasma, and the antibody depleted plasma is then returned to the subject.
  • IAP In IAP the removal of antibodies results in also removing protective antibodies; however, this technique also reduces the risk. IAP removes about ⁇ 80% of total Ig in plasma after one session, increasing to ⁇ 98% after multiple sessions. IAP exchanges about 2-3 plasma volumes per treatment session. [115] Multiple studies have supported the use of plasma filtering methods for the removal of anti-AAV antibodies in vitro (in non-clinical species including mice, rats and monkeys) as well as clinically (Kaspryk et al. Mol. Ther.2022, Majowicz et al., Mol. Ther.14:27-38, 2017, Orlowski et al., Mol. Ther.2020, Bertin et al., Nat. Sci.
  • the plasma is filtered through an affinity column that binds immunoglobulins.
  • the affinity columns may be a porous matrix coated with recombinant camelid Ig which will remove all subtypes of human antibodies.
  • the disclosed methods may be carried out with a column that removes IgG, IgM, IgA, IgGE or a combination therefor.
  • Exemplary porous matrix of the column may be Sepharose, silica, polyacrylate, or polyvinyl alcohol.
  • Exemplary columns include THERASORB Ig column which comprises polyclonal sheep anti-human IgG, or column comprising protein A.
  • methods of subjecting a subject’s plasma to IAP removes at least about 50% of anti-AAV antibodies of the subject, or removes at least about 55% of anti-AAV antibodies, or removes at least about 60% of anti-AAV antibodies, or removes at least about 70% of anti-AAV antibodies or removes at least about 80% of anti-AAV antibodies, or removes at least about 90% of anti-AAV antibodies, or removes at least about 95% of anti-AAV antibodies in the plasma of the subject or removes at least about 99% of anti-AAV antibodies in the plasma of the subject, this includes removal of FVIII inhibitors when the FVIII inhibitor is an antibody.
  • the disclosed methods comprising subjecting the subject’s plasma to at least one IAP session, or at least two IAP sessions, or at least three IAP sessions, or at least four IAP sessions.
  • IAP sessions are carried out once a day over about 1 to 3 days, or 1 to 4 day or 1 to 5 days, or about 1 to 10 days, or about 5 to 10 days, or about 5 to 7 days or about 7 to 10 days.
  • the IAP sessions are carried out once a day for two consecutive days, or once a day for three consecutive days or once a day for four consecutive days for 5 consecutive days, or once a day for 6 consecutive days, or once a day for 7 consecutive days, or once a day for 7 consecutive days, or once a day for 8 consecutive days, or once a day for 9 consecutive days or once a day for 10 consecutive days.
  • the IAP sessions are carried out 2, 3 or 4 times a day for two consecutive days, or 2, 3 or 4 times a day for three consecutive days or 2, 3 or 4 times a day for four consecutive days or 2, 3 or 4 times a day for 5 consecutive days, or 2, 3 or 4 times a day for 6 consecutive days, or 2, 3 or 4 times a day for 7 consecutive days, or 2, 3 or 4 times a day for 7 consecutive days, or 2, 3 or 4 times a day for 8 consecutive days, or 2, 3 or 4 times a day for 9 consecutive days or 2, 3 or 4 times a day for 10 consecutive days.
  • Immunosuppressive Agents [119] The disclosure also provides for carrying out any of the disclosed methods using an alternative immunosuppressive agent instead of or in combination with a corticosteroid.
  • the immunosuppressive agent is any agent that inhibits the subject’s immune system, reduces the effectiveness of the subject’s immune system or modulates the activity or effectiveness of the subject’s immune system.
  • the immunosuppressive agent may be administered prophylactically at the same time as administration of the FVIII AAV or administered prior to an elevation of ALT levels after administration of the FVIII AAV.
  • the immunosuppressive agent is administered therapeutically.
  • the immunosuppressive agent is administered after elevated levels of ALT are detected in the subject after administration of the FVIII AAV.
  • immunosuppressive agents include glucocorticosteroids, janus kinase inhibitors, calcineurin inhibitors, mTOR inhibitors, cyctostatic agents such as purine analogs, methotrexate and cyclophosphamide, inosine monophosphate dehydrogenase (IMDH) inhibitors and biologics such as monoclonal antibodies or fusion proteins and polypeptides.
  • Janus kinase inhibitors are inhibitors of the JAK/STAT signaling pathway by targeting one or more of the Janus kinase family of enzymes.
  • Exemplary janus kinase inhibitors include tofacitinib, baricitinib, upadacitinib, peficitinib, and oclacitinib.
  • Calcineurin inhibitors bind to cyclophilin and inhibits the activity of calcineurin
  • Exemplary calcineuine inhibitors includes cyclosporine, tacrolimus and picecrolimus.
  • mTOR inhibitors reduce or inhibit the serine/threonine-specific protein kinase mTOR.
  • Exemplary mTOR inhibitors include sirolimus, everolimus, and temsirolimus. Additional immunosuppressive agents include matacrolimus, pimecrolimus, and sirolimus.
  • Purine analogs block nucleotide synthesis and include IMDH inhibitors.
  • Exemplary purine analogs include azathioprine, mycophenolate and lefunomide.
  • Exemplary immunosuppressing biologics include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, toccilizumab, ustekinenumab, vedolizumab, basiliximab, belatacep, and daclizumab, ocrelizumab, ofatumumab, otelixizumab, teplizumab and visilizumab, and alemtuzumab.
  • FVIII-SQ protein assay [125] A sandwich electrochemiluminescence (ECL) assay was performed on the MSD QuickPlex SQ 120 imager (QuickPlex imager) to measure the concentration of hFVIII in sodium- citrated normal pooled cynomolgus monkey plasma.
  • a monoclonal antibody to the a2 domain of hFVIII was conjugated to an extra-long-chain amine-reactive n-hydroxysulfosuccinimide (lc-lc- NHS) biotin, and a sheep polyclonal antibody to hFVIII was conjugated to a ruthenium NHS (sulfo-NHS) tag.
  • lc-lc- NHS extra-long-chain amine-reactive n-hydroxysulfosuccinimide
  • Standard calibrators and quality controls were prepared with xyntHA (clinical-grade hFVIII-SQ) in 100% pooled cynomolgus monkey plasma, ranging from 301 to 0.294 ng/ml (a total of 11 points), with the bottom three designated as anchor points, making the range of quantitation (RoQ) from 301 to 2.35 ng/ml FVIII-SQ.
  • RoQ quantitation
  • High-, mid-, and two LQC samples were tested at concentrations of 226, 60.3, 5.00, and 3.00 ng/ml FVIII-SQ, respectively.
  • the standard calibrators, QCS, and study samples were diluted to a minimum residual disease (MRD) factor of 1:10 in assay diluent (Cedarlane, catalog number cl2003sk- diluent) prior to addition to the MSD plate wells.
  • MRD minimum residual disease
  • Samples and combined labeled anti-FVIII detection reagents were incubated for 2 hours at room temperature with shaking.
  • an MSD plate coated with streptavidin was blocked with 6% BSA in TBST for 2 hours at room temperature with shaking.
  • the blocking buffer in the wells of the MSD plate was removed without washing.
  • the mixture of the labeled antibodies and plasma samples was then incubated for 1 hour at room temperature with shaking on the blocked MSD plate to capture the FVIII-SQ-antibody complexes via the biotin label.
  • 1x MSD read buffer containing the substrate tripropylamine (TPA) was added to react chemically with ruthenium in the presence of applied voltage.
  • TPA substrate tripropylamine
  • Standard curve regression analysis using a 4-parameter logistic algorithm with 1/y weighting in Watson Laboratory Information Management System (LIMS) version 7.4.2 was used to report concentrations, percent coefficient of variation (CV), and percent relative error (RE) of back-calculated unknown qc and study samples.
  • the lower limit of quantitation for the assay was 2.35 ng/ml FVIII-SQ.
  • FIX protein assay [126] Factor IX protein levels were assessed by a fluorescence assay. Nunc MaxiSorb Black Opaque plates were coated with anti-FIX capture antibody (gma002, green mountain antibodies) at 4°c overnight.
  • the whole blood samples were checked for clots and transferred to the appropriate laboratory at the testing facility. Upon receipt, the samples were stored at ambient temperature. Absolute cell counts were determined using BD TRUCOUNTTM tubes per testing facility standard operating procedure (SOP). Calculation of absolute counts for each cell population was performed using the relative percentages of each cell population and the corresponding lymphocyte or lymphocyte/monocyte/granulocyte count obtained using BD TRUCOUNTTM tubes with CD45 (SSC/CD45+). The cellular antigens and cell populations identified were quantified according to testing facility validated methods. Longitudinal plots of immunophenotyping data were generated using GRAPHPAD PRISMTM software version 8.4.2.
  • PBMC peripheral blood mononuclear cells
  • PBMCs were assessed for ex-vivo cytokine release in response to staphylococcal enterotoxin b (seb), anti- CD3 (positive controls), DMSO (negative control), or two sponsor-derived peptide pools according to the testing facilities analytical procedure.
  • Cytokine Sample Collection, Processing, and Analysis Blood was collected by venipuncture and resultant plasma was divided (approximately equal volumes were visually estimated), transferred to 2 appropriately labeled polypropylene tubes, and frozen immediately in a freezer set to maintain -80°c until transferred to the appropriate laboratory at the testing facility.
  • the samples were analyzed using a validated luminex method (ap.i-001489.im.06) for the detection of IL-1 ⁇ , IL -1ra, IL-2, IL -4, IL-5, IL -6, IL- 8, IL -10, IL-12/23 (p40), IL-13, IL-17a, MCP-1, MIP-1 ⁇ , IFN- ⁇ , TNF- ⁇ , G-CSF, and gm-CSF.
  • a validated luminex method (ap.i-001489.im.06) for the detection of IL-1 ⁇ , IL -1ra, IL-2, IL -4, IL-5, IL -6, IL- 8, IL -10, IL-12/23 (p40), IL-13, IL-17a, MCP-1, MIP-1 ⁇ , IFN- ⁇ , TNF- ⁇ , G-CSF, and gm-CSF.
  • Example 2 Safety Study in Nonhuman Primates The objective of the present study was to determine the pharmacodynamics and safety following a single bolus injection of AAV-FVIII-SQ into cynomolgus monkeys (nonhuman primates or NHP) with varying pre-existing levels of neutralizing AAV5 antibodies (referred to as total antibody (TAb)/transduction inhibition (ti) titers) and non-antibody inhibitors (AAV5 TI assay).
  • the experimental design is presented in Table 2.
  • AAV-FVIII-SQ was equilibrated at room temperature for approximately 1 hour on the day of use, prepared for administration under a laminar flow hood, and administered within 5 hours after preparation.
  • AAV-FVIII-SQ was administered as a single slow intravenous bolus injection on study day 1.
  • Detection of pre-existing AAV5 immunity in monkeys (screening phase): [132] To study the impact of pre-existing AAV5 immunity on AAV-FVIII-SQ-mediated gene transfer, this study aimed to specifically enroll cynomolgus monkeys that met pre-defined criteria for AAV5 TAb/TI status.
  • TI cell-based transduction inhibition
  • TAB total binding antibody
  • Group 4 (N 5) contained animals with both AAV5 TAb and detectable transduction inhibition (TAb+/TI+; neutralizing AAV5 antibodies).
  • Dosing and In-Life Phase [133] AAV-FVIII-SQ was administered as a single, slow intravenous bolus injection on study day 1. Blood was obtained by venipuncture for routine hematology throughout the study at designated time points (week -1 and days 29 and 56).
  • Coagulation parameters (activated partial thromboplastin time, fibrinogen and prothrombin time) were assessed at week -1 and days 29 and 56, and fasting clinical chemistry studies were performed at week -1 and on days 15, 29, 43, and 56. NHPs were euthanized by exsanguination on study day 56. At necropsy, a complete set of tissues was collected for histopathology. A standard list of protocol-required tissues was processed for routine light microscopic evaluation. In-life procedures and necropsies were conducted at Charles River Laboratories (Reno, Nevada). [134] Human FVIII-SQ levels in cynomolgus monkey plasma group mean data (sd) across three different time points are listed in Table 3.
  • NHPs in group 4 (TAb+ and TI titers of 6-100) administered AAV-FVIII-SQ had a statistically significant increase (1.5x, data not shown) in lymphocyte counts on day 56 compared to group 1 (TAb- and TI-).
  • the splenic weight change was considered incidental with no relationship to TAb/TI status or to the administration of the test articles. Histopathologic examination of livers from nhps from all groups revealed no test article-related or adverse findings. A few scattered foci of mixed inflammatory cell infiltrates observed across all treatment groups were considered incidental and normal background findings of cynomolgus monkeys (Sato et al 2012; Chamanza et al., 2010). Overall, there were no microscopic changes in the spleen.
  • Example 3 Safety and Efficacy of Vector Redosing in Non-Human Primates [139] The objective of this study was re to assess the safety (and efficacy) of vector re-dosing in NHPs previously exposed to same serotype (AAV5). A key objective of this study was to evaluate transduction efficacy and safety of vector re-administration with high capsid titers for the same serotype. The experimental design is presented in Table 5. Frozen test articles [AAV5-cgb (batch no.17-754) and AAV5-hFIX (batch no.17-738)] were stored at -80°c until use and were thawed on the day of dose administration.
  • NHPs in group 1 served as positive controls and were dosed once on day 29 with an AAV5 vector expressing human FIX [AAV5-hFIX]. Following dose administration, group 1 was expected to achieve maximal expression of the FIX transgene (FIX plasma protein concentration) since these NHPs pre-screened negative for AAV5 TAb and also did not receive prior gene therapy dose administrations).
  • NHP in groups 2 were dosed on study day -7 with a subcutaneous administration of 5e12 vg AAV5-bCG and a second administration of 3e13 vg/kg AAV5-bCG IV at day 1.
  • Group 2 animals were expected to mount an AAV5 TAb response following administration of AAV5-bCG.
  • the same animals in this group (group 2) were then administered 3e13 vg/kg AAV5-fix at day 29 to evaluate the safety and pharmacodynamic effect of gene therapy administration in the presence of a high titer AAV5 TAb.
  • the purpose of the subcutaneous injection was to target the vector capsids to the draining lymph nodes in an attempt to elicit a more localized immune response, which would not have been achieved as efficiently with an IV or systemic administration.
  • Table 6 Group N Day 1 Day 29 Day 43 1 3 ⁇ 20 ⁇ 20 12500 2 3 ⁇ 20 62500* 312500 *plasma samples were collected at day -7 (baseline) and at days 1, 15, 29, 43, 57, 71, and 84 (study end) and were assessed for AAV5 TAb. Vertical lines indicate time of AAV dose administrations and all samples were collected. [145] Human FIX was observed only in AAV5-hFIX animals (group 1) that were not previously sensitized to AAV5 prior to challenge dose administration.
  • hFIX plasma protein concentrations ranged from 5636.6-11355.5 mIU/mL on Days 57 and 84.
  • Human FIX plasma protein expression was not detected in the animals administered AAV5-CGB + AAV5-hFIX (Group 2; Table 7) suggesting the anti-AAV5 capsid TAb response following the prior sensitizing dose administration was capable of neutralizing transduction by the second dose (data not shown).
  • NHPs in both treatment groups had no test article-related clinical observations, body weight changes, or food consumption changes during the course of the study. There were no changes in the coagulation or clinical chemistry parameters, including serum transaminases (ALT and AST, Table 4). Similar to study described in Example 2, histopathologic examination of livers from NHPs from all groups revealed no test article-related or adverse findings.
  • Peripheral blood samples were drawn at baseline (day -14) and days 15, 43, 71 and 84 and PBMC populations were immunophenotyped by flow cytometry for enumeration of T-cells (CD4+ Th subsets and CD8+ CTL and Foxp3+ T-regs), B-cell, NK-cells and CD14+ monocytes.
  • MCP-1 plasma monocyte chemoattractant protein-1
  • interleukin-1 receptor antagonist IL -1Ra
  • IL-4 interleukin-4
  • IL-6 interleukin-6
  • IL -8 IL-12/23(p40)
  • g-CSF granulocyte-colony stimulating factor
  • TNF- ⁇ tumor necrosis factor alpha
  • AAV5 capsid-specific cellular immune responses were measured by ELIspot assay for secreted IFN- ⁇ from cryopreserved cynomolgus monkey PBMCS collected at days -10, 15, 43, 71, and 85 and stimulated with AAV5 peptide pools.
  • Example 4 Immunoadsorption Plasmapheresis for the Removal of Plasma Immunoglobulins
  • AAV TAb pre-existing anti-AAV total binding antibodies
  • AAV NAb in vitro neutralizing antibodies
  • IAP immunoadsorption plasmapheresis
  • IAP IAP for a minimum of 1 day of 4 runs (plasma volume exchanges) to a maximum of 3 consecutive days of 3 runs.
  • the IAP were carried out using Miltenyi Biotec apheresis equipment paired with THERASORB TM affinity columns (CE marked in the EU) to support use in clinical patients.
  • THERASORB columns utilize a porous matrix coated with recombinant Camelid Ig to remove all subtypes of human antibodies (regardless of specificity).
  • All 5 animals were challenged with the same AAV5 capsid encoding a different protein, human coagulation factor IX (AAV5-hFIX) at a dose of 6E13 vg/kg, administered within 10 minutes of the last run IAP.
  • AAV5-hFIX human coagulation factor IX
  • Efficacy of the IAP procedure was functionally evaluated by laboratory measures of plasma IgG and AAV5 total binding antibody (AAV5 TAb) titer, hFIX plasma protein concentration, and quantitation of vector genomes and transcripts in liver tissue.
  • the design of the study is summarized in Table 8 below.
  • Peak hFIX expression and area under the concentration time curve are shown from the time of challenge dose administration through 4 weeks post challenge.
  • the two animals which achieved maximum depletion of AAV TAb titer >99% also achieved approximately 25% and 50% of reference hFIX plasma protein levels, respectively, compared to the na ⁇ ve animal (0.8 IU/mL), and a proportional percentage of vector genome copies measured in liver tissue compared to the na ⁇ ve animal (1.6E7 cp/mg DNA).
  • Example 5 Seroprevalence Study in Human Hemophilia A Patients A global clinical AAV seroprevalence study (referred to the 270-901 study) that enrolled 547 (478 adults and 69 adolescents) participants from the United States, United Kingdom, France, Russia, Germany, Italy, Japan, South Africa and Brazil was carried out (Hayes, 2019). It compared seroprevalence and antibody titers against multiple AAV serotypes to provide epidemiological data characterizing pre-existing AAV immunity among hemophilia A patients.
  • the anti-AAV TAb assay appears to be more discriminating than transduction inhibition (TI) in pre-clinical studies, with regards to the ability to detect low titers (Falese, 2017; Sun, 2013).
  • the AAV5 TAb assay better predicted AAV-FVIII-SQ efficacy, whereas TI titer in tab-negative non-human primates were not associated with reduced transduction or efficacy (Long, 2019). Therefore, the AAV5 TAb assay has been chosen as the diagnostic to screen potential subjects in the AAV-FVIII-SQ clinical studies and is intended as a companion diagnostic for the program.
  • AAV seropositivity using the global ha weighted average was calculated by multiplying the percentage of participants who tested positive in each country by the number of people with ha in that country, divided by the total number of people with ha in all countries in the study. The values were based on individual participant titers for individual participants in the global population. Participants with negative titers plotted as a value of 1. Participants with positive titer results and a titer ⁇ 20, the MRD, are shown as 20. Width is representative of the number of points at a particular value (see Klamroth et al. Hum Gene Ther.2022 apr;33(7-8):432-441).
  • Figure 11 demonstrates that about 65% of participants in the seroprevalence study with pre-existing immunity would be potentially addressable in day 1 of IAP treatment (2 cycles), and as a result about 97% of the hemophilia patients may be transduced after 2 days of IAP (4 cycles).
  • Clinical Study [1] The present study builds on the 270-901 global study to further describe the seroprevalence and rate of seroconversion of subjects with hemophilia A, with a focus on the US population. Seroprevalence and rate off seroconversion of AAV5, AAV6, AAV8, as well as seroprevalence of exploratory vectors are evaluated and characterized through analysis of vector titer measurements over time within and across subjects.
  • AAV5, AAV6, and AAV8 WERE elected for the study as they represent the serotypes being evaluated in several late-stage gene therapy trials for hemophilia patients, and the data generated by this study may facilitate development of these therapeutic options.
  • Exploratory vectors are included as potential viral delivery forms being explored as a delivery option for future gene therapies.
  • This is a single-center, decentralized, patient-centered, prospective, observational study utilizing biospecimen samples collected from hemophilia A subjects across the United States to evaluate and characterize seroprevalence and the rate of seroconversion of antibodies against AAV serotypes and exploratory vectors, and to investigate the associated factors that may influence the vector titers.
  • the primary objection of the study is to quantify the seroprevalence of antibodies to AAV5, AAV6, and AAV8 and the seroconversion rate over varying follow-up intervals in subjects with hemophilia A.
  • the secondary objections are i) To describe and characterize AAV5, AAV6, and AAV8 titer values in subjects with hemophilia A.
  • the secondary end points are i) to determine AAV5, AAV6 and AAV8 absolute titer levels, ii) to determine correlation between seroprevalence, seroconversion rate at specified time points and factors of interest (e.g., regions, certain demographic and physiologic), and iii) determine the cross-reactivity rates of antibodies across AAV serotypes.
  • the tertiary end point is to determine exploratory vector titer values.
  • Seroconversion [166] To evaluate antibody level consistency over time, a re-test procedure will be requested at either 12 or 24 weeks ( ⁇ 2 weeks) after initial testing (baseline). This re-test will follow the same biospecimen collection procedures as the initial testing.
  • subjects After the initial baseline measurement has become available, subjects will be randomized in a 1:1 ratio for the timing of re-testing at either 12 or 24 weeks ( ⁇ 2 weeks) after initial testing (baseline). Subjects who are exposed to AAV vector gene therapy during the course of the study will be discontinued from the study. Subjects are allowed to have blood re-drawn to obtain a valid seroprevalence measurement. Study Duration [167] Each subject may be in the study for up to 28 weeks. The initial testing for antibodies will be performed within 4 weeks of signed consent, and re-testing is either 12 or 24 weeks ( ⁇ 2 weeks) after initial testing (baseline) which will determine the total length of participation. Number of Subjects and Subject Selection [168] This study will enroll approximately 1000 subjects with hemophilia A across the United States.
  • Subjects deemed potentially eligible for the study will be invited to participate in the study via email or push notification. After providing consent, subjects who fulfil the requirements of the inclusion and exclusion criteria will be accepted for the study. Subjects will be assigned a unique identifier by the electronic data capture system used for the study.
  • the inclusion criteria include i) subjects previously diagnosed with hemophilia A, ii) Subjects ⁇ 18 years of age, iii) Subject (or legally authorized representative) is willing and able to provide electronic informed consent after the nature of the study has been explained and prior to any data collection. iv) Subject is willing and able to comply with all study procedures, including blood sampling and follow up for adverse reactions.
  • the exclusion criteria include i) legal incapacity or limited legal capacity without a legally authorized representative and ii) Currently participating in an interventional study of any investigational product, device or procedure.
  • Seroconversion Testing Initial Testing and Re-Testing
  • Randomization Subjects are randomized in a 1:1 ratio for the timing of re-testing [either 12 or 24 weeks ( ⁇ 2 weeks) after initial testing (baseline)]. Randomization is performed through the electronic data capture system. Additional details will be available in a separate plan outlining randomization requirements and system function. [172] In general, subjects who enter the study with an available seroprevalence measurement at baseline but missing (or having a non-analyzable test outcome for) the re-test 12- or 24-week measurement will not be replaced. These subjects will be included in the database and in the denominator for the seroprevalence calculation. However, they will be excluded for the seroconversion calculation due to a missing re-test value.
  • Seroprevalence for AAV5, AAV6 and AAV8 is summarized.
  • the number of subjects is tabulated by their seroprevalence status at Baseline, Week 12 or Week 24, the corresponding proportion, presented as a percentage, and the 95% CI of the proportion will be provided in the overall population as well as by subgroups of interest.
  • Seroconversion rate by AAV serotypes is summarized.
  • the number of subjects whose seropositivity changes between baseline to Week 12 or Week 24 will be tabulated (positive to negative, or negative to positive) along with the number who do change status.
  • Example 6 Clinical Study Investigating Clinical Phenotype Hemophilia A Patients with FVIII Activity
  • 270-201 study Three-year results from a previous clinical study (referred to herein as “270-201 study”) demonstrated that following gene transfer, mean and median FVIII activity levels increased above 15% (15 IU/dl), as measured by a chromogenic substrate assay, were achievable and sustained following a single infusion of 6e13 vg/kg of AAV-FVIII-SQ, with an acceptable safety profile (Pasi, 2020).
  • Preliminary results from optional liver biopsies confirm pan-lobular and otherwise healthy liver transduction at 2.5 years.
  • the present study is a phase 1/2, two-part, open-label, multi-center study designed to assess whether AAV-FVIII-SQ can safely alter the clinical phenotype of HA patients with FVIII activity ⁇ 1 IU/dl at the time of detected active inhibitors, who have developed FVIII neutralizing antibodies (inhibitors) during HA treatment.
  • AAV-FVIII-SQ could include eradication of inhibitors by attaining immunological tolerance to FVIII, and/or achievement of hemostasis with either endogenous production of hFVIII or prophylactic FVIII treatment.
  • ITI immune tolerance induction
  • the primary objective of the study is to assess the safety of a single IV administration of AAV-FVIII-SQ in HA subjects with active inhibitors, or prior inhibitors.
  • the secondary objectives of the study are i) to assess the efficacy of AAV-FVIII-SQ as measured by FVIII activity together with the level of inhibitor titer and the recurrence of inhibitors, ii) to assess the impact of AAV- FVIII-SQ on the use of emicizumab and FVIII prophylaxis, and iii) to assess the impact of AAV- FVIII-SQ on the number of bleeding episodes requiring pharmacologic intervention.
  • Part A Activate Inhibitor Population (Part A) [182] Subjects enrolling in Part A must have inhibitors detectable at screening and at least 6 months use of emicizumab prior to study entry, as well as at least 12 months of well-documented bleeding events and hemophilia treatment.
  • subjects In order to be eligible for treatment with AAV-FVIII-SQ, subjects must have a positive inhibitor titer at screening: the first 3 subjects enrolling in Part A must have high-titer inhibitors at screening (> 5 BU in the chromogenic Nijmegen Bethesda assay), while the remaining subjects may have a lower titer (> 0.6 Bu). [183] Approximately 10 subjects will be enrolled in part A, dosed sequentially. The first subject is enrolled in part A is administered AAV-FVIII-SQ at a dose of 6e13 vg/kg. The next subject can be dosed at least one week after the first subject, if there are no precluding safety findings in the immediate post-infusion period.
  • the initial 2 subjects will then be followed up for a minimum of 12 weeks, at which point the accrued safety and efficacy data will be reviewed, to determine the appropriate does for subject 3.
  • Twelve weeks of post-infusion data is considered to provide an appropriate timeframe to evaluate FVIII activity after gene transduction, any potential changes in inhibitor titers subsequent to endogenous FVIII production, as well as any development of any potential delayed hypersensitivity reaction (e.g., serum sickness).
  • subject 3 has reached a minimum of 6 weeks follow-up, the totality of the data in all three subjects is reviewed to determine whether to expand Part A (i.e. to recruit up to 7 additional subjects to be dosed in parallel).
  • Part B Prior inhibitor population
  • Part B subjects must have a documented history of a positive inhibitor titer but a current negative inhibitor titer ( ⁇ 0.6 Bu) and been receiving FVIII replacement therapy for at least 12 months prior to study entry, as well as at least 12 months of well-documented bleeding events and FVIII usage. Approximately 10 subjects will be enrolled in Part B. [185] The dosing scheme in Part B is similar to Part A: the first 2 subjects will be enrolled sequentially by at least one week apart, with a review of the data after a minimum follow-up of 12 weeks for each participant prior to enrolling the third subject.
  • the investigator will assess the data and determine whether the Part B cohort should be expanded to include up to 7 additional subjects to be dosed in parallel, with ongoing review of safety and efficacy data. After Part B expansion, the investigator will continue to assess subject data every 12 weeks to confirm the continued absence of inhibitors, stability of FVIII activity levels, and a tolerable safety profile.
  • Subjects in Part A will discontinue their emicizumab treatment only after reaching FVIII activity levels > 5 IU/dL following AAV-FVIII-SQ infusion; and Subjects in Part B will discontinue their regular FVIII treatment regimen starting 4 weeks after the day of infusion and switch to an “on-demand” schedule.
  • Subjects in Part B will discontinue their regular FVIII treatment regimen starting 4 weeks after the day of infusion and switch to an “on-demand” schedule.
  • the decision on whether to resume prior treatment regimen will be discussed between Investigator and Medical Monitor. Upon review of the data, it may be recommended that additional subjects be enrolled, up to a total of approximately 40 subjects in the study. Subjects in both parts will be followed post- infusion for 5 years.
  • AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
  • the IP is labelled according to the particulars approved by the relevant regulatory agencies.
  • AAV-FVIII-SQ will be administered at a qualified dosing site, and subjects will be monitored for at least 24 hours (for subjects in Part A) or 8 hours (for subjects in Part B) post- infusion for any immediate hypersensitivity or adverse drug reaction.
  • a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory cytokine bead array (CBA) to assess inflammatory biomarkers and plasma cytokine levels.
  • CBA exploratory cytokine bead array
  • Inpatient observation can be extended and additional blood samples can be collected if deemed necessary at the discretion of the Investigator and Medical Monitor.
  • the subject On the day of infusion, the subject will come to the infusion site, where a physical examination will be performed by the Investigator or designee. If the subject is found to have an active acute illness at the time of planned infusion, then the infusion should be deferred until the illness has resolved; screening procedures may require repetition if outside the specified window.
  • An IV catheter will be inserted into a suitable peripheral vein (e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will not be given since venipuncture is a minimally invasive procedure in these individuals under ordinary conditions.
  • AAV-FVIII-SQ will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at room temperature prior to administration. Refer to the Pharmacy Manual for IP administration instructions. [194] AAV-FVIII-SQ will be infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase. Of note, the IP has been shown to be stable at room temperature for 10 hours following completion of product thaw.
  • Vital signs should be monitored at 15 minute ( ⁇ 5 minutes) intervals throughout the time period of the infusion.
  • any infused biological product there is a potential risk of acute, systemic hypersensitivity reactions (including anaphylaxis) with AAV-FVIII-SQ. Dosing will be administered at a qualified infusion site, with appropriate resuscitation equipment and medication available and easily accessible.
  • the infusion may be slowed or halted at the Investigator’s discretion, with consideration of the subject’s clinical condition. If the infusion is halted, it should only be restarted if the Investigator considers it safe and appropriate to do so.
  • Antihistamines, anti-pyretic, and/or corticosteroid administration is permitted prior to restarting an interrupted infusion after an infusion-related reaction.
  • the infusion rate may be adjusted (ie, to a slower rate [minimum of 1 mL/min], with the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the subject’s clinical condition permits such an increase) with careful monitoring of the subject.
  • the infusion rate would not go beyond 1mL/min.
  • any safety signal may trigger a review of the data and possible additional immunogenicity studies or other diagnostics deemed necessary to assess cellular immune responses using collected PBMCs.
  • certain study assessments may be performed by a mobile nursing (MN) professional at the patient's home or another suitable location such as their school or office (if the subject has given written informed consent to participate in MN visits), or at the site of approved lab facility as a shortened lab draw-only visit, to improve access and convenience for patients participating in the study, as indicated in the protocol.
  • MN mobile nursing
  • the Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor).
  • the MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed. If the investigator at a participating site determines that MN services are appropriate for a patient and the patient gives written informed consent to participate in MN visits, the MN network will communicate with the patients and the patient’s visit.
  • Inclusion Criteria Individuals eligible to participate in this study must meet all of the following inclusion criteria: i) Males 18 years of age with hemophilia A and documented prior residual FVIII activity ⁇ 1 IU/dL including, but not limited to, at the time of detected inhibitors, at the time of signing the informed consent, ii) Documented history of a prior positive inhibitor result (results from a Bethesda Assay or Nijmegen Bethesda Assay > 0.6 BU), with the first detection of the inhibitor at least 12 months prior to Screening.
  • Part A Positive FVIII inhibitor test per central lab at Screening, defined as inhibitor titer > 0.6 BU from the chromogenic Nijmegen-Bethesda Assay (cNBA). The first 3 subjects enrolled in Part A must have an inhibitor titer > 5 BU.
  • For Part B Negative FVIII inhibitor test per central lab at Screening, defined as inhibitor titer ⁇ 0.6 BU from cNBA.
  • Part A Subject must be on emicizumab prophylaxis for at least 6 months prior to Screening.
  • Subjects are required to be taking emicizumab at a maintenance dose of 1.5 mg/kg weekly, or be willing to switch to this regimen, prior to dosing with AAV-FVIII-SQ. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available.
  • For Part B Subject must be on FVIII replacement prophylaxis therapy for at least 12 months prior to Screening. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available.
  • ALT aminotransferase
  • AST aminotransferase
  • GTT gamma-glutamyltransferase
  • Total bilirubin > 1.25x ULN
  • Alkaline phosphatase > 1.25x ULN
  • INR international normalized ratio
  • Subject most recent, prior FibroScan or prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used.
  • Additional exclusion criteria include : evidence of any bleeding disorder not related to hemophilia A, Platelet count of ⁇ 100 x 109/L, significant renal dysfunction with any of the following abnormal laboratory results: serum creatinine >1.5 mg/dL, estimated glomerular filtration rate (eGFR) ⁇ 90 mL/min by the Modification of Diet in Renal Disease (MDRD) equation hematuria or proteinuria as indicated by urine dipstick test at screening, liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.
  • MDRD Modification of Diet in Renal Disease
  • Further exclusion criteria include chronic or active hepatitis B as evidence by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing.
  • hepatitis B surface antigen [HBsAg] hepatitis B surface antigen [HBsAg]
  • HBsAb hepatitis B surface antibody
  • HBcAb hepatitis B core antibody
  • AEs adverse events
  • Additional exclusion criteria include prior treatment with any vector or gene transfer agent. Major surgery planned in the 26-week period following the infusion with AAV-FVIII-SQ. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the AAV-FVIII-SQ infusion.
  • Prophylactic Corticosteroids [214] All subjects will be started on prophylactic corticosteroids: For Part A subjects, prophylactic corticosteroids will be started at the Week 2 visit (Day 15). If clinically indicated (eg, ALT elevation, rising inhibitor titers), corticosteroids may be started earlier than Week 2. [215] For Part B subjects, prophylactic corticosteroids will be started on Study Day 1.
  • the first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, or an equivalent dose of another corticosteroid) should be taken at least 3 hours prior to the start of the AAV- FVIII-SQ infusion and continued on a daily basis.
  • Figure 12A (for Part A) and Figure 12B (for Part B) provide an example of a possible prophylactic corticosteroid course for each study part, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses.
  • corticosteroids may be started earlier than Week 2 (eg, in the event of an ALT increase, increasing inhibitor titers, etc.). Following initiation or completion of corticosteroid regimen, if a recurrence of ALT VALUES > ULN or ⁇ 1.5x baseline value is reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation, relationship between increases in ALT and FVIII activity, ALT levels/FVIII activity post-corticosteroid initiation, and adverse events related to corticosteroid dosing.
  • ALT levels and FVIII activity will be measured once a week for 4 weeks to ensure stability in values.
  • Test for hepatitis B or Hepatitis C should only be performed in subjects with a history of these diseases prior to study entry.
  • ALT levels become increased (eg, ⁇ 1.5x baseline value or > ULN) and alternative etiologies have been ruled out, and/or if FVIII activity levels significantly decline, prompt institution of newly administered or an increased dose of therapeutic or on-demand oral corticosteroids (prednisone or an equivalent dose of another corticosteroid) should be considered after consultation with the Medical Monitor.
  • ALT a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids. Newly administered corticosteroids or dose increased are not indicated if elevations in ALT are clearly not related to AAV-FVIII-SQ (eg, elevated in ALT with concurrent increase in CPK due to intensive exercise) although this should be discussed with the Medical Monitor.
  • Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. If the ALT level immediately returns to ⁇ 1.5x baseline and FVIII activity levels continue to rise and/or remain within or above the normal range in the 2 weeks following corticosteroid initiation, on- demand corticosteroids can be discontinued.
  • therapeutic corticosteroids should be tapered over a longer period of time.
  • the recommended duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter.
  • a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments.
  • ALT levels eg, > ULN or ⁇ 1.5x baseline value
  • corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
  • Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if possible.
  • Efficacy Variables FVIII Activity The efficacy variable of primary interest for Part A and Part B is hFVIII activity, as measured by chromogenic substrate assay. The efficacy goal is to establish the timing to FVIII activity > 5 IU/dL post-AAV-FVIII-SQ infusion.
  • FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [227] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred (upon consultation between the Investigator and the Medical Monitor) until either a clearer trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase.
  • Subjects in Part B who do not respond to AAV-FVIII-SQ treatment may, at the Investigator’s discretion and after discussion with the Medical Monitor or Sponsor-designated Data Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year visits during Years 2-5.
  • Anti-FVIII Inhibitor Titer Changes [229] For Part A, decrease in anti-FVIII inhibitor titer post-infusion will be measured.
  • Subjects must have high quality documented historical data available concerning previous bleeding episodes and hemophilia treatment over the previous 12 months in order to be eligible to enroll in the study. During the study, subjects will be asked at each study visit to report the use of factor replacement therapy and the number of bleeding episodes since the previous visit. This information will be captured on the subject’s diary or other subject records. [232] Subjects are strongly encouraged to immediately consult Investigator for guidance regarding management of suspected bleeds or bleeding episodes within the first 30 days post AAV-FVIII-SQ infusion. [233] In subjects who experience recurrent bleeding episodes, the Investigaor and Medical Monitor will discuss whether to resume prior FVIII prophylaxis or use of emicizumab.
  • Immunogenicity assays will be performed on plasma and PBMCs.
  • the assays will include detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (Transduction Inhibitors, TI).
  • FVIII Inhibitors will be assessed using the cNBA for both local and centralized testing. Any abnormality of the liver parameters will lead to a retrospective - immunogenicity assessment to evaluate FVIII and capsid-specific cellular immunogenicity.
  • FVIII- and capsid-specific cellular immunity will be assessed by stimulated cytokine secretion using an interferon gamma (IFNg) ELISpot assay performed on collected PBMCs. Activation of complement will be evaluated by measuring plasma levels of C3, C3a, C4, Bb, and sC5b-9. Exploratory immunophenotyping of patients PBMC by flow cytometry will investigate changes over time in cellular immune responses, regulatory T-cell populations, and their relationship to FVIII inhibitor titers.
  • IFNg interferon gamma
  • Pharmacodynamics [235] The FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters. Pharmacokinetics [236] For Part B, sparse FVIII activity assessments, prior to AAV-FVIII-SQ administration, will be collected to estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours post-FVIII infusion.
  • Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A.
  • All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol.
  • samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed.
  • Safety Variables [239] Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity.
  • Table 11 a Coagulation Screen Blood Chemistry Hematology Urine Tests including: activated partial Albumin Hemoglobin Appearance thromboplastin time (APTT) blood urea nitrogen prothrombin time/ ( BUN) Hematocrit Color international normalized ratio (PT/INR) Calcium White Blood Cell pH thrombin time (TT) (WBC) count C hloride Red Bloo c d o u C n e t ll (RBC) Specific gravity Total cholesterol Platelet count Ketones creatinine phosphokinase Differential cell count Protein (CPK) RBC indices mean corpuscular volume (MCV) and mean Creatinine corpuscular Glucose Other Tests: hemoglobin (MCH) CRP Bilirubin ABO blood typing* G lucose Nitrite Phosphorus Urobilinogen Potassium Hemoglobin T otal protein UACR Sodium Uric Acid [241] For Part A, a local urine dipstick will be
  • the urine sample should be sent for additional laboratory testing as outlined in the table.
  • a fasting blood lipid panel including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol
  • fasting FibroTest will be assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit.
  • a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour and 8-24 hours following the hypersensitivity reaction for assessment of complement and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points, if possible, 1 week after the event for an optional exploratory CBA to assess inflammatory biomarkers and plasma cytokine levels.
  • certain study assessments may be performed by a MN professional at the patient's home or another suitable location, such as their school or office, to improve access and convenience for patients participating in the study.
  • the Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor).
  • the MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed. If the investigator at a participating site determines that MN services are appropriate for a patient and the patient gives written informed consent to participate in MN visits, the MN network will communicate with the patient and the patient’s site. MN visits will be allowed at the visits indicated in the Schedules of Events. Unscheduled visits may also be conducted by MN as appropriate.
  • hepatitis B screening should include HBsAg, HBsAb, and HBcAb.
  • Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period.
  • Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary.
  • Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening and will be tested for hepatitis B and hepatitis C reactivation. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening. [247] A liver ultrasound/FibroScan and LTs during Screening will identify any significant hepatic dysfunction.
  • LTs will be monitored on a regular basis; at each time point, the following LTs should be assessed: alkaline phosphatase, ALT (SGPT), AST (SGOT), direct bilirubin, total bilirubin, CGT and LDH.
  • Elevated ALT levels should be evaluated according to the following plan: Table 12 ALT Level Work-Up ⁇ 1.5x • Continue to monitor LTs and FVIII per protocol (repeat within 24-72 Bas -e ⁇ lin2ex p hrooutrosco ifl n secxhteduled visit is >24-72 hours from the time of the reported Baseline • ALT elevation)
  • alternative etiology eg, concomitant medications, viral or autoimmune hepatitis, alcohol use, recreational drug use, special diets, strenuous exercise, prior and/or concurrent illnesses, exposure to environmental and/or industrial chemicals, etc.
  • ALT is > ULN or > 2x baseline in 2 consecutive assessments within 24-72 hours and alternative etiologies have been ruled out, start oral corticosteroids upon consultation with the Medical Monitor ⁇ 2x • Repeat LTs and FVIII within 24-72 hours or > Ba UsLeNlin -e ⁇ 3x
  • Events meeting the AE definition include Exacerbation of a chronic or intermittent pre- existing condition including either an increase in frequency and/or intensity of the condition. New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study. Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
  • Events not meeting the AE definition include: Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition. The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.
  • Clinical laboratory data will be summarized by the type of laboratory test. For each clinical laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent visits. Descriptive statistics for physical examination results and vital signs will also be provided.
  • Immunogenicity Analysis [256] Anti-AAV5 capsid and anti-FVIII total antibodies, as well as neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (Transduction Inhibitors, TI) will be summarized.
  • Plasma profiles will utilize the FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively.
  • PD parameters determined using FVIII protein and activity will be summarized with descriptive statistical measures (e.g. mean, standard deviation, CV%, min, median, max).
  • Example 7 Endopeptidase cleavage of IgG to remove circulating antibody.
  • a pilot study was conducted in non-human primates (NHPs) that demonstrated a single dose of Imlifidase (IdeS) reduced pre-existing antibody titers and enabled successful transduction of the liver.
  • NHS non-human primates
  • a rabbit model system was developed to evaluate immunogenicity and AAV5 vectored gene therapy that adopted a low dose AAV sensitization model, to induce immunity, followed by rechallenge with AAV to assess effectiveness of IdeS in overcoming anti-AAV antibodies. IdeS was also well tolerated in rabbits with no safety observations.
  • the rabbit IdeS study design is depicted in Figure 14A. Animals sensitized in with AAV5-bCG produced a range of NAb and TAb titers and were evenly distributed into IdeS-treated and Control groups. ( Figure 14B).
  • IdeS treatment enabled efficacious gene therapy dose administration in a redosing scenario where animals were sensitized to have physiologically meaningful TAb and NAb titers.
  • a 99% decrease would reduce TAb titers in all hemophilia A patients from the study described above (Example 7) to below the AAV 5 companion diagnostic cut-point, assuming IdeS was equally efficacious in human patients (Figure 16).
  • a 1 mg/kg dose in rabbits has a human equivalent dose of 0.3 mg/kg (based on body surface area) which is comparable to 0.25 mg/kg approved clinical dose of IdeS. While pre-existing antibody titers are lowered and more manageable than treatment emergent titers, sequential IdeS dosing or combination with plasmpaheresis could allow redosing as well. [261] Patients that test positive for AAV5 TAb in the CDx are ineligible for AAV-FVIII-SQ treatment ( ⁇ 30% of the population). The IgG degrading enzyme approach for seropositive people to access gene therapy will unlock additional patients for AAV-FVIII-SQ gene therapy and other gene therapies.
  • IdeS IgG cleaving enzyme
  • a single dose of an IgG cleaving enzyme, IdeS could address essentially all patients with pre-existing immunity, is easy to administer and is well tolerated and could also provide a potential path to redosing patients when FVIII levels wane.
  • EXAMPLE 8 Preliminary Results from Clinical Study Investigating Clinical Phenotype Hemophilia A Patients with FVIII Activity [262] The following is data obtained in the clinical study described above in Example 6 to assess the safety of a single IV administration of AAV-FVIII-SQ (valoctocogene roxaparvovec) for individuals with severe hemophilia A and active (part A) or prior (part B) FVIII inhibitors.
  • the primary outcome was safety, and the secondary outcomes were efficacy as indicted by a change in baseline for FVIII activity and antibody titer, annualized bleeding rate, annualized utilization of hemophilia therapy and hemophilia-specific quality of life questionnaire for adults (Haemo-Qol-A).
  • the study schedule is provided in Figure 17.
  • Participant 1 was a 30 year old male, who received emicizumab prior to and throughout the study. This participant received prophylactic corticosteroids from week 2 to week 21, then received reactive corticosteroids from week 24 to week 31 and from week 34 to week 42.
  • the inhibitor titer level at screening was 3.5 BU, with a peak inhibitor titer of 200 BU for participant 1.
  • Participant 2 was a 27 year old male, who received emicizumab before and throughout the time of the trial. This participant received prophylactic corticosteroids from week 2 to week 21.
  • the inhibitor level at screening was 2.2 BU with a peak inhibitor titer of 72 BU.
  • the normal ALT range is 5-48 U/L.
  • Figures 18A and 18B provide the inhibitor levels, FVIII activity levels, FVIII antigen levels and ALT levels over 52 weeks.
  • FVIII activity levels of ⁇ 1.5 IU/dL were imputed as 0 and FVIII antigen levels of ⁇ 4.7 ng/mL were imputed as 1.
  • the FVIII inhibitor titers increased as expected, and the rise in FVIII inhibitor levels suggest FVIII is being produced in the liver although it was undetectable by chromogenic substrate assay (CSA).
  • Participant 1 exhibited fluctuation in FVIII inhibitor titers.
  • Participant 2 exhibited a decrease in FVIII inhibitor titers and a decrease in detectable FVIII activity by week 28.
  • Participant 1 was a 33 year old male, who received FVIII prophylaxis from week 1 through week 4. This participant received prophylactic corticosteroids from week 1 to week 6, and received immunosuppressive agent mycophenolate mofetil (1000 mg 2x a day) from week 11 to week 18 and again from week 20 to week 26.
  • the inhibitor titer level at screening was ⁇ 0.6 BU, with a peak inhibitor titer of 20 BU.
  • Participant 2 was a 26 year old male, who received FVIII prophylaxis from week 1 through week 5. This participant received prophylactic corticosteroids from week 1 to week 8, and then reactive corticosteroids from week 8 to week 18, from week 21 to week 26 and then again from week 26 to week 34.
  • Figures 19 A and B provide the inhibitor levels, FVIII activity levels and ALT levels over 36 weeks.
  • the normal ALT range is 5-48 U/L. This data demonstrated that both participants demonstrated an increase in FVIII activity levels by week 4.
  • All of the participants in the study showed a similar safety profile. The most common adverse event was ALT elevation. There were not serious or severe adverse events reported related to administration of valoctocogene roxaparvec or IS therapy. There were no thromboembolic events or malignancy. No FVIII inhibitor recurrence in the prior inhibitor population (part B).
  • EXAMPLE 9 Clinical Study To Evaluate Efficacy And Safety Of Administration Of AAV-FVIII-SQ And Prophylactic Corticosteroids [267] In the study described above in Example 6, subjects were started on corticosteroids by Week 3 (either therapeutically, in response to an alanine aminotransferase (ALT) elevation, or prophylactically), and in another clinical study (referred to the 270-301 study) subjects received corticosteroids only in response to an ALT elevation.
  • ALT alanine aminotransferase
  • the current study is a Phase 3b, single arm, open-label study designed to assess whether AAV-FVIII-SQ, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia A patients with residual FVIII activity ⁇ 1 IU/dL.
  • Subjects are enrolled at approximately 10 sites worldwide. Subjects must have high-quality, well-documented historical data available concerning previous bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study.
  • AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
  • CZ Crystal Zenith®
  • AAV-FVIII-SQ is prepared and infused as a pure solution over a dose-dependent time. Prepared drug is kept at room temperature prior to administration. [271] AAV-FVIII-SQ is infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min. The infusion rate is increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase.
  • the IP has been shown to be stable at room temperature for 10 hours following completion of product thaw.
  • Vital signs (pulse, blood pressure, respiration rate and temperature) are monitored at 15 minute ( ⁇ 5 minutes) intervals throughout the time period of the infusion.
  • Therapeutic Corticosteroid Treatment and/or Alternative Immunosuppressive Agent Treatment of Elevated Hepatic Transaminases [272] Refer to steroid prescription guidelines to determine eligibility, monitoring and managing of side effects during steroid treatment. Prior to dosing, all subjects are screened per steroid prescription guidelines to ensure the subject is eligible to receive corticosteroid treatment as outlined in the protocol.
  • corticosteroid prescription guidelines for recommended monitoring for, and management of, potential side effects of corticosteroids, including guidance on medications that should be avoided during corticosteroid treatment.
  • All subjects are started on prophylactic corticosteroids starting on the day of infusion (Day 1).
  • the first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, or an equivalent dose of another corticosteroid) is taken at least 3 hours prior to the start of the AAV-FVIII-SQ infusion and continued on a daily basis.
  • FIG. 12B provides an example of a possible prophylactic corticosteroid course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses. [274] Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (e.g.
  • ⁇ 1.5x baseline value or > ULN ⁇ 1.5x baseline value or > ULN
  • prompt institution of newly administered or an increased dose of therapeutic or on-demand oral corticosteroids prednisone or an equivalent dose of another corticosteroid
  • a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids.
  • Newly administered corticosteroids or dose increases are not indicated if elevations in ALT are clearly not related to AAV-FVIII-SQ (e.g., elevated ALT with concurrent increase in CPK due to intensive exercise).
  • Alternative immunosuppressive agents may also be considered for use on a case-by-case basis (e.g., if prolonged corticosteroid use is contraindicated).
  • therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. If the ALT level immediately returns to ⁇ 1.5x baseline and FVIII activity levels continue to rise and/or remain within or above the normal range in the 2 weeks following corticosteroid initiation, on-demand corticosteroids can be discontinued. However, if this is not the case, therapeutic corticosteroids should be tapered over a longer period of time.
  • the recommended duration of on-demand corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter.
  • Corticosteroids may be tapered if: Corticosteroids should be tapered on an individual • ALT ⁇ 1.5x baseline value; and subje thcet b foalsloisw winigth guiding • FVIII activity levels > 90% of the pre-decline FVIII principles: activity levels; and • There is no concern for adrenal insufficiency post- withdrawal If ALT level is increasing or FVIII activity level is decreasing Increasing Corticosteroid o w r h a i l le c o r n ticosteroids, any increases in oral corticosteroid Dose dosing should be made only upon consultation with the Medical Monitor For any scenarios that are not accounted for in the above table, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments.
  • ALT and FVIII levels are measured once a week for 4 weeks to ensure stability in values.
  • ALT levels eg, > ULN or ⁇ 1.5x baseline value
  • corticosteroid management decisions will be based on discussions with the Investigator. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
  • Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA.
  • COX-2 inhibitors while not contraindicated during corticosteroid treatment, should be limited, if possible. Practical management to prevent complications related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (e.g., evaluation of glucose intolerance, hyperlipidemia etc.). Alternative, non-steroidal systemic immunosuppressive agents may be used should corticosteroid use be deemed by an Investigator to be clinically ineffective, not tolerated, and/or contraindicated.
  • Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start of oral corticosteroid/immunosuppressive agent treatment in corticosteroid/immunosuppressive agent treatment and then 1 week and 13 weeks after the completion of oral corticosteroid/immunosuppressive agent subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse events suspected to be caused by or related to corticosteroid/immunosuppressive agent use) should be reported.
  • Subjects [279] Approximately 20 adult subjects with severe HA (e.g.
  • Subjects who do not respond to AAV-FVIII-SQ treatment may, at the Investigator’s discretion and after discussion with the Medical Monitor or Sponsor- designated Data Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year visits during Years 2-5.
  • An optional liver biopsy is performed (in subjects who consent to do so) at or around Week 26, Week 52, and/or during Years 2-5 following AAV-FVIII-SQ infusion.
  • the primary efficacy objective of the study is to assess the efficacy of AAV-FVIII-SQ with prophylactic corticosteroids defined as FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52, following intravenous infusion of AAV-FVIII-SQ.
  • the secondary efficacy objectives of the study are to assess the impact of AAV-FVIII- SQ with prophylactic corticosteroids on the use of exogenous FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving prior emicizumab prophylaxis.
  • ii) Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on the number of bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving prior emicizumab prophylaxis. iii) Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on quality of life as measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to baseline.
  • the tertiary efficacy objective of the study is to Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on patient-reported outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to baseline.
  • the exploratory efficacy objective of the study is to assess the efficacy of AAV-FVIII-SQ with prophylactic corticosteroids defined as FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52, following intravenous infusion of AAV-FVIII-SQ for subjects with detectable AAV5 total antibodies below the minimum required dilution at Screening.
  • the safety objectives of the study are to evaluate the safety of AAV-FVIII-SQ with prophylactic corticosteroids during the first 52 weeks following intravenous infusion of AAV- FVIII-SQ and to assess the long-term safety of AAV-FVIII-SQ with prophylactic corticosteroids.
  • Inclusion and Exclusion Criteria [289] Individuals eligible to participate in this study must meet all of the following inclusion criteria: 1. Males ⁇ 18 years of age with hemophilia A and residual FVIII levels ⁇ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent. 2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to study entry.
  • BU Bethesda Units
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • GGT gamma-glutamyltransferase
  • Total bilirubin > 1.25x ULN
  • Alkaline phosphatase > 1.25x ULN
  • INR international normalized ratio
  • Evidence of any bleeding disorder not related to hemophilia A. Platelet count of ⁇ 100 x 109/L. Creatinine > 1.5 mg/dL. Liver cirrhosis of any etiology as assessed by FibroScan or liver ultrasound.
  • hepatitis B chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing.
  • HBsAg hepatitis B surface antigen
  • HBsAb hepatitis B surface antibody
  • HBcAb hepatitis B core antibody
  • thromboembolic events e.g., deep vein thrombosis, non- hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus
  • 21 Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.
  • 22 Treatment with any investigational product within 30 days or 5 half-lives of the investigational product prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study. 23.
  • AEs ongoing adverse events
  • iii The occurrence of an AE of hepatic failure.
  • iv) The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in two subjects.
  • v) The occurrence of any cancer (except non-melanoma skin cancer) at any point after AAV-FVIII-SQ infusion.
  • vi) The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one subject.
  • the primary efficacy variable is change of the hFVIII activity, as measured by chromogenic substrate assay during Weeks 49-52 post-AAV-FVIII-SQ infusion from baseline.
  • FVIII activity has declined ⁇ 35% from the peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [298] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred until either a clearer trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase.
  • Secondary efficacy variables include: i) ⁇ Change in the annualized utilization (IU/kg/year) and infusion (number/year) rates of exogenous FVIII replacement therapy during Week 5 to Week 52 post-AAV-FVIII-SQ infusion from the baseline number and utilization of exogenous FVIII replacement therapy, for subjects receiving FVIII prophylaxis during the 12 months prior to study entry, or change in administration of exogenous FVIII replacement therapy Week 27 to Week 52 post-AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis.
  • EQ-5D-5L instrument is a self-reported questionnaire designed to measure general health status (The EuroQol Group, 1990) (Brooks, 1996).
  • the EQ-5D-5L is composed of 2- parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual analogue scale (EQ VAS) assessment for overall health.
  • the Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of disease symptom severity on work productivity and classroom productivity (if applicable) (Recht, 2014).
  • the WPAI+CIQ:HS questionnaire yields scores related to work/classroom absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and activity impairment.
  • WPAI+CIQ HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (Reilly, 2002).
  • PROBE Patient Reported Outcomes, Burdens, and Experiences
  • PROBE aims to develop a new global tool to enhance the direct patient- voice in health care decision-making (Chai-Adisaksopha, 2017).
  • Immunogenicity [306] Immunogenicity assays will be performed on plasma and PBMCs.
  • the assays will include detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (transduction inhibitors, TI).
  • FVIII inhibitors are assessed using the chromogenic Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will lead to a retrospective immunogenicity assessment to evaluate FVIII- and capsid-specific cellular immunogenicity.
  • FVIII- and capsid-specific cellular immunity is assessed by stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs.
  • FVIII protein concentration and activity level is measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters.
  • Pharmacokinetics [308] Sparse FVIII activity assessments, prior to AAV-FVIII-SQ administration, is collected to estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours post-FVIII infusion.
  • FVIII activity clearance (CL) value FVIII activity clearance
  • Individual subject CL estimates are then evaluated against post-AAV-FVIII-SQ FVIII activity levels to determine if an association exists between an individual’s FVIII activity CL value and FVIII activity levels achieved with AAV-FVIII-SQ.
  • pharmacokinetics assessment is optional. Exploratory Assessments [309] Blood samples are collected from subjects at particular time points to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations.
  • Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A.
  • All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol.
  • samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed.
  • Optional Liver Biopsy [311] Subjects electing to undergo an optional liver biopsy are required to consent to the procedure and collection of tissue in the study ICF. The analysis of the optional liver biopsy is considered exploratory. Patients who elect to proceed will have a liver biopsy performed around Week 26, Week 52, and/or during Years 2-5.
  • liver biopsies at times deemed to be clinically relevant (e.g., decreasing FVIII at a time of increased ALT) may be pursued.
  • Subjects will be asked to consent to the procedure for each liver biopsy performed during the study.
  • Subjects who consent to the procedure will have a liver biopsy via either transjugular or percutaneous (ultrasound-guided) route, according to the standard procedures of the institution. Two tissue cores will be harvested in the context of the optional liver biopsy. Subjects will be required to observe an 8-hour fasting period before the procedure.
  • subjects Within 24 hours prior to the biopsy being performed, subjects must have a documented FVIII activity level of ⁇ 50 IU/dL (or higher, depending on local guidelines and/or investigator discretion).
  • FVIII activity levels for this purpose should be assessed at the local laboratory within 7 days before the biopsy and again on the day the biopsy, prior to the procedure. As needed, subjects may be treated with additional exogenous FVIII replacement products in order to increase their FVIII activity levels to an appropriate level, under the supervision/instruction of the investigator, to ensure the safety of the subject during the procedure.
  • Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy assessments at least 7 days before the procedure, as follows: Local FVIII activity level assessment and/or Pre-biopsy consultation (with hepatologist and/or radiologist).
  • Pre-biopsy consultation with hepatologist and/or radiologist.
  • FVIII activity assessment should also be performed to ensure the subject has sufficient FVIII activity to protect against procedure-related bleeding (as discussed above).
  • LT assessment and a whole blood draw for PBMC collection should be performed on the biopsy day or ⁇ 1 week from the biopsy day.
  • the optional liver biopsy is performed in the morning if feasible, and the biopsy procedure and follow-up care should be done according to the local standard of care. Following completion of the biopsy, the subject should remain under observation in the clinic for at least 4- 6 hours. Overnight post-procedure observation may be done at the investigator’s discretion and/or according to local guidelines.
  • Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity.
  • additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected at the same time as the local unscheduled sample.
  • Clinical Laboratory Assessments [318] The scheduled clinical laboratory tests are listed in Table 11 (see Example 6 above).
  • any abnormal test results determined to be clinically significant by the Investigator should be repeated (at the Investigator’s discretion) until: (1) the cause of the abnormality is determined; (2) the value returns to baseline or to within normal limits; or (3) the Investigator determines that the abnormal value is no longer clinically significant.
  • a fasting blood lipid panel including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol
  • Fibrotest will be assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit.
  • hepatitis B screening should include HBsAg, HBsAb, and HBcAb.
  • Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period.
  • Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary.
  • Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B and hepatitis C reactivation at the timepoints.
  • Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening.
  • Table 15 Viral Hepatitis Workup Testing Autoimmune Hepatitis Workup Testing Hepatitis A Smooth muscle antibody Hepatitis B Mitochondrial antibody Hepatitis C Liver/kidney microsomal antibodies Hepatitis E Antinuclear antibody (ANA) HEP-2 Cytomegalovirus (CMV) Epstein-Barr virus (EBV) Herpes simplex virus (HSV) 1 & 2 HIV Testing [325] HIV testing will be performed at Screening. Subjects with documented negative results within the last 30 days prior to screening do not need to be retested.
  • CMV Cytomegalovirus
  • EBV Epstein-Barr virus
  • HSV Herpes simplex virus
  • Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration rate, and temperature. Any clinically significant change in vital signs will be recorded as an AE.
  • Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature will be assessed at the time points indicated in the schedules of events. On the day of the AAV-FVIII-SQ infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes ( ⁇ 5 minutes), following the infusion hourly ( ⁇ 5 minutes) for at least 8 hours during the subject’s stay in the clinic.
  • a complete physical examination should be performed during Screening/Baseline, at Week 26 ( ⁇ 2 weeks) and 52 and every 52 weeks thereafter; at other visits, brief physical examinations may be performed at the discretion of the Investigator based on the subject’s clinical condition. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses.
  • a complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems.
  • a brief physical examination will include general appearance, cardiovascular, dermatologic, respiratory, gastrointestinal, musculoskeletal, and neurologic assessments.
  • Vector Shedding [330] During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily samples to look for evidence of vector shedding for possible viral transmission. Bodily fluids will be tested by polymerase chain reaction (PCR). Fluids tested will include: blood, saliva, semen, urine and/or stool. [331] Vector shedding will also be extensively studied in the present clinical trial. Testing will continue until at least 3 consecutive results below the limit of detection are obtained; additional collection and testing may be performed based on batch testing schedules, result turnaround times, or discussions between Medical Monitor and Investigator.
  • PCR polymerase chain reaction
  • Samples may be fractionated prior to shedding analysis in order to better characterize the presence, structure, and location of vector DNA and/or vector capsid within each matrix. If needed, the fractionation may be performed with samples collected specifically for shedding analysis (saliva, blood, semen, urine, stool).
  • the vector DNA characterization during shedding analysis may utilize already fractionated exploratory samples obtained from the above biofluids, such as exploratory plasma samples, exploratory PBMC samples, and red blood cells recovered during PBMC/plasma isolations.
  • Fractionation of semen to collect purified sperm separately from non-sperm cells may be performed, after consultation between the Medical Monitor and the Investigator, in parallel at any visit where semen samples are collected. The shedding analysis of a fractionated semen sample will only be performed if vector DNA was detected in the whole semen sample for the same visit.
  • Fractionation of semen during shedding analysis may be stopped if purified sperm tested positive for vector DNA on at least three visits, or if purified sperm tested below the limit of detection for vector DNA on at least three consecutive visits.
  • Contraception use may need to be extended beyond 12 weeks in individual subjects based on observed vector shedding in semen. After 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples below the limit of detection (upon consultation between the Investigator and Medical Monitor).
  • Baseline value of 1 IU/dL (eligible subjects must have residual FVIII levels ⁇ 1 IU/dL as evidenced by medical history) will be used in the calculation of change from baseline since all the subjects will be on prophylactic hemophilia therapy prior to AAV-FVIII-SQ infusion where the FVIII activity level cannot be reliably measured. Descriptive summaries of the proportions of subjects whose hFVIII activity during Weeks 49-52 is greater than or equal to select thresholds, such as 5, 15, 25, 30, and 40 IU/dL, and the confidence intervals of the proportions will also be provided.
  • select thresholds such as 5, 15, 25, 30, and 40 IU/dL
  • Mean and associated 95% confidence interval will be provided for the following secondary endpoints, where the baseline value will be derived from the data in the approximately 12-month period prior to AAV-FVIII-SQ infusion: i) Change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy during Weeks 5-52 post-AAV-FVIII-SQ infusion, for subjects receiving FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 post- AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis.
  • a sensitivity analysis is planned to analyze ABR using a generalized linear mixed model assuming negative binomial as the underlying distribution.
  • the model will include period (pre- to post-AAV-FVIII-SQ infusion) as the only factor, repeated within subject.
  • the actual number of bleeding episodes will be used as the dependent variable with the time period adjustment (annualization) being implemented as the offset.
  • analyses using observed case are planned as sensitivity analyses for the secondary endpoints. Multiple imputation methods may also be performed.
  • tertiary efficacy endpoints The analyses of the tertiary efficacy endpoints will be descriptive. Mean change from baseline and associated 95% confidence interval will be provided for EQ-5D-5L, WPAI+CIQ: HS and PROBE scores at Week 52 post- AAV-FVIII-SQ infusion. Immunogenicity [344] Analysis of total and neutralizing antibody response and other immunological parameters will be primarily descriptive and involve both inter-subject and intra-subject comparisons. Pharmacodynamic Analyses [345] Plasma FVIII protein concentrations and FVIII activities determined over the course of the study will primarily be evaluated and summarized with descriptive statistical measures (eg, mean, standard deviation, CV%, min, median, max).
  • AAV-FVIII-SQ is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation study in subjects with severe HA designed to assess the safety and efficacy of AAV-FVIII-SQ at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg).
  • 270-201 explores the relationship of vector dose to the augmentation of residual FVIII activity and whether these levels are sufficient to alter the clinical phenotype.
  • AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV serotypes (Boutin, 2010; Hayes, 2019). [351] Current data describing the extent of neutralization or inhibited transduction has been inconsistent across studies, each employing one of several varying methodologies to evaluate both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described successful transduction in patients who, in retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017). Importantly, no drug-related adverse events were described in these patients.
  • the secondary objectives are i) Assess the efficacy of AAV-FVIII-SQ defined as FVIII activity at or above 5 IU/dL at Week 26. ii) Assess the impact of AAV-FVIII-SQ on usage of exogenous FVIII replacement therapy. iii) Assess the impact of AAV-FVIII-SQ on the number of bleeding episodes requiring exogenous FVIII therapy. iv) Evaluate the pharmacodynamics of FVIII expression following IV infusion of AAV-FVIII-SQ and v) Assess the impact of AAV-FVIII-SQ on patient-reported outcomes (PROs).
  • Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening AAV5 TAb titers.
  • Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of6 weeks post-infusion) reviewed.
  • FVIII activity ⁇ 5% after six weeks post- infusion is expected to be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII activity levels, compared with the one subject who had a slightly lower response, based on data from 270-201.
  • ALT alanine aminotransferase
  • AST anaspartate aminotransferase
  • GGT gamma-glutamyltransferase
  • Total bilirubin > 1.25x ULN
  • Alkaline phosphatase > 1.25x ULN
  • INR international normalized ratio
  • Known inherited or acquired thrombophilia including conditions associated with increased thromboembolic risk, such as atrial fibrillation.
  • a history of known inflammatory, connective tissue, or autoimmune disorders eg, vasculitis).
  • Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic etiology): ALT >5x ULN, for more than 2 weeks, ALT >3x ULN and (total bilirubin >2x ULN or INR >1.5), ALT >3x ULN with signs and symptoms of liver dysfunction, ii) The occurrence of an AE of hepatic failure, or iii) The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in two subjects. iii) The occurrence of any cancer (except non- melanoma skin cancer) at any point after AAV-FVIII-SQ infusion.
  • thromboembolic event with FVIII activity > 150 IU/dL in one subject.
  • a prompt evaluation will be required. Further enrollment into the trial will continue while evaluation is ongoing, unless deemed otherwise: i) 1. Acute hypersensitivity assessed as related to AAV-FVIII-SQ, ii) The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in one subject. iii) Occurrence of a thromboembolic event.
  • AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each CZ vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer.
  • CZ Crystal Zenith®
  • AAV-FVIII-SQ will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at room temperature prior to administration. An electric syringe pump will be used to infuse through an in-line, low protein binding 0.22 micron filter.
  • AAV-FVIII- SQ will be infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min.
  • the infusion rate should be increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase.
  • the IP has been shown to be stable at room temperature for approximately 10 hours following completion of product thaw.
  • Vital signs (pulse, blood pressure, respiration rate and temperature) should be monitored at 15 minute ( ⁇ 5 minutes) intervals throughout the period of the infusion.
  • FIG. 12A provides an example of a possible prophylactic corticosteroid course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses.
  • ALT levels become increased (eg, > ULN or > 2x baseline value) and alternative etiologies have been ruled out, prompt institution of therapeutic or on-demand oral corticosteroids (prednisone or converted equivalent) should be considered.
  • a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids.
  • Corticosteroids may be delayed if elevations in ALT are clearly not related to AAV-FVIII-SQ (e.g., elevated in ALT with concurrent increase in CPK due to intensive exercise).
  • Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. At minimum, the recommended duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter. Should a scenario arise in which a deviation from the minimum recommended dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. Tapering of corticosteroid dosages should be guided as set out in Table 16.
  • ALT levels eg, > ULN or > 2x baseline value
  • corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression.
  • Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if possible.
  • Efficacy Variables FVIII Activity Efficacy (response to treatment) will be defined as FVIII activity > 5 IU/dL at Week 26 following AAV-FVIII-SQ infusion. [376] Values for FVIII activity will be excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII protein concentrates.
  • FVIII activity has declined >35% from the peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [378] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred (upon consultation between the Investigator and the Medical Monitor) until either a more clear trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase.
  • the Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality of life questionnaire for adults (Rentz, 2008). It consists of 41 questions covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns). Items are answered on a 6-point Likert-type scale, ranging from 0 (None of the time) to 5 (All of the time). Higher scores mean better health-related quality of life or less impairment for a particular subscale (Haemo-QoL Study Group, 2017). Details regarding the Haemo-QoL-A assessment will be included in the Study Reference Manual.
  • the EQ-5D-5L instrument is a self-reported questionnaire designed to measure general health status (The EuroQol Group, 1990) (Brooks, 1996).
  • the EQ-5D-5L is composed of 2- parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual analogue scale (EQ VAS) assessment for overall health.
  • HAL Haemophilia Activities List measures the impact of hemophilia on self-perceived functional abilities in adults (van Genderen, 2006).
  • the instrument consists of multiple domains including lying/sitting/kneeling/standing, leg and arm function, use of transportation, self-care, household tasks, and leisure activities where subjects are asked to rate their level of difficulty with activities of daily living on a 6-point Likert-type scale from 1 (Impossible) to 6 (Never). For some items, subjects are given the choice to answer ‘Not applicable’.
  • WPAI+CIQ:HS Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of disease symptom severity on work productivity and classroom productivity (if applicable) (Recht, 2014).
  • the WPAI+CIQ:HS questionnaire yields scores related to work/classroom absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and activity impairment. WPAI+CIQ:HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (Reilly, 2002).
  • Immunogenicity assays will be performed on plasma and PBMCs. The assays will include detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 vector capsid (Transduction Inhibitors, TI). FVIII Inhibitors will be assessed using the Bethesda assay with Nijmegen modification.
  • any abnormality of the liver parameters will lead to a retrospective immunogenicity assessment to evaluate FVIII-and vector capsid-specific cellular immunogenicity.
  • FVIII- and vector capsid-specific cellular immunity will be assessed by stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs.
  • Pharmacodynamics [390] The FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters. Exploratory Assessments [391] A cytokine bead array assay assessment will be performed at Baseline and then weekly through Week 26.
  • blood samples will be collected from subjects at particular time points to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV5 gene transfer, and to develop assays used for these evaluations.
  • Subject may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A.
  • All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol.
  • samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed.
  • Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity.
  • Clinical Laboratory Assessments [395] The scheduled clinical laboratory tests are listed in Table 11 (provided in Example 6) Urine tests will be performed locally and centrally; all other laboratory assessments will be performed at the central laboratory. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample.
  • any abnormal test results determined to be clinically significant by the Investigator should be repeated (at the Investigator’s discretion) until: (1) the cause of the abnormality is determined; (2) the value returns to baseline or to within normal limits; or (3) the Investigator determines that the abnormal value is no longer clinically significant.
  • All abnormal clinical laboratory results should be initialed and dated by an Investigator, along with a comment regarding whether or not the result is clinically significant. Each clinically significant laboratory result should be recorded as an adverse event.
  • the diagnosis, if known, associated with abnormalities in clinical laboratory tests that are considered clinically significant by the Investigator will be recorded on the AE eCRF.
  • a fasting blood lipid panel (including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) is assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit.
  • Exploratory biomarker samples at baseline and at post- infusion study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" as described in the rationale of changes.
  • certain study assessments may be performed by a mobile nursing (MN) professional at the patient's home or another suitable location, such as their school or office, to improve access and convenience for patients participating in the study.
  • the Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor).
  • the MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed.
  • hepatitis B screening should include HBsAg, HBsAb, and HBcAb.
  • hepatitis B or hepatitis C Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period.
  • Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening.
  • hepatitis B or hepatitis C who receive therapeutic oral corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C reactivation at the required time points.
  • a liver ultrasound and liver tests (LTs) during Screening will identify any significant hepatic dysfunction. Liver tests will be monitored on a regular basis; at each time point specified in the SoA, the following LTs should be assessed as set out in Table 17.
  • Table 17 LIVER TESTS (LTS) ALKALINE AST (SGOT) TOTAL BILIRUBIN LDH PH AOLSTP (SHGATPATS)E DIRECT BILIRUBIN GGT [406] Elevated ALT levels should be evaluated according to the plan as set out in Table 12 (see Example 6).
  • HIV Testing [407] HIV testing is performed at Screening. Subjects with documented negative results within the last 30 days prior to screening do not need to be retested. Vital Signs, Physical Examinations and Other Observations Related to Safety [408] Vital signs include seated systolic and diastolic blood pressure, heart rate, respiration rate, and temperature. Any clinically significant change in vital signs will be recorded as an AE.
  • Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature will be assessed at Screening, Baseline, and at the beginning of each visit during the Post-Infusion Follow-Up and Long-Term Follow-Up periods.
  • vital signs will be monitored prior to infusion, during the infusion every 15 minutes ( ⁇ 5 minutes), following the infusion hourly ( ⁇ 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Any abnormal vital sign assessments should be repeated, and both values should be recorded in the eCRF.
  • a complete physical examination should be performed at Screening, Week 26, Week 52, and at the End of Year visits.
  • a complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems.
  • brief physical examinations may be performed at the discretion of the Investigator based on the subject’s clinical condition.
  • a brief physical examination will include general appearance, cardiovascular, dermatologic, respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses.
  • Height will be recorded at Screening only.
  • Testing will continue until at least 3 consecutive results below the limit of detection are obtained. Testing of semen will continue at least through Week 12, even if 3 consecutive results below the limit of detection have been recorded in that compartment prior to that time point. Subjects who have not had 3 consecutive semen samples below the limit of detection by Week 26 should continue to have PCR testing in semen every 4 weeks until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and Medical Monitor). Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule (refer to Section 12.5.3) but who have not cleared vector shedding from all fluids must still provide samples for assessment until vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1) and every 4 weeks during Years 2- 5.
  • Samples may be fractionated prior to shedding analysis in order to better characterize the presence, structure, and location of vector DNA and/or vector capsid within each matrix. If needed, the fractionation may be performed with samples collected specifically for shedding analysis (saliva, blood, semen, urine, feces). Alternatively, the vector DNA characterization during shedding analysis may utilize already fractionated exploratory samples obtained from the above biofluids, such as exploratory plasma samples, exploratory PBMC samples, and red blood cells recovered during PBMC/plasma isolations.
  • Fractionation of semen to collect purified sperm separately from non-sperm cells may be performed in parallel at any visit where semen samples are collected. The shedding analysis of a fractionated semen sample will only be performed if vector DNA was detected in the whole semen sample for the same visit. Fractionation of semen during shedding analysis may be stopped if purified sperm tested positive for vector DNA on at least three visits, or if purified sperm tested below the limit of detection for vector DNA on at least three consecutive visits. [418] Contraception use may need to be extended beyond 12 weeks in individual subjects based on observed vector shedding in semen.

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Abstract

The disclosure relates to methods of treating hemophilia patients with Factor VIII (FVIII) adeno-associated virus (AAV), wherein the patients have pre-existing AAV antibodies or require re-administration or redosing of a gene therapy vector. The disclosure also provides for methods of treating hemophilia patients with active FVIII inhibitors or patients that have undergone seroconversion to AAV5 capsid proteins.

Description

METHODS OF TREATING ANTI-AAV SEROPOSITIVE HEMOPHILIA PATIENTS Cross Reference to Related Applications [1] This application claims priority benefit of U.S. Provisional Application No.63/466,643, filed on May 15, 2023, and U.S. Provisional Application No.63/549,816 filed February 5, 2024, both of which are incorporated herein by reference in their entirety. Incorporation By Reference Of Material Submitted Electronically [2] Incorporated by reference in its entirety is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: 55661_SeqListing.xml; Size: 300,421 bytes; Created: May 8, 2024. Field of invention [3] The disclosure relates to methods of treating hemophilia patients with Factor VIII (FVIII) adeno-associated virus (AAV), wherein the patients have pre-existing AAV antibodies or require re-administration or redosing of a gene therapy vector. The disclosure also provides for methods of treating hemophilia patients with active FVIII inhibitors or patients that have undergone seroconversion to AAV capsid proteins. Background [4] AAV-based vectors are promising tools for gene therapy applications, in part because AAVs have no known human pathologies, and vector genomes generally persist in an epi-chromosomal state that drive long-term transgene expression with little or no integration into the host genome. Though widely disseminated among the human population (Gao et al. 2004), wild-type (WT) AAV human infection has not been clearly associated with any clinical pathology or disease (Berns et al.2017). However, AAV gene therapy still faces significant hurdles. AAVs are not strongly immunogenic, but they can, nonetheless, give rise to both a cellular and humoral immune response. The host immune system (humoral and cellular) represents one of the most important obstacles to overcome in terms of safety and efficacy of gene transfer in vivo with AAV vectors (Mingozzi and High, 2013). Seroprevalence studies have indicated that initial exposure to WT AAV often occurs early during childhood (Blacklow et al., 1968) when humoral and cellular immune responses directed against the AAV capsid might be mounted Basner- Tschakarjan, 2014; Tse et al., 2015). As such, memory AAV-specific T- and B-cells might persist lifelong and be recalled upon rAAV-mediated gene transfer. In addition to humoral response, a modest cellular immune response can result in the targeted ablation of transduced cells, and in some instances results in a failure to establish long-term transgene expression (Mingozzi et al.2009). Pre-existing humoral responses are likely more problematic than the cellular immune responses against the AAV capsid as even very low levels of antibodies have been shown to prevent successful transduction. [5] Neutralizing antibodies (Nabs) can be present in the blood of a patient prior to AAV treatment due to naturally acquired infections with the wild type AAV (pre-existing NAbs) or acquired NAbs as a result of prior treatment with an AAV vector. Literature regarding the impact of pre-existing or antibodies elicited after administration of adenoviral vectors on transduction efficiency has been well documented (Scallan et al.2006; Zaiss and Muruve 2008; Wang et al. 2011, Mingozzi and High 2017; Fitzpatrick et al.2018; Long et al.2019). A detailed understanding of the interaction of AAV vectors with the immune system is of great importance for the safety and success of gene therapy applications. The current practice in the clinic with regard to pre-existing immunity involves the screening of human patients for exclusion should patients have neutralizing antibodies against the AAV capsid (Brimble et al. Expert Opin Biol Ther 2016, 16(1):79-92 and Boutin et al. Hum Gene Ther 2010, 21:704-712). Immunosuppressive regimens have been tried in order to reduce the formation of NAb upon first administration to allow for a second administration (Corti et al., Mol Ther-Meth Clin Dev (2014) 1, 14033; Mingozzi et al. Mol Ther vol.20 no.7, 1410-1416; McIntosh et al. Gene Ther 2012, 19, 78-85)). Furthermore, strategies have been suggested to overcome pre-existing antibodies which include plasma exchange and the use of immunosuppressive regimens (e.g. Chicoine et al., Mol Ther 2014, vol.22 no.2338-347; Hurlbut et al. Mol Ther 2010, vol.18 no.111983- 1984 and Mingozzi et al. Mol Ther vol.20 no.7, 1410-1416). These strategies have been tested in animal models obtaining limited success. [6] Another challenge for the AAV vector gene transfer platform is the durability of the effect. Because of their non-integrative nature, systemic gene therapy with AAV vectors in pediatric patients is expected to be limited by tissue proliferation associated with organ growth, which results in significant vector dilution over time (Bortolussi et al., Hum. Gene Ther.25, 844-855 (2014); Ronzitti et al., Mol. Ther. Methods Clin. Dev.3, 16049 (2016); Wang et al., Hum. Gene Ther.23, 533-539 (2012)). In addition, vector readministration in both pediatric and adult patients would be desirable to enable vector titration, to increase the proportion of patients that achieve therapeutic levels of the transgene expression, while avoiding supra-physiological transgene expression and potential toxicities associated with large vector doses (Hinderer et al., Hum. Gene Ther.29, 285-298 (2018)). Thus, there is a need in the art to enable the administration of rAAV gene therapy vectors in human patients that have, or may be suspected to have, AAV neutralizing antibodies. Furthermore, safe and effective strategies aimed at reducing AAV vector immunogenicity that allow for stable transgene expression and vector re- dosing are urgently needed. [7] Valoctocogene roxaparvovec (ROCTAVIAN; BMN 270) is a gene therapy for severe hemophilia A using an adeno-associated virus serotype 5 (AAV5) capsid to deliver a B-domain- deleted (BDD) FVIII coding sequence controlled by a hepatocyte-selective promoter through a single infusion; it has been granted conditional marketing authorization by the European Medicines Agency (Bunting et al. Mol Ther 2018;26:496-509; Fong et al. Nat Med 2022;28:789- 97; Rangarajan et al. S. N Engl J Med 2017;377:2519-30; Pasi et al. N Engl J Med 2020;382:29-40; Pasi et al. Haemophilia 2021;27:947-56; Ozelo et al.. N Engl J Med 2022;386:1013-25; First gene therapy for adults with severe hemophilia A, BioMarin’s ROCTAVIAN™ (valoctocogene roxaparvovec), approved by European Commission (EC) [press release]. San Rafael, CA: BioMarin Pharmaceutical Inc.; Aug 24, 2022. https://investors.biomarin.com/2022-08-24-First-Gene-Therapy-for-Adults-with-Severe- Hemophilia-A,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by- European-Commission-EC). In phase 1/2 and phase 3 clinical trials in adult participants with severe hemophilia A, valoctocogene roxaparvovec provided sustained transgene expression sufficient for hemostasis, and participants experienced significantly lower rates of bleeding compared with baseline on FVIII prophylaxis (Rangarajan et al. N Engl J Med 2020;382:29-40; Pasi et al. Haemophilia 2021;27:947-56; Ozelo et al. N Engl J Med 2022;386:1013-25; Mahlangu et al., J. N Engl J Med 2022;388:694-705). Across both studies, the most common adverse events were alanine aminotransferase (ALT) elevations, which occurred early on study and were manageable with immunosuppressants; in the phase 3 trial, infusion-related reactions and steroid-related adverse events were also common (same as above). [8] Nonclinical investigations into the role of pre-existing immunity in AAV5-based FVIII gene therapy (valoctocogene roxaparvovec, BMN 270) in non-human primates (NHP) have demonstrated greater correlation of pre-existing TAb with decreased in vivo efficacy as measured by vector transduction and FVIII activity, compared to Transduction Inhibitors (TI, including NAb) (Long B. et al. Mol Ther Methods Clin Dev.2019; 13:440-452). As results were predictive of poor response to the therapy, the AAV5 TAb assay was determined to be the preferred assay format in screening for Hemophilia A patients most likely to receive benefit from the treatment in the clinic. AAV5 TAb positivity, estimated to be applicable to approximately 30% of Hemophilia A patients globally (Klamroth et al. Hum Gene Ther.2022; 33:432-441), was incorporated as an exclusion criterion in BMN 270 clinical studies. Interim results from the pivotal GENEr8-1 study have recapitulated findings from the NHP study, with median FVIII activity indicating gene therapy efficacy in TAb-negative but TI-positive subjects (Long et al. Interim 52-week Analysis of Immunogenicity to the Vector Capsid and Transgene-Expressed Human FVIII in GENEr8-1, a Phase 3 Clinical Study of Valoctocogene Roxaparvovec, an AAV5- Mediated Gene Therapy for Hemophilia A. WFH World Congress presentation. May 2022). Thus, the AAV5 TAb assay was selected for development as a Companion Diagnostic (CDx) to identify patients that lack plasma AAV5 antibodies in determining eligibility for treatment with BMN 270. [9] Currently, many hemophilia patients are excluded from receiving gene therapy due to seroconversion to anti-AAV antibodies. There is also likely to be a need for vector readministration in both pediatric and adult patients to enable vector titration and to increase the proportion of patients that achieve therapeutic levels of the transgene expression. Thus, there is a need for methods of administering gene therapy encoding a functionally active FVIII coding region to seropositive hemophilia patients and hemophilia patients having active or prior FVIII inhibitors. Summary of invention [10] The disclosure provides for methods of overcoming humoral immunity (i.e., antibodies) to AAV capsids, which may result from pre-existing exposure to the AAV or prior exposure to an AAV-based gene therapy vector, that can limit transduction efficiency and may pose safety concerns for AAV vectored gene therapy. [11] In one aspect of the invention, the disclosure provides for methods of using therapeutic plasma exchange (TPE) or immuno-adsorption plasmapheresis (IAP) to transiently remove or reduce levels of immunoglobulins, including AAV5 capsid specific antibodies, from the plasma of individuals who had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy. Individuals are then administered a dose of AAV5 vector gene therapy shortly after plasmapheresis while AAV5 antibody levels are absent or low, circumventing any interference. Antibodies will naturally rebound within a few days after plasmapheresis treatment; therefore, several rounds of IAP are needed per session; wherein a “round” refers to the processing of 1 plasma volume. It is contemplated that several sessions (cycles) over consecutive days may be needed to effectively reduce the pre-existing humoral immunity. [12] In one embodiment, the disclosure provides for methods of treating hemophilia in a subject comprising administering an AAV comprising a functionally active FVIII coding region wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV. In addition, the disclosure provides for use of an adeno-associated virus (AAV) vector for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region. [13] In some embodiments, the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1. In exemplary embodiments, the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2. In particular, the subject is suffering from hemophilia A. In other embodiments, the AAV is the gene therapy product referred to as FVIII-V3 which comprised the FVIII coding sequence of SEQ ID NO: 48. In some embodiments, the method further comprises subjecting the subject to at least one session of TPE or IAP prior to administration of the AAV. [14] In another aspect of the invention, the disclosure provides methods of using an IgG degrading enzyme prior to administration of the AAV to transiently remove or reduce levels of immunoglobulins, including AAV5 capsid specific antibodies, from the plasma of individuals who had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy. Individuals are then administered a dose of AAV5 vector gene therapy shortly after receiving the IgG degrading enzyme while AAV5 antibody levels are absent or low, circumventing any interference. An exemplary IgG degrading enzyme is Imlifidase (IdeS), which is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. Other IgG degrading enzymes include IdeZ, IgdE (family) and IdeP, which all cleave IgG in the hinge region. Another example are glycosidase EndoS and EndoS2, which hydrolyses the glycans on IgG Fc, thereby removing the majority of the glycans. [15] In one embodiment, the disclosure provides for methods of treating hemophilia in a subject comprising administering an IgG degrading enzyme prior to treatment with an AAV comprising a functionally active FVIII coding region wherein the subject has antibodies specific for an AAV capsid protein. The disclosure also provides for use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject has received a dose of the AAV vector prior to administration of the medicament, and wherein the AAV vector comprises a functionally active FVIII coding region. In addition, the disclosure provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises an adeno-associated virus (AAV) vector comprising a functionally active FVIII coding region and wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector. In some embodiments, the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1. In exemplary embodiments, the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48. In particular, the subject is suffering from hemophilia A. [16] Antibodies specific for an AAV capsid refer to antibodies that specifically target or bind to a capsid protein of an AAV (also referred to as “anti-AAV antibodies”). These antibodies include anti-AAV neutralizing antibodies and pre-existing anti-AAV antibodies. Neutralizing antibodies (NAbs) are antibodies which target or bind to viral epitopes that are critical for cellular entry, e,g. these antibodies reduce or inhibit virus infectivity. When anti-AAV antibodies target viral epitopes critical for cellular entry, they can block virus infectivity and are deemed neutralizing antibodies. [17] The anti-AAV antibodies are specific for or bind to a capsid protein from any AAV serotype or for a chimeric AAV capsid protein. For example, the anti-AAV antibodies specifically target or bind to a capsid protein from an AAV5, AAV6 or AAV8. The anti-AAV antibodies may be caused by natural exposure to wild-type AAV, prior AAV infection or previous administration of AAV vector gene therapy. [18] In another embodiment, the disclosure provides for methods of treating hemophilia in a subject comprising administering to a subject a second dose of an AAV comprising a functionally active FVIII coding region, wherein the subject has received a dose of the AAV prior to administration of the second dose of the AAV. The disclosure also provides for use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject has received a dose of the AAV vector prior to administration of the medicament, and wherein the AAV vector comprises a functionally active FVIII coding region. In addition, the disclosure provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises an AAV vector comprises a functionally active FVIII coding region and the subject has received a dose of the AAV vector prior to administration of the composition. In some embodiments, the method, use or composition further comprises subjecting the subject to at least one session of TPE or IAP prior to administration of the second dose of AAV. In other embodiments, the method, use or composition further comprises administering to the subject an IgG degrading enzyme prior to administration of the second dose of AAV. In exemplary embodiments, the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48. In particular, the subject is suffering from hemophilia A. In another aspect of the invention, the disclosure also provides for methods of treating hemophilia in a subject comprising administering a corticosteroid and an AAV comprising a functionally active FVIII coding region to a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV. The disclosure also provides for use of a corticosteroid and an AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV, and wherein the AAV comprises a functionally active FVIII coding region. In addition, the disclosure provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises i) a corticosteroid and ii) an AAV comprising a functionally active FVIII coding region, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV. [19] In some embodiments, the corticosteroid is administered on the day of AAV administration, or at least about 2 hours prior to administration of the AAV, or at least about 4 hours prior to administration of the AAV, or at least about 6 hours prior to administration of the AAV, or at least 12 hours prior to administration of the AAV, or at least 24 hours prior to administration of the AAV. In exemplary embodiments, the methods further comprise the step of continuing administration of a corticosteroid once a day for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 8 weeks, or at least 16 weeks, or at least 19 weeks after administration of the AAV. In some embodiments, corticosteroid is administered orally. [20] The corticosteroid may be administered at a dose in the range of 20-60 mg/day. In some embodiments, the corticosteroid is administered for a set period of time and then gradually tapered off. For example, the corticosteroid is administered for 21 days, and the dose of therapeutic corticosteroid is gradually tapered off at day 22, optionally at day 22 the therapeutic corticosteroid is administered at 40mg/day for 28 days, and at day 29 the therapeutic corticosteroid is administered at 30 mg/day for 28 days. [21] In any of the foregoing methods, uses or compositions, a corticosteroid or a non- steroidal immunosuppressive agent may be used. In certain embodiments the corticosteroid is presnisone, prednisolone, dexamethasone, prednisone, fludrocortisone or hydrocortisone. In embodiments utilizing a non-steroidal immunosuppressive agent, cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab may be used, and optionally the immunosuppressive agent is administered systemically. [22] In another aspect of the invention, the disclosure provides for methods of treating hemophilia in a subject comprising administering an effective dose of AAV to a subject with pre- existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region. The disclosure also provides for use of an effective dose of AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has pre-existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region. The disclosure also provides for compositions for use in treating hemophilia in a subject, wherein the composition comprises an effective dose of AAV ad wherein the subject has pre-existing antibodies against an AAV vector capsid prior to or at the time of administration of a therapeutic AAV, wherein the AAV comprising a functionally active FVIII coding region. In one embodiment, an effective dose of AAV-FVIII-SQ is administered to patients with severe hemophilia A having pre-existing antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. In some embodiments, the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1. In exemplary embodiments, the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48. In particular, the subject is suffering from hemophilia A. [23] In one embodiment, subjects are dosed based on the results of their AAV antibody titers as determined by a total antibody (TAb) assay. In a preferred embodiment, the antibody titers are determined by an AAV5 TAb assay. In certain embodiments, the titer cutoff for AAV treatment is ^ 100, ^ 200, ^ 500, or ^ 1000 using a proprietary AAV5 TAb screening assay. In one embodiment, an AAV5 TAb ^ 500 is used as a titer cutoff, reflecting the distribution of observed titer data for pre-existing antibodies to the AAV5 vector capsid. [24] In another aspect of the invention, the disclosure also provides for methods of treating hemophilia in a subject comprising administering an AAV to a subject having active FVIII inhibitors prior to or at the time of administration of the AAV, wherein the AAV comprises a functionally active FVIII coding region. The disclosure also provides for use of a AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV, wherein the AAV comprises a functionally active FVIII coding region. The disclosure also provides for composition for use in treating hemophilia, wherein the composition comprises an AAV comprising a functionally active FVIII coding region and wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV. In some embodiments, the AAV comprises a nucleic acid sequence comprising the functionally active FVIII coding region of SEQ ID NO: 1. In exemplary embodiments, the AAV is the gene therapy product referred to as AAV-FVIII-SQ which comprises the nucleotide sequence of SEQ ID NO: 2 or the AAV is the gene therapy product referred to FVIII-V3 which comprises the nucleotide sequence of SEQ ID NO: 48. In particular, the subject is suffering from hemophilia A. [25] FVIII inhibitors are molecules that interfere with FVIII replacement therapy and render the replacement therapy ineffective. FVIII inhibitors may be antibodies that neutralize FVIII activity (anti-FVIII NAb) or non-antibody inhibitors. Neutralizing anti-FVIII antibodies are alloantibodies that bind exogenous FVIII. For example, FVIII inhibitors interfere with the infused FVIII concentrates of the replacement therapy rendering them ineffective. [26] A subject with an “active FVIII inhibitor” is a subject having a titer of FVIII inhibitors, such as a high titer of FVIII inhibitors, a moderate titer of FVIII inhibitors or a low titer of FVIII inhibitors. FVIII inhibitors are detected and quantified using the Bethesda assay or the Nijmegen Bethesda Assay (NBA). For the NBA, 1 Bethesda unit (Bu) neutralizes about 50% of FVIII activity. A subject having a titer of less than 0.6 BU is considered to be negative for FVIII inhibitors, while titers between 0.6 BU and 2.0 BU are considered low-titer FVIII inhibitors, titer between 2.1 BU to 5.0 BU are considered moderate-titer FVIII inhibitors and titers of > 5.0 BU are considered high-titer FVIII inhibitors. [27] For example, the subject having active FVIII inhibitors has a titer of greater than about 5.0 Bu, or at least about 5.1 Bu, or at least about 5.2 Bu, or at least about 5.2 Bu, or at least about 5.3 Bu, or at least about 5.4 Bu, or at least about 5.5 Bu, or at least about 5.6 Bu, or at least about 5.7 Bu, or at least about 5.8 Bu, or at least about 5.9 Bu, or at least about 6.0 Bu, or at least about 6.5 Bu, at least about 7.0 Bu, at least about 7.5 Bu, at least about 8.0 Bu, at least about 8.5 Bu, or at least about 9.0 BU or at least about 9.5 Bu. [28] In other embodiments, the subject has FVIII inhibitors ranging from about 5.1 BU to about 8.0 Bu, or ranging from about 5.2 BU to about 8.0 Bu, or ranging from about 5.5 BU to about 8.0 Bu, or ranging from about 5.7 BU to about 8.0 Bu, or about 6.0 BU to about 9.0 Bu, or ranging from about 6.2 BU to about 9.0 Bu, or ranging from about 6.5 BU to about 9.0 Bu, or ranging from about 6.7 BU to about 6.0 Bu, or about 7.1 BU to about 9.0 Bu, or ranging from about 7.2 BU to about 9.0 Bu, or ranging from about 7.5 BU to about 9.0 Bu, or ranging from about 7.7 BU to about 9.0 Bu, or about 5.1 BU to about 7.0 Bu, or ranging from about 5.1 BU to about 7.2 Bu, or ranging from about 5.1 BU to about 7.5 Bu, or ranging from about 5.1 BU to about 7.7 Bu, or about 5.1 BU to about 6.0 Bu, or ranging from about 5.1 BU to about 6.2 Bu, or ranging from about 5.1 BU to about 6.5 Bu, or ranging from about 5.1 BU to about 6.7 Bu, or about 5.1 BU to about 9.0 Bu, or ranging from about 5.1 BU to about 9.2 Bu, or ranging from about 5.1 BU to about 9.5 Bu, or ranging from about 5.1 BU to about 9.7 Bu. [29] In other embodiments, the subject has FVIII inhibitors ranging from about 3.0 BU to about 5.0 Bu, or ranging from about 3.2 BU to about 5.0 Bu, or ranging from about 3.5 BU to about 5.0 Bu, or ranging from about 3.7 BU to about 5.0 Bu, or about 4.0 BU to about 5.0 Bu, or ranging from about 4.2 BU to about 5.0 Bu, or ranging from about 4.5 BU to about 5.0 Bu, or ranging from about 4.7 BU to about 5.0 Bu, or about 2.1 BU to about 4.0 Bu, or ranging from about 2.2 BU to about 4.0 Bu, or ranging from about 2.5 BU to about 2.0 Bu, or ranging from about 2.7 BU to about 4.0 Bu, or about 2.1 BU to about 3.0 Bu, or ranging from about 2.1 BU to about 3.2 Bu, or ranging from about 2.1 BU to about 3.5 Bu, or ranging from about 2.1 BU to about 3.7 Bu. [30] In other embodiments, the subject has FVIII inhibitors ranging from about 0.6 BU to about 2.0 Bu, or ranging from about 0.7 BU to about 2.0 Bu, or ranging from about 0.8 BU to about 2.0 Bu, or ranging from about 0.9 BU to about 2.0 Bu, or about 1.0 BU to about 2.0 Bu, or ranging from about 1.2 to about 2.0 Bu, or ranging from about 1.3 to about 2.0 BU or ranging from about 1.4 BU to about 2.0 Bu, or ranging from about 1.4 BU to about 2.0 Bu, or ranging from about 1.5 BU to about 2.0 Bu, or ranging from about 1.6 BU to about 2.0 Bu, or ranging from about 1.7 BU to about 2.0 Bu. [31] In additional embodiments, any of the disclosed methods, compositions or uses further comprise a step of subjecting the subject to TPE or IAP prior to administration of the AAV to remove the antibodies from the subject’s plasma. The subject may be subjected to at least one session of TPE or IAP, or at least two sessions of TPE or IAP or at least three sessions of TPE or IAP. [32] In additional embodiments, any of the foregoing methods, compositions or uses further comprise the step of administering a corticosteroid or a non-steroidal immunosuppressive agent therapeutically after administration of the AAV. In certain of these embodiments, the corticosteroid is presnisone, prednisolone, dexamethasone, prednisone, fludrocortisone or hydrocortisone. In other of these embodiments, the non-steroidal immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab, and optionally the immunosuppressive agent is administered systemically. [33] In any of the foregoing methods, compositions or uses, the therapeutic corticosteroid is administered to a subject having elevated alanine aminotransferase (ALT) levels after administration of the AAV compared to ALT level before administration of the AAV. For example, the ALT level is at least 1.5x the ALT level prior to administration of the AAV vector, or at least 2x the ALT level prior to administration of the AAV vector, 2.5x the ALT level prior to administration of the AAV vector, or 3x the ALT level prior to administration of the AAV vector. [34] In any of the disclosed methods, compositions or uses, the AAV is administered intravenously. In addition, in any of the disclosed methods, the AAV is administered at a dose of 6E13 vg/kg. [35] In any of the disclosed methods, compositions or uses, the subject has a residual FVIII activity ^ 1 IU/dL prior to administration of AAV. In addition, in any of the disclosed methods, administration of the AAV results in > 1 IU/dL FVIII activity, or >5 IU/dL. Brief description of drawings [36] Figure 1 provides a schematic of AAV5-hFVIII-SQ vector genome and encoded protein. Abbreviations: aa = amino acids, ITR = inverted terminal repeats, HLP= human liver promoter, Kozak = Kozak consensus sequence (GCCACC; SEQ ID NO: 49), SpA = synthetic polyA signal. [37] Figure 2 provides the percent change in leukocyte populations in PBMC from individual monkeys in study described in Example 3. [38] Figure 3 provides the fold change for baseline in cytokine values in individual animals in study described in Example 3. [39] Figure 4 provides the results from one NHP as an example that multiple rounds of IAP over multiple days enabled up to 99% reduction of anti-AAV5 TAb titers. [40] Figure 5 provides a graph showing the mean reduction in AAV5 TAb titers per day in n- 2-10 NHPs that underwent variable days of IAP. [41] Figures 6A-6B provides the AAV total antibody (TAb) titer reduction following IAP. In Fig.6A, the black dotted lines mark the beginning of each day of IAP (before the first run) while the light dotted line marks the administration of AAV5-hFIX. Fig.6B demonstrate that the depletion of IgG corresponds with declining TAb titer in nonhuman primates. [42] Figures 7A-7B: Fig.7A demonstrates antibody titer reductions following IAP is associated with improved transduction, RNA levels and protein expression. Fig 7B demonstrates vector genome DNA and RNA well correlated with peak hFIX in nonhuman primates. [43] Figure 8 provides the decision tree for AAV vector gene therapy challenge dose administration. [44] Figure 9 provides a graph showing global seroprevalence of persons with hemophilia A which are positive for AAV 5 antibodies. The upper graph shows the precent seropositive for AAV5 antibodies in the global population. The lower graph shows individual participant titers for individual participants in the global population. Mean (SD) values are for participants with quantifiable titers only: AAV2, n = 294; AAV5, n = 188; AAV6, n = 247; AAV8, n = 227; AAVrh10, n = 233. [45] Figure 10 provides a graph showing pre-existing immunity within the global populations and demonstrates that the pre-existing immunity titer are significantly lower than the treatment- emergent titers. [46] Figure 11 provides a graph showing seroprevalence of AAV5 TAb data. [47] Figures 12A provide a suggested schedule of prophylactic corticosteroid dosing in Part A of the study described in Example 6. [48] Figure 12B provides a suggested schedule of prophylactic corticosteroid dosing in Part B of the study described in Example 6. [49] Figures 13 A-13D provide data showing IdeS reduced pre-existing titers in an NHP pilot study and successful liver transduction. [50] Figures 14A-14B provide (A) a schematic of the rabbit model system to evaluate immunogenicity and AAV5 vectored gene therapy, and (B) a graph showing sensitized animals produced a range of NAb and TAb titers and were evenly distributed into IdeS and control groups. [51] Figures 15A-15C provide (A) a graph showing treatment with IdeS resulted in 99% reduction of TAb titer, and (B and C) provide graphs showing a single dose of IdeS enabled successful FIX transgene expression in sensitized rabbits. [52] Figure 16 provides a graph showing how a 99% decrease would reduce TAb titers to below a comparable CDx cutoff in hemophilia A patients. [53] Figure 17 provides the design of the study described in detail in Example 7 and the data provided in Example 8. The abbreviations in this figure are defined as follows: DMC (data monitoring committee); FVIII (factor VIII); HA (hemophilia A); Haemo-QoL-A (hemophilia- specific quality of life questionnaire for adults); wk (week). [54] Figures 18A-18B provide the data for participants having active FVIII inhibitors (part A). ALT normal range was 5–48 U/L; ALT 1.5x baseline was 45 U/L (participant 1), 24 U/L (participant 2). FVIII activity values <1.5 IU/dL were imputed as 0 and FVIII antigen values <4.7 ng/mL were imputed as 1. The abbreviations in this figure are defined as follows: ALT (alanine aminotransferase); BU (Bethesda units); CS (corticosteroid) FVIII (factor VIII); W (week). [55] Figures 19A-19B provide the data for participant having received prior FVIII inhibitors (part B). ALT normal range was 5–48 U/L; ALT 1.5x baseline, 28.5 U/L (participant 1) or 27 U/L (participant 2). Abbreviation for this figure are as follows: ALT (alanine aminotransferase); CS (corticosteroid); D (Day); FVIII (factor VIII); MMF (mycophenolate mofetil); W (week). Detailed description [56] A single intravenous dose of this codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) was infused in nine men with severe hemophilia A. These subjects were enrolled sequentially into one of three dose cohorts (6e12 vector genomes vg/kg, 2e13 vg/kg, or 6e13 vg/kg) and followed for a planned 5 years following infusion. In six of the seven subjects who received a 6e13 vg/kg dose and were followed for at least 52 weeks, there was sustained normalization of FVII activity level, and in all seven subjects, there was stabilization of hemostasis and a profound reduction in FVIII use (Rangarajan, 2017). The 3-year follow-up study of these subjects demonstrated the safety and efficacy of the gene therapy, with sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use (Pasi et al.2020) [57] The humoral response results in the generation of neutralizing anti-AAV antibodies, both pre-existing due to WT AAV exposure or antibodies generated as a result of therapeutic dose administration of recombinant AAVs. Whereas pre-existing anti-AAV antibodies might prevent the use of AAV gene therapy in a particular individual altogether, administration of recombinant AAV gives rise to quantitatively higher antibody responses even in immunologically naive patients, thereby precluding repeat dose administration. Iterative administration of AAV of the same or antigenically similar serotype, which would be beneficial in certain instances, will only be possible with therapeutic interventions that either prevent the formation of the antibody response, or subversion of existing antibody response by other means. In addition to the humoral response, a modest cellular immune response can result in the targeted ablation of transduced cells and failure to establish long-term transgene expression in some instances (Mingozzi et al., Blood.2009;114(10):2077–2086). [58] Since humoral (and cellular) immune responses are critical parameters for evaluating the efficacy and safety of AAV-based gene therapy, two separate NHP studies (described in detail in Example 2 and 3) were carried out to evaluate the impact of pre-existing, as well as de novo generated antibodies following dose administration of an AAV5 vector. The objective of the first NHP study was to determine the pharmacodynamics of gene delivery and human FVIII-SQ expression following a single bolus injection of AAV-FVIII-SQ, an investigational AAV5-based gene therapy vector for the treatment of hemophilia A, to NHPS with varying pre-existing (naturally occurring) levels of AAV5 total binding antibodies (AAV5 TAb) and antibody or non-antibody inhibitors of transduction (AAV5 TI). The objectives of the second study were to evaluate the impact of re-administration of an AAV5 vector to NHPs that had previously received the same serotype (AAV5) with high levels of antibodies generated due to intentional exposure to an AAV5 vector. Safety and transduction efficiency in NHPs with either pre-existing or treatment-induced antibodies are discussed herein. [59] The study described in Example 2 (referred to herein as Study 1) reported here was designed to characterize the safety of dosing an AAV5 vector with known anti-AAV5 titers. Transduction results from study 1 have been published elsewhere (Long et al.2019). As expected, injection of AAV-FVIII-SQ (6e13 vg/kg) to animals with pre-existing anti-AAV5 antibodies resulted in a mean decrease in maximal FVIII-SQ plasma concentration (cmax) and area under the drug concentration-time curve (AUC) of 74.8% and 66.9%, respectively, compared with non-immune control animals. In contrast, animals with only non-antibody transduction inhibitors showed FVIII-SQ plasma concentrations and liver vector copies comparable with those of controls. These findings suggest an association between pre-existing neutralizing anti-AAV5 antibody and reduced hFVIII-SQ levels. In study 1, NHPs were considered to be positive for AAV5 capsid titers, with a screening cutpoint for positivity if the signal/noise ratio was 1.70 (TAb assay). There were no adverse effects of dosing NHPs with known pre-existing AAV5 antibodies at the levels detected (TAbs ECL values up to 137.94). As expected, by day 8, all dosed animals were AAV5 antibody-positive, indicating that the onset of the AAV5 antibody response occurred rapidly after AAV-FVIII-SQ injection and with similar kinetics across all four study groups, regardless of the presence of pre-existing AAV5 immunity. Plasma from all dosed animals remained positive for AAV5 antibodies throughout the study until day 56, without any apparent effect of pre-existing AAV5 immunity. [60] The study described in Example 3 (referred to herein as study 2) was aimed at re-dosing (the same animals) with the same capsid amid higher levels of (induced) AAV5 antibody. Prior to dosing NHPs all animals (in groups 1 & 2) were negative for NAbs (<20) confirming that they were not previously exposed to AAV5. Antibody levels in group 2 animals prior to re-dosing (i.e. On study day 29) were rather high by normalized titer values (~62500) and continued to increase following the second administration, with peak titers around 312500 on study day 43. NHPs in group 2 were re-dosed shortly (29 days) after receiving the first vector on study day 1 and these animals had antibody levels around 62500 at the time of re-dosing (with AAV5-hFIX). The antibody titers continued to rise reaching 312500 on study day 43. NHPs tolerated the second dose (re-dosing) of the vector AAV5-hFIX, showing no adverse clinical signs. Additionally, there were no clinical chemistry changes or histopathologic changes in the tissues at the end of the study. [61] Expression of human FIX was observed only in AAV5-hFIX animals (group 1) that were not previously sensitized to AAV5 prior to challenge dose administration. FIX plasma protein expression was not detected in group 2 animals (as expected the AAV5 NAbs elicited after the first vector administration prevented successful transduction of the second vector, AAV5-hFIX). [62] Extrapolation of the safety findings from the studies described in examples 2 and 3 to other capsids should be done after consideration of certain key variables, including the AAV serotypes, strain or species of laboratory animals, age at dosing, and vector dose level. NHPs in these two studies received a single dose of AAV5-hFVIII-SQ at 6e13 vg/kg (study 1), while NHPs in the second study (study 2) received AAV5-cgb at 5e12 vg/kg (group 2) or a single dose of AAV5-hfix at 3e13 vg/kg (groups 1, 2). NHPs in both studies were pre-screened specifically to include animals with pre-existing titers to AAV5 (study 1) or exclude animals with pre-existing titers to AAV5 (study 2). For example, a recent study reported severe toxicity after high vector doses (2e14 vg/kg) of an AAV9 variant (AAVhu68) were administered to young rhesus monkeys (14 months old) or piglets (7/30 day old). One (of three) developed acute liver failure and shock and was euthanized 4 days after vector injection. The piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection, all three animals exhibited proprioceptive deficits and ataxia, which profoundly impaired ambulation and necessitated euthanasia. (Hinderer et al.2018). The acute toxicity in the latter study is likely due to an innate immune response rather than a humoral response to the viral capsid. Unfortunately, severe toxicity due to exacerbated innate immune response to viral vectors has been reported in the clinical setting as well (2018; Raper et al 2003). [63] In addition to humoral (antibody response) and innate immune response, administration of AAV can induce a (cytotoxic) T-cell response directed against the AAV capsid, as well as the transgene product particularly at high doses (Mingozzi et al.2007, 2009 Basner-Tschakarjan et al., 2014). A cytotoxic t-cell response, either against the capsid proteins or the transgene, is likely to be manifested by hepatic inflammation or hepatic injury, with concomitant increase in serum transaminases. Elevated transaminases (ALT or AST) were not observed in either study at any time point and with no histopathologic changes (at terminal necropsy). No IFN-^ secretion from stimulated peripheral blood mononuclear cells (PBMCS) was detected by Elispot assay in study 2 (data not shown). [64] The findings from these two studies indicate re-dosing or inadvertent dosing of an AAV5 capsid vector to NHPs with varying pre-existing antibodies was safe without any adverse findings. Extrapolation of safety finding from AAV5 to other serotypes should be used judiciously as a variety of AAV serotypes are currently being evaluated for gene therapy. FVIII Inhibitors [65] Hemophilia A (HA) a X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males. It is caused by an absence or deficiency in FVIII activity, an essential cofactor in the intrinsic coagulation pathway. Severe HA is classified as FVIII activity less than 1% of normal activity (< 1 IU/dL), moderate disease comprises 1-5% of normal activity and the mild form is 5- 40% of normal activity. The clinical manifestations of severe HA are frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially increased risk of death from hemorrhage when the brain is involved. [66] For decades, patients with HA have received infusions of replacement FVIII concentrates to prevent or treat bleeding episodes. However, the most severe treatment complication associated with this is the development of FVIII neutralizing antibodies (inhibitors). Inhibitors arise in about 35% HA patients. HA patients developing inhibitors express the clinical phenotype of severe ha, with residual FVIII activity ^ 1 IU/dL at the time of detected inhibitors. Not only do HA patients with inhibitors experience an increased number of bleeding episodes, these bleeds are difficult to manage since the usual method of achieving hemostasis through the use of FVIII infusions is rendered ineffective due to the presence of inhibitors. Bypassing agents are available as alternative therapeutic options, but they are more burdensome to administer, less effective than replacement FVIII, and/or require more frequent infusions due to extremely short half-lives. Therefore, overall morbidity and mortality is worse in inhibitor patients, in conjunction with substantially increased health care costs due to the usage of expensive bypassing agents to manage bleeds (Walsh, 2016). [67] FVIII inhibitors may be antibodies that neutralize FVIII activity or non-antibody inhibitors. Neutralizing antibodies are alloantibodies that bind exogenous FVIII. FVIII inhibitors interfere with the infused factor concentrates rendering them ineffective and necessitating the use of more costly and less effective alternative hemostatic agents. For example, the FVIII inhibitor is a polyclonal high-affinity immunoglobulin G (IgG) that is directed against the FVIII protein, such as an IgG4 antibody. The inhibitory antibodies may be directed to any against domain in the FVIII protein (FVIII contains three A domains (A1, A2, A3), one B domain and two C domains (C1, C2). Exemplary inhibitors bind to the A2, A3 and C2 domains in FVIII. Antibodies in inhibitor patients can simultaneously target multiple FVIII epitopes and these epitope targets can change over time. [68] FVIII inhibitors are classified based on the kinetics and extent of inhibition of FVIII. Type I inhibitors follow second-order kinetics (dose-dependent linear inhibition) and completely inactivate FVIII. Type II inhibitors have complex kinetics and incompletely inactivate FVIII. Type I inhibitors are more common in severe hemophilia. Type II inhibitors are more common in inhibitor patients with mild hemophilia or in patients without hemophilia who develop an acquired FVIII inhibitor. [69] FVIII inhibitors are detected and quantified using the Bethesda assay or the Nijmegen Bethesda Assays (NBA). Both assays utilize serial dilutions of a patient’s plasma that is incubated with equal volumes of normal plasma for 2 h at 37°C. For the NBA, where 1 Bethesda unit (Bu) neutralizes about 50% of FVIII activity. Measurement of less than 0.6 BU is considered to be negative for inhibitors, while assessments between 0.6 and 5.0 Bus are considered low-titer inhibitors and > 5.0 Bus are considered high-titer inhibitors. Inhibitors are most likely to develop in an HA patient during the first 20 exposure days (ed) to FVIII treatment – typically during childhood for patients with severe disease - after which, the risk decreases from 20 ed to 50 ed. After 50 ed, the risk decreases even further, reaching a very low steady- state rate of 2-5 per 1,000 patients per year after 150 ed (Hay, 2011). In later life, HA patients who have previously been stably managed with replacement FVIII products without any evidence of inhibitors may go on to subsequently develop inhibitors following periods of intensive FVIII exposure, such as may be required following major trauma or during surgical procedures. In these situations, a combination of inflammation and cytokine release through tissue damage with excessive amounts of exogenous FVIII antigen is thought to make the immune system more susceptible to develop inhibitors (Eckhardt, 2016). [70] The FVIII inhibitors are also classified as into low- or high-responding inhibitors based on a patient’s peak inhibitor titer after repeated FVIII exposure. An inhibitor titer of 5 BU differentiates low- from high-responding inhibitors (White et al.2001). An antibody titer that is persistently below 5 BU despite repeat challenges with factor VIII is considered a low- responding inhibitor. A high-responsive inhibitor is applied if the assay has been greater than 5 BU at any time (White et al.2001). [71] Once HA patients develop inhibitors, the usual treatment options to prevent bleeding are either conventional bypassing agents (BPA) or emicizumab, a novel type of BPA recently approved for use in HA. Conventional bpas are pro-thrombotic coagulation factors that augment other parts of the coagulation cascade and include activated prothrombin complex concentrate (apcc) and recombinant activated human FVIIIa (rFVIIIa). Both APCC and FVIIIa are administered intravenously, with APCC requiring every other day dosing and FVIIIa requiring dosing from 2 times per day up to 2 times per week when used as prophylaxis; as a result, many HA patients with inhibitors require surgical implantation of central venous access devices, which are associated with risks of infection, bacteremia, thrombosis, device failure, and bleeding (Campbell, 2019). Emicizumab, a bi-specific monoclonal antibody that binds FIXa and FX and is administered subcutaneously, is unaffected by anti-FVIII antibodies and hence can be used to manage HA patients with inhibitors (Oldenburg 2017). However, bpas and emicizumab both require chronic administrations and carry with them associated patient compliance issues. In addition, the inability to manage hemostasis with replacement FVIII remains for HA patients with inhibitors on emicizumab, as these patients still need episodic treatment with bpas should they experience a bleed or undergo surgery. Finally, hemostatic monitoring of bpas and emicizumab may be difficult or impossible using conventional clot-based assays. Considering the frequencies of chronic infusions and/or injections, persistent need for non-FVIII therapies to treat bleeds, and challenges associated with laboratory monitoring of bpas and emicizumab, there remains an unmet medical need for alternative therapies with reduced risk, along with improved efficacy and monitoring, for HA patients with inhibitors. [72] Immunotolerance by constant high exposure to antigen has been demonstrated in animal models since the late 1970s and is currently used in allergy clinics to desensitize allergens. In the same manner, HA patients with inhibitors undergo immune tolerance induction (ITI), which requires frequent and intensive administration of large amounts of replacement FVIII products over a prolonged period, with the goal of achieving eradication of the inhibitor to permit reinstitution of long-term FVIII prophylaxis. Whilst the optimal treatment regimen for ITI is still subject to evaluation (e.g., low-dose vs high-dose ITI; twice a day to 3 times a week administration), overall, the success rates of ITI have been reported to be in the range of 6080% of patients achieving tolerance, which in part may be due to the difficulty of being able to maintain constant, appreciable levels of FVIII to achieve tolerance, even with high-dose ITI regimens. Positive predictive parameters for successful ITI include historical peak inhibitor titer < 200 BU and pre- ITI inhibitor titer <10 BU as well as patient compliance to the ITI regimen with uninterrupted treatment schedules. Ha patients with inhibitors can experience improvement within 12 months of ITI initiation, but some patients can be on ITI for 2 or more years. However, the high cost, requirement for access to large amounts of FVIII, and treatment burden make it challenging for some HA patients with inhibitors to pursue this treatment course and in countries with limited resources to offer ITI. [73] The liver is the body’s largest organ and is highly perfused with a rich supply of blood from the hepatic artery and hepatic portal vein containing microbial products and food antigens derived from the gut. The liver parenchymal tissue and other resident cell populations are highly competent to present antigens to effector cells of the immune system. As such, the liver serves as a waystation for the confluence of normally harmless antigens and immune effector cells that necessitates a mechanism by which unwarranted immune responses are suppressed (Morris, 2017; Tiegs 2010) to this end, the healthy liver represents a tolerogenic immune environment in which the default setting is an attenuated response to most gut derived molecules and immune suppression through the generation of antigen-specific regulatory t cells (t-regs). Consequently, liver directed gene therapy that results in efficient transgene expression in liver parenchyma cells, may reduce or eliminate immune responses specific for the transgene expressed protein. It follows then that liver directed gene therapy offers the opportunity to attenuate FVIII-specific immune responses and eradicate inhibitors in hemophilia A patients. A single intravenous infusion of a vector encoding a functional FVIII gene can result in the formation of stable episomes leading to long-term endogenous production of FVIII in liver hepatocytes, and it is this stable, constant expression of FVIII protein that has the potential to induce immune tolerance. Liver-directed gene therapy utilizing AAV vectors in animal models of hemophilia has been reported to induce immune tolerance to both FVIII and fix through induction of factor-specific T- regs (Finn, 2010; Markusic, 2013; Arruda, 2016). In a canine model of hemophilia A, inhibitors are common upon exposure to normal canine plasma. Following administration of a liver directed AAV mediated gene therapy encoding for canine FVIII (cFVIII), inhibitor titers were observed to gradually decline as plasma cFVIII levels increased (Finn, 2010). Expression of cFVIII in this system appeared to result in durable immune tolerance to FVIII with a decline in inhibitor titers to undetectable levels that did not rebound upon challenge with 500 u of recombinant cFVIII. Though the precise immunological mechanisms of immune tolerance in the canine model have yet to be worked out, the decline in cFVIII inhibitors was associated with an increase in cd25+ foxp3+ cd4+ T-reg cells which are suggestive of suppression of antibody and t cell responses specific for FVIII (Arruda, 2016). Similar work in a mouse model of hemophilia b has demonstrated the development of fix specific neutralizing antibodies following repeated administration of recombinant human fix (hFIX) (Markusic, 2013). Within one month following administration of a liver directed, AAV8 mediated gene therapy encoding hFIX, inhibitor titers declined to undetectable levels. This decline in inhibitor titers was associated with a loss of anti- fix antibody secreting b cells and cytokine secreting T-helper cells. Further, adoptive transfer of T-reg cells from vector treated mice suppressed anti-hFIX antibody formation in fix challenged recipient mice, demonstrating immune tolerance is T-reg dependent. Although these pre-clinical data are encouraging, the translation of gene therapy as a means to induce immune tolerance in HA patients with inhibitors has yet to be demonstrated. Exploratory immunophenotyping of patients’ peripheral blood mononuclear cells (PBMC) by flow cytometry will investigate changes over time in cellular immune parameters, regulatory T-cell populations, and their relationship to FVIII inhibitor titers. [74] HA patients that have been able to successfully achieve immune tolerance with an ITI regimen can be re-established on a FVIII prophylaxis regimen. Additionally, there are some HA patients that only transiently express inhibitors, and these patients may also be treated with standard FVIII prophylaxis without issue. At present, these patients with a prior history of inhibitors have been excluded from clinical trials of gene therapy for ha, presumably due to concerns regarding the potential risk of a recurrence of the inhibitors, although this concern is primarily theoretical since there is no clear plausible mechanism as to why this patient group should re-develop inhibitors following gene therapy. AAV-FVIII-SQ [75] AAV-FVIII-SQ is an AAV5-based gene therapy vector that expresses the SQ form of hFVIII under the control of a hybrid human liver-specific promoter (Figure 1). The codon- optimized FVIII encoding SQ sequence referred to herein as " FVIII-SQ" is set out as SEQ ID NO: 1. AAV-FVIII-SQ is 4970 bases in length and comprises, from left to right, a modified AAV serotype 2 (AAV2) 5’ ITR, a 34 base human apolipoprotein e (ApoE)/c1 enhancer element, a 32 base human alpha anti-trypsin (AAT) promoter distal x region, a 186 base HAAT promoter, including 42 bases of 5’ untranslated region (UTR) sequence, a novel codon-optimized human FVIII sequence in which the FVIII b domain is replaced with the 14 amino acid SQ sequence, a 49 bases synthetic proudfoot polyadenylation sequence, and a modified AAV23’ITR. The 4970 bp nucleotide sequence of the recombinant AAV Proto 1 construct is provided in SEQ ID NO: 2. In an exemplary embodiment, AAV-FVIII-SQ is delivered by a single intravenous dose and is designed to achieve stable, durable expression of active hFVIII in the plasma, synthesized from vector-transduced liver tissue. Exemplary doses of AAV-FVIII-SQ include 6e12 vg/kg, 2e13 vg/kg, 4e13 vg/kg, and 6e13 vg/kg. AAV-FVIII-SQ has an acceptable safety and tolerability profile that supports a positive benefit-risk assessment. Single infusions have been generally well tolerated by treated subjects across all investigated doses. No deaths have been reported in any of the AAV-FVIII-SQ studies, and no participants discontinued from studies as a result of an ae. Frequency of adverse events decreased over time with no delayed adverse drug reactions. Infusion reactions associated with AAV-FVIII-SQ administration included symptoms such as maculopapular rash, urticaria, nausea, diarrhea, watery eyes, rigors, chills, myalgia, fever, tachycardia and hypotension emerging within 24 hours of receiving AAV-FVIII-SQ. All of these events subsided without clinical sequela within 48 hours following medical management infusion-related reactions were effectively mitigated by managing infusion rate and medications. Exemplary AAV FVIII Vectors [76] The exemplary recombinant AAV FVIII vector is described in detail in WO 2011/005968, published January 13, 2011, which is incorporated herein by reference in its entirety, and McIntosh et al. Blood 121:3335-3344, 2013, is an oversized, i.e., greater than 5.0 kb, AAV FVIII vector. This AAV FVIII vector comprises, from left to right, the AAV serotype 2 (AAV2) 5’ ITR, wild-type AAV2-derived viral sequence, a 34 base human apolipoprotein E ApoE)/c1 enhancer element, a 32 base human alpha anti-trypsin (AAT) promoter distal x region, a 186 base human AAT (hAAT) promoter, including 42 bases of 5’ untranslated region (UTR) sequence, a codon- optimized human FVIII sequence in which the FVIII b domain is replaced with the 14 amino acid SQ sequence, a 49 bases synthetic proudfoot polyadenylation sequence, wild-type AAV2- derived viral sequence, and the AAV23’ ITR. This vector is 5081 bases in length and, as shown in WO 2011/005968, expresses functionally active FVIII both in vitro and in vivo. [77] In addition, any of the disclosed methods may comprise the step of administering the following FVIII AAV: Proto1S (SEQ ID NO: 3), Proto 2S (SEQ ID NO: 4), Proto 3S (SEQ ID NO: 5), Proto 4 (SEQ ID NO: 6), Proto 5 (SEQ ID NO: 7), Proto 6 (SEQ ID NO: 8), Proto 7 (SEQ ID NO: 9), Construct 100ATG (SEQ ID NO: 10), Construct 100ATG bGH poly A (SEQ ID NO: 11), Construct 100ATG short bGH poly A (SEQ ID NO: 12), Construct 103ATG (SEQ ID NO: 13), Construct 103ATG short bGH poly A (SEQ ID NO: 14), Construct 105ATG short bGH poly A (SEQ ID NO: 15), Construct DC172ATG FVIII (SEQ ID NO:16), Construct DC172ATG FVIII hAAT (SEQ ID NO: 17), Construct DC1722xHCR ATG FVIII (SEQ ID NO: 18), Construct DC1722xHCR ATG FVIII hAAT (SEQ ID NO: 19), Construct 2x SerpinA hAAT ATG FVIII (SEQ ID NO: 20), Construct 2x SerpinA hAAT ATG FVIII 2x ^-globulin enhancer (SEQ ID NO: 21), Construct 100ATG short bGH poly A 2x ^-globulin enhancer (SEQ ID NO: 22), Construct Factor VIII-BMN001 (SEQ ID NO: 23), Construct Factor VIII-BMN002 (SEQ ID NO: 24), Construct 99 (SEQ ID NO: 25), Construct 100 (SEQ ID NO: 26), Construct 100 reverse orientation (SEQ ID NO: 27), Construct 100AT (SEQ ID NO: 28), Construct 100AT 2x MG (SEQ ID NO: 29), Construct 100AT 2x MG bGH poly A (SEQ ID NO: 30), Construct 100AT 2x MG (reverse) bGH poly A (SEQ ID NO: 31), Construct 100 bGH poly A (SEQ ID NO: 32), Construct 100-400 (SEQ ID NO: 33), Construct 101 (SEQ ID NO: 34), Construct 102 (SEQ ID NO: 35), Construct 103 (SEQ ID NO: 36), Construct 103 reverse orientation (SEQ ID NO: 37), Construct 103AT (SEQ ID NO: 38), Construct 103AT 2x MG (SEQ ID NO: 39), Construct 103AT 2x MG bGH poly A (SEQ ID NO: 40), Construct 103 bGH poly A (SEQ ID NO: 41), Construct 104 (SEQ ID NO: 42), Construct 105 (SEQ ID NO: 43), Construct 106 (SEQ ID NO: 44), Construct 106AT (SEQ ID NO: 45), and Construct 2x SerpinA hAAT (SEQ ID NO: 46). [78] An additional exemplary recombinant AAV FVIII vector is described in detail in WO 2013/186563, published December 19, 2013, which is incorporated herein by reference in its entirety. In particular, the AAV FVIII vector comprises a nucleotide sequence encoding for a functional factor VIII protein, wherein the portion of the nucleotide sequence encoding for the B domain of the factor VIII protein is between 90 and 111 base pairs in length and comprises a sequence having at least 95% identity to the nucleotide sequence of SEQ ID NO: 47 and which encodes for six asparagine residues, such as the nucleotide sequence encoding for a functional FVIII protein comprising the nucleotide sequence of SEQ ID NO: 48. AAV Vectors [79] As used herein, the term "AAV" is a standard abbreviation for adeno-associated virus. Adeno-associated virus is a single-stranded DNA parvovirus that grows only in cells in which certain functions are provided by a co-infecting helper virus. There are currently thirteen serotypes of AAV that have been characterized, as shown below in Table 1. General information and reviews of AAV can be found in, for example, Carter, 1989, Handbook of Parvoviruses, Vol.1, pp.169-228, and Berns, 1990, Virology, pp.1743-1764, Raven Press, (New York). However, it is fully expected that these same principles will be applicable to additional AAV serotypes since it is well known that the various serotypes are quite closely related, both structurally and functionally, even at the genetic level. (See, for example, Blacklowe, 1988, pp.165-174 of Parvoviruses and Human Disease, J. R. Pattison, ed.; and Rose, Comprehensive Virology 3:1-61 (1974)). For example, all AAV serotypes apparently exhibit very similar replication properties mediated by homologous rep genes; and all bear three related capsid proteins. The degree of relatedness is further suggested by heteroduplex analysis which reveals extensive cross-hybridization between serotypes along the length of the genome; and the presence of analogous self-annealing segments at the termini that correspond to "inverted terminal repeat sequences" (ITRs). The similar infectivity patterns also suggest that the replication functions in each serotype are under similar regulatory control. [80] An "AAV vector" as used herein refers to a vector comprising one or more polynucleotides of interest (or transgenes) that are flanked by one or more AAV terminal repeat sequences (ITRs) and operably linked to one or more expression control elements. Such AAV vectors can be replicated and packaged into infectious viral particles when present in a host cell that has been transfected with a vector encoding and expressing rep and cap gene products. [81] An "AAV virion" or "AAV viral particle" or "AAV vector particle" refers to a viral particle composed of at least one AAV capsid protein and an encapsidated polynucleotide AAV vector. If the particle comprises a heterologous polynucleotide (i.e. a polynucleotide other than a wild- type AAV genome such as a transgene to be delivered to a mammalian cell), it is typically referred to as an "AAV vector particle" or simply an "AAV vector". Thus, production of AAV vector particle necessarily includes production of AAV vector, as such a vector is contained within an AAV vector particle. [82] AAV "rep" and "cap" genes are genes encoding replication and encapsidation proteins, respectively. AAV rep and cap genes have been found in all AAV serotypes examined to date, and are described herein and in the references cited. In wild-type AAV, the rep and cap genes are generally found adjacent to each other in the viral genome (i.e., they are "coupled" together as adjoining or overlapping transcriptional units), and they are generally conserved among AAV serotypes. AAV rep and cap genes are also individually and collectively referred to as "AAV packaging genes." The AAV cap genes in accordance with the present invention encode Cap proteins which are capable of packaging AAV vectors in the presence of rep and adeno helper function and are capable of binding target cellular receptors. In some embodiments, the AAV cap gene encodes a capsid protein having an amino acid sequence derived from a particular AAV serotype, for example the serotypes shown in Table 1. Table 1. AAV serotypes AAV Serotype Genbank Accession No. AAV-1 NC_002077.1 AAV-2 NC_001401.2 AAV-3 NC_001729.1 AAV-3B AF028705.1 AAV-4 NC_001829.1 AAV-5 NC_006152.1 AAV-6 AF028704.1 AAV-7 NC_006260.1 AAV-8 NC_006261.1 AAV-9 AX753250.1 AAV-10 AY631965.1 AAV-11 AY631966.1 AAV-12 DQ813647.1 AAV-13 EU285562.1 [83] The AAV sequences employed for the production of AAV can be derived from the genome of any AAV serotype. Generally, the AAV serotypes have genomic sequences of significant homology at the amino acid and the nucleic acid levels, provide a similar set of genetic functions, produce virions which are essentially physically and functionally equivalent, and replicate and assemble by practically identical mechanisms. For the genomic sequence of AAV serotypes and a discussion of the genomic similarities see, for example, GenBank Accession number U89790; GenBank Accession number J01901; GenBank Accession number AF043303; GenBank Accession number AF085716; Chiorini et al., J. Vir.71: 6823-33(1997); Srivastava et al., J. Vir.45:555-64 (1983); Chiorini et al., J. Vir.73:1309-1319 (1999); Rutledge et al., J. Vir.72:309-319 (1998); and Wu et al., J. Vir.74: 8635-47 (2000). [84] The genomic organization of all known AAV serotypes is very similar. The genome of AAV is a linear, single-stranded DNA molecule that is less than about 5,000 nucleotides (nt) in length. Inverted terminal repeats (ITRs) flank the unique coding nucleotide sequences for the non-structural replication (Rep) proteins and the structural (VP) proteins. The VP proteins form the capsid. The terminal 145 nt are self-complementary and are organized so that an energetically stable intramolecular duplex forming a T-shaped hairpin may be formed. These hairpin structures function as an origin for viral DNA replication, serving as primers for the cellular DNA polymerase complex. The Rep genes encode the Rep proteins, Rep78, Rep68, Rep52, and Rep40. Rep78 and Rep68 are transcribed from the p5 promoter, and Rep 52 and Rep40 are transcribed from the p19 promoter. The cap genes encode the VP proteins, VP1, VP2, and VP3. The cap genes are transcribed from the p40 promoter. The ITRs employed in the vectors of the present invention may correspond to the same serotype as the associated cap genes, or may differ. In a particularly preferred embodiment, the ITRs employed in the vectors of the present invention correspond to an AAV2 serotype and the cap genes correspond to an AAV5 serotype. [85] In some embodiments, a nucleic acid sequence encoding an AAV capsid protein is operably linked to expression control sequences for expression in a specific cell type, such as Sf9 or HEK cells. Techniques known to one skilled in the art for expressing foreign genes in insect host cells or mammalian host cells can be used to practice the invention. Methodology for molecular engineering and expression of polypeptides in insect cells is described, for example, in Summers and Smith.1986. A Manual of Methods for Baculovirus Vectors and Insect Culture Procedures, Texas Agricultural Experimental Station Bull. No.7555, College Station, Tex.; Luckow.1991. In Prokop et al., Cloning and Expression of Heterologous Genes in Insect Cells with Baculovirus Vectors' Recombinant DNA Technology and Applications, 97-152; King, L. A. and R. D. Possee, 1992, The baculovirus expression system, Chapman and Hall, United Kingdom; O'Reilly, D. R., L. K. Miller, V. A. Luckow, 1992, Baculovirus Expression Vectors: A Laboratory Manual, New York; W.H. Freeman and Richardson, C. D., 1995, Baculovirus Expression Protocols, Methods in Molecular Biology, volume 39; U.S. Pat. No.4,745,051; US2003148506; and WO 03/074714. A particularly suitable promoter for transcription of a nucleotide sequence encoding an AAV capsid protein is e.g. the polyhedron promoter. However, other promoters that are active in insect cells are known in the art, e.g. the p10, p35 or IE-1 promoters and further promoters described in the above references are also contemplated. [86] Use of insect cells for expression of heterologous proteins is well documented, as are methods of introducing nucleic acids, such as vectors, e.g., insect-cell compatible vectors, into such cells and methods of maintaining such cells in culture. See, for example, METHODS IN MOLECULAR BIOLOGY, ed. Richard, Humana Press, NJ (1995); O'Reilly et al., BACULOVIRUS EXPRESSION VECTORS, A LABORATORY MANUAL, Oxford Univ. Press (1994); Samulski et al., J. Vir.63:3822-8 (1989); Kajigaya et al., Proc. Nat'l. Acad. Sci. USA 88: 4646-50 (1991); Ruffing et al., J. Vir.66:6922-30 (1992); Kirnbauer et al., Vir.219:37-44 (1996); Zhao et al., Vir.272:382-93 (2000); and Samulski et al., U.S. Pat. No.6,204,059. In some embodiments, the nucleic acid construct encoding AAV in insect cells is an insect cell- compatible vector. An "insect cell-compatible vector" or "vector" as used herein refers to a nucleic acid molecule capable of productive transformation or transfection of an insect or insect cell. Exemplary biological vectors include plasmids, linear nucleic acid molecules, and recombinant viruses. Any vector can be employed as long as it is insect cell-compatible. The vector may integrate into the insect cells genome but the presence of the vector in the insect cell need not be permanent and transient episomal vectors are also included. The vectors can be introduced by any means known, for example by chemical treatment of the cells, electroporation, or infection. In some embodiments, the vector is a baculovirus, a viral vector, or a plasmid. In a more preferred embodiment, the vector is a baculovirus, i.e. the construct is a baculoviral vector. Baculoviral vectors and methods for their use are described in the above cited references on molecular engineering of insect cells. [87] Baculoviruses are enveloped DNA viruses of arthropods, two members of which are well known expression vectors for producing recombinant proteins in cell cultures. Baculoviruses have circular double-stranded genomes (80-200 kbp) which can be engineered to allow the delivery of large genomic content to specific cells. The viruses used as a vector are generally Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) or Bombyx mori (Bm)NPV) (Kato et al., 2010). [88] Baculoviruses are commonly used for the infection of insect cells for the expression of recombinant proteins. In particular, expression of heterologous genes in insects can be accomplished as described in for instance U.S. Pat. No.4,745,051; Friesen et al (1986); EP 127,839; EP 155,476; Vlak et al (1988); Miller et al (1988); Carbonell et al (1988); Maeda et al (1985); Lebacq-Verheyden et al (1988); Smith et al (1985); Miyajima et al (1987); and Martin et al (1988). Numerous baculovirus strains and variants and corresponding permissive insect host cells that can be used for protein production are described in Luckow et al (1988), Miller et al (1986); Maeda et al (1985) and McKenna (1989). Pharmaceutical Formulations [89] In other embodiments, the present invention is directed to pharmaceutical formulations of FVIII AAV vectors/virions useful for administration to subjects suffering from hemophilia A. In certain aspects, the pharmaceutical formulations of the present invention are liquid formulations that comprise recombinant AAV FVIII virions produced from the vectors disclosed herein, wherein the concentration of recombinant AAV FVIII virions in the formulation may vary widely. In certain embodiments, the concentration of recombinant AAV FVIII virion in the formulation may range from 1E12 vg/ml to 2E14 vg/ml. In a particularly preferred embodiment, the concentration of recombinant AAV FVIII virion in the formulation is about 2E13 vg/ml. In another preferred embodiment, the recombinant AAV FVIII virion present in the formulation is AAV5-FVIII-SQ derived from encapsidation of the Proto 1 vector shown schematically in Figure 1 in an AAV5 capsid. [90] In other aspects, the AAV FVIII pharmaceutical formulation of the invention comprises one or more pharmaceutically acceptable excipients to provide the formulation with advantageous properties for storage and/or administration to subjects for the treatment of hemophilia A. In certain embodiments, the pharmaceutical formulations of the present invention are capable of being stored at ^ 65oC for a period of at least 2 weeks, preferably at least 4 weeks, more preferably at least 6 weeks and yet more preferably at least about 8 weeks, without detectable change in stability. In this regard, the term "stable" means that the recombinant AAV FVIII virus present in the formulation essentially retains its physical stability, chemical stability and/or biological activity during storage. In certain embodiments of the present invention, the recombinant AAV FVIII virus present in the pharmaceutical formulation retains at least about 80% of its biological activity in a human patient during storage for a determined period of time at -65oC, more preferably at least about 85%, 90%, 95%, 98% or 99% of its biological activity in a human patient. [91] In certain aspects, the formulation comprising recombinant AAV FVIII virions further comprises one or more buffering agents. For example, in various aspects, the formulation of the present invention comprises sodium phosphate dibasic at a concentration of about 0.1 mg/ml to about 3 mg/ml, about 0.5 mg/ml to about 2.5 mg/ml, about 1 mg/ml to about 2 mg/ml, or about 1.4 mg/ml to about 1.6 mg/ml. In a particularly preferred embodiment, the AAV FVIII formulation of the present invention comprises about 1.42 mg/ml of sodium phosphate, dibasic (dried). Another buffering agent that may find use in the recombinant AAV FVIII formulations of the present invention is sodium phosphate, monobasic which, in some embodiments, finds use at a concentration of from about 0.1 mg/ml to about 3 mg/ml, about 0.5 mg/ml to about 2.5 mg/ml, about 1 mg/ml to about 2 mg/ml, or about 1.3 mg/ml to about 1.5 mg/ml. In a particularly preferred embodiment, the AAV FVIII formulation of the present invention comprises about 1.38 mg/ml of sodium phosphate, monobasic. In a yet more particularly preferred embodiment of the present invention, the recombinant AAV FVIII formulation of the present invention comprises about 1.42 mg/ml of sodium phosphate, dibasic and about 1.38 mg/ml of sodium phosphate, monobasic. [92] In another aspect, the recombinant AAV FVIII formulation of the present invention may comprise one or more isotonicity agents, such as sodium chloride, preferably at a concentration of about 1 mg/ml to about 20 mg/ml, for example, about 1 mg/ml to about 10 mg/ml, about 5 mg/ml to about 15 mg/ml, or about 8 mg/ml to about 20 mg/ml. In a particularly preferred embodiment, the formulation of the present invention comprises about 8.18 mg/ml sodium chloride. Other buffering agents and isotonicity agents known in the art are suitable and may be routinely employed for use in the formulations of the present disclosure. [93] In another aspect, the recombinant AAV FVIII formulations of the present invention may comprise one or more bulking agents. Exemplary bulking agents include without limitation mannitol, sucrose, dextran, lactose, trehalose, and povidone (PVP K24). In certain preferred embodiments, the formulations of the present invention comprise mannitol, which may be present in an amount from about 5 mg/ml to about 40 mg/ml, or from about 10 mg/ml to about 30 mg/ml, or from about 15 mg/ml to about 25 mg/ml. In a particularly preferred embodiment, mannitol is present at a concentration of about 20 mg/ml. [94] In yet another aspect, the recombinant AAV FVIII formulations of the present invention may comprise one or more surfactants, which may be non-ionic surfactants. Exemplary surfactants include ionic surfactants, non-ionic surfactants, and combinations thereof. For example, the surfactant can be, without limitation, TWEEN 80 (also known as polysorbate 80, or its chemical name polyoxyethylene sorbitan monooleate), sodium dodecylsulfate, sodium stearate, ammonium lauryl sulfate, TRITON AG 98 (Rhone-Poulenc), poloxamer 407, poloxamer 188 and the like, and combinations thereof. In a particularly preferred embodiment, the formulation of the present invention comprises poloxamer 188, which may be present at a concentration of from about 0.1 mg/ml to about 4 mg/ml, or from about 0.5 mg/ml to about 3 mg/ml, from about 1 mg/ml to about 3 mg/ml, about 1.5 mg/ml to about 2.5 mg/ml, or from about 1.8 mg/ml to about 2.2 mg/ml. In a particularly preferred embodiment, poloxamer 188 is present at a concentration of about 2.0 mg/ml. [95] In a particular preferred embodiment of the present invention, the pharmaceutical formulation of the present invention comprises AAV5-FVIII-SQ formulated in a liquid solution that comprises about 1.42 mg/ml of sodium phosphate, dibasic, about 1.38 mg/ml of sodium phosphate, monobasic monohydrate, about 8.18 mg/ml sodium chloride, about 20 mg/ml mannitol and about 2 mg/ml poloxamer 188. [96] The recombinant AAV FVIII virus-containing formulations of the present disclosure are stable and can be stored for extended periods of time without an unacceptable change in quality, potency, or purity. In one aspect, the formulation is stable at a temperature of about 5oC (e.g., 2oC to 8oC) for at least 1 month, for example, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or more. In another aspect, the formulation is stable at a temperature of less than or equal to about -20oC for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more. In another aspect, the formulation is stable at a temperature of less than or equal to about -40oC for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more. In another aspect, the formulation is stable at a temperature of less than or equal to about -60oC for at least 6 months, for example, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or more. Methods Of Treatment [97] In certain embodiments, the present invention is directed to methods for treating a subject suffering from hemophilia A comprising administering to that subject a therapeutically effective amount of an AAV FVIII vector, recombinant AAV FVIII virus or a pharmaceutical composition comprising the same. In yet other embodiments, the present invention is directed to methods for reducing bleeding time during a bleeding episode in a subject suffering from hemophilia A comprising administering to that subject a therapeutically effective amount of an AAV FVIII vector, recombinant AAV FVIII virus or a pharmaceutical composition comprising the same. In this regard, a "therapeutically effective amount", in reference to the treatment of hemophilia A or for use in a method for reducing bleeding time during a bleeding episode in a subject suffering from hemophilia A, refers to an amount capable of invoking one or more of the following effects: (1) reduction, inhibition, or prevention, to some extent, of one or more of the physiological symptoms of hemophilia A including, for example, bruising, joint pain or swelling, prolonged headache, vomiting or fatigue, (2) improvement in the capability to clot blood, (3) reduction of overall bleeding time during a bleeding episode, (4) administration resulting in a measurable increase in the concentration or activity of functional FVIII protein in the plasma of a subject, and/or (5) relief, to some extent, of one or more symptoms associated with the disorder. A "therapeutically effective amount" of an AAV FVIII vector or virus or a pharmaceutical composition comprising the same for purposes of treatment as described herein may be determined empirically and in a routine manner. In certain embodiments, however, a "therapeutically effective amount" of recombinant AAV FVIII virus ranges from about 1E12 vg/kg body weight to about 1E14 vg/kg body weight, preferably from about 6E12 vg/kg body weight to about 6E13 vg/kg body weight. In a particularly preferred embodiment, a therapeutically effective amount of recombinant AAV FVIII virus is about 2E13 vg/kg body weight. In another particularly preferred embodiment, a therapeutically effective amount of recombinant AAV FVIII virus is about 6E13 vg/kg body weight. [98] Recombinant AAV FVIII vectors/virus of the present invention may be administered to a subject, preferably a mammalian subject, more preferably a human subject, through a variety of known administration techniques. In a preferred embodiment, the recombinant AAV FVIII gene therapy virus is administered by intravenous injection either as a single bolus or over a prolonged time period, which may be at least about 1, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210 or 240 minutes, or more. In a particularly preferred embodiment of the present invention, the recombinant AAV FVIII virus administered is AAV5-FVIII-SQ. [99] Administration of a recombinant AAV FVIII vector/virus, or pharmaceutical formulation comprising the same, of the present invention preferably results in an increase in functional FVIII protein activity in the plasma of the subject of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more IU/dl as compared to the amount of functional FVIII protein activity present in the plasma in the subject prior to administration. In certain embodiments, administration of a recombinant AAV FVIII vector/virus, or pharmaceutical formulation comprising the same, of the present invention results in the expression of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more IU/dl of functional FVIII protein activity in the plasma of the subject. In this regard, the term "IU" or "international unit" in regards to FVIII activity is a well understood and accepted term, wherein 1 IU of FVIII activity is equivalent to the quantity of FVIII in one ml of normal human plasma. FVIII activity in the plasma may be quantitatively determined by a number of well-known and accepted assays including, for example, the activated partial thromboplastin time (APPT) method (see, e.g., Miletich JP: Activated partial thromboplastin time. In Williams Hematology. Fifth edition. Edited by E Beutler, MA Lichtman, BA Coller, TJ Kipps. New York, McGraw-Hill, 1995, pp L85-86, Greaves and Preston, Approach to the bleeding patient. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, JB Lippincott Co, 2001, pp 1197-1234 and Olson et al, Arch. Pathol. Lab. Med.122:782-798 (1998)) or chromogenic FXa assay (Harris et al., Thromb. Res.128(6):125-129 (2011)). [100] In other embodiments of the present invention, bleeding time in a subject may be measured by well-known and accepted techniques including, for example, the Ivy method (see, e.g., Ivy et al., Surg. Gynec. Obstet.60:781 (1935) and Ivy et al., J. Lab. Clin. Med.26:1812 (1941)) or the Duke method (see, e.g., Duke et al., JAMA 55:1185 (1910)). A "bleeding episode" in a subject refers to an injury that results in bleeding in the subject, either externally or internally, and generally comprises the time period from injury to formation of a blood clot. [101] Administration of an AAV FVIII virus of the present invention may, in some cases, result in an observable degree of hepatotoxicity. Hepatotoxicity may be measured by a variety of well- known and routinely used techniques for example, measuring concentrations of certain liver- associated enzyme(s) (e.g., alanine transaminase, ALT) in the bloodstream of a subject both prior to AAV FVIII administration (i.e., baseline) and after AAV FVIII administration. An observable increase in ALT concentration after AAV FVIII administration (as compared to prior to administration) is indicative of drug-induced hepatotoxicity. In certain embodiments of the present invention, in addition to administration of a therapeutically effective amount of AAV FVIII virus, the subject may be treated either prophylactically, therapeutically, or both with a corticosteroid to prevent and/or treat any hepatotoxicity associated with administration of the AAV FVIII virus. "Prophylactic" corticosteroid treatment refers to the administration of a corticosteroid to prevent hepatotoxicity and/or to prevent an increase in measured ALT levels in the subject. In addition, prophylactic corticosteroid treatment is administered before hepatoxicity is detected in the subject or prior to an elevation of ALT levels, such as at the time of administration of the AAV FVIII. "Therapeutic" corticosteroid treatment refers to the administration of a corticosteroid to reduce hepatotoxicity caused by administration of an AVV FVIII virus and/or to reduce an elevated ALT concentration in the bloodstream of the subject caused by administration of an AAV FVIII virus. In certain embodiments, prophylactic or therapeutic corticosteroid treatment may comprise administration of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more mg/day of the corticosteroid to the subject. In certain embodiments, prophylactic or therapeutic corticosteroid treatment of a subject may occur over a continuous period of at least about 3, 4, 5, 6, 7, 8, 9, 10 weeks, or more. Corticosteroids that find use in the methods described herein include any known or routinely employed corticosteroid including, for example, dexamethasone, prednisone, fludrocortisone, hydrocortisone, and the like. Detection of Antibodies [102] Seroconversion refers to the development of detectable antibodies in the serum of the subject, such as the subject develops antibodies to AAV capsid protein and/or antibodies to exogenous FVIII. To evaluate antibody level consistency over time, a re-test procedure will be requested at either 12 or 24 weeks (± 2 weeks) after initial testing (baseline). This re-test will follow the same biospecimen collection procedures as the initial testing. After the initial baseline measurement has become available, subjects will be randomized in a 1:1 ratio for the timing of re-testing at either 12 or 24 weeks (± 2 weeks) after initial testing (baseline). Subjects who are exposed to AAV vector gene therapy during the course of the study will be discontinued from the study. Subjects are allowed to have blood re-drawn to obtain a valid seroprevalence measurement. [103] Seroprevalance refers to the number of persons in a population who test positive for a antibodies to a specific antigen. [104] Prior to administration of an AAV vector in a therapeutic regimen to a human patient as described above, the prospective patient may be assessed for the presence of anti-AAV capsid antibodies, AAV neutralizing antibodies and FVIII inhibitors that are capable of blocking cell transduction or otherwise reduce the overall efficiency of the therapeutic regimen. Such antibodies may be present in the serum of the prospective patient and may be directed against an AAV capsid of any serotype or FVIII produced by the AAV vector. In one embodiment, the serotype against which pre-existing antibodies are directed is AAV5. [105] In general, the determination of the presence of anti-AAV may be determined utilizing an immunofluorescence assay, an immunohistochemical assay, a Western blot, a direct enzyme-linked immunosorbent assay (ELISA), an indirect ELISA, a sandwich ELISA, a competitive ELISA, a reverse ELISA, a chemiluminescence assay, a radioimmunoassay, or an immunoprecipitation assay. [106] In particular, methods to detect pre-existing AAV immunity are well known and routinely employed in the art and include cell-based in vitro transduction inhibition (TI) assays, in vivo (e.g., in mice) TI assays, and ELISA-based detection of total anti-capsid antibodies (TAb) (see, e.g., Masat et al., Discov. Med.15:379-389 (2013) and Boutin et al., Hum. Gene Ther.21:704- 712 (2010)). TI assays may employ host cells into which an AAV-inducible reporter vector has been previously introduced. The reporter vector may comprise an inducible reporter gene such as GFP, etc. whose expression is induced upon transduction of the host cell by an AAV virus. Anti-AAV antibodies present in human serum that are capable of preventing/reducing host cell transduction would thereby reduce overall expression of the reporter gene in the system. Therefore, such assays may be employed to detect the presence of anti-AAV antibodies in human serum that are capable of preventing/reducing cell transduction by the therapeutic FVIII AAV virus. [107] TAb assays to detect anti-AAV antibodies may employ solid-phase-bound AAV capsid as a "capture agent" over which human serum is passed, thereby allowing anti-capsid antibodies present in the serum to bind to the solid-phase-bound capsid "capture agent". Once washed to remove non-specific binding, a "detection agent" may be employed to detect the presence of anti-AAV antibodies bound to the capture agent. The detection agent may be an antibody, an AAV capsid, or the like, and may be detectably labeled to aid in detection and quantitation of bound anti-capsid antibody. In one embodiment, the detection agent is labeled with ruthenium or a ruthenium-complex that may be detected using electrochemiluminescence techniques and equipment. [108] The same above-described methodology may be employed to assess and detect the generation of an anti-AAV immune response in a patient previously treated with a therapeutic AAV virus of interest. As such, not only may these techniques be employed to assess the presence of anti-AAV antibodies prior to treatment with a therapeutic FVIII AAV virus, they may also be employed to assess and measure the induction of an immune response against the administered therapeutic FVIII AAV virus after administration. As such, the present invention contemplates methods that combine techniques for detecting anti-AAV capsid antibodies in human serum and administration of a therapeutic FVIII AAV virus for the treatment of hemophilia A, wherein the techniques for detecting anti-AAV antibodies in human serum may be performed either prior to or after administration of the therapeutic FVIII AAV virus. Therapeutic Apheresis [109] Therapeutic apheresis refers to the process of separating the cellular and soluble components of blood, such as removing plasma based on specific gravity. For example, therapeutic apheresis is therapeutic plasma exchange (TPE) or plasmapheresis. TPE is an extracorporal blood purification technique designed to remove high molecular weight substances, such as antibodies. In the TPE process, whole blood is removed via vascular access and subsequently spun through a centrifuge within the apheresis machine, where the plasma (antibodies) is removed. Alternatively, the whole blood is removed using highly permeable membranes. Red blood cells are delivered back along with a replacement fluid (Human Albumin) for maintenance fluid for the subject, e.g. a plasma surrogate such as 3% albumin solution. Alternatively, after removal of the plasma, the plasma undergoes treatment and then is returned to the circulation of the subject. [110] The amount of plasma to be exchanged in a TPE session is determined in relation to the subject’s estimated plasma volume (EPV). A number of formulas may be used to calculate the EPV (see, e.g. Inkley et al., J. Lab Clin. Med.45:841-850, 1955, Retzlaff et al., Blood 33: 649-887, 1969, Feldschuh et al., Circulation 56: 605-612, 1977). An exemplary method of estimating the EPV is calculated using the subject’s weight and hematocrit according to the following formula which is described in Kaplan et al. Kidney Intl.38:160-166, 1990, which is incorporated by reference herein in its entirety. [111] The TPE is carried out with techniques incorporating blood bank procedures using selective cell removal (cytopheresis) as described in Gurland et al., Int. J. Artif Organs 7:35-38, 1984, or using membrane plasma separation (MPS) which uses a highly permeable filter and dialysis equipment as described in Gurland et al., Nephron 36:173-182, 1984. Additional methods of carrying out TPE are described in Sowada et al. (Available removal systems: state of the art. In Nydegger UE, editor. Therapeuitc Hemapheresis in the 1990s. Current Studies in Hematology and Blood Transfusions, Vol 57. Basal Switzerland: Karger.1990 pp.57-113). These references are incorporated herein by reference in their entirety. [112] For example, methods of subjecting a subject’s plasma to TPE removes at least about 50% of anti-AAV antibodies within the intravascular space of the subject, or removes at least about 55% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 60% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 70% of anti-AAV antibodies or FVIII inhibitors or removes at least about 80% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 90% of anti-AAV antibodies or FVIII inhibitors, or removes at least about 95% of anti-AAV antibodies or FVIII inhibitors in the plasma of the subject or removes at least about 99% of anti-AAV antibodies or FVIII inhibitors in the plasma of the subject. [113] The disclosed methods comprising subjecting the subject’s plasma to at least one TPE session, or at least two TPE sessions, or at least three TPE sessions, or at least four TPE sessions. In addition, the TPE sessions are carried out once a day over about 1 to 5 days, or about 1 to 10 days, or about 5 to 10 days, or about 5 to 7 days or about 7 to 10 days. The TPE sessions are carried out once a day for two consecutive days, or once a day for three consecutive days or once a day for four consecutive days for 5 consecutive days, or once a day for 6 consecutive days, or once a day for 7 consecutive days, or once a day for 7 consecutive days, or once a day for 8 consecutive days, or once a day for 9 consecutive days or once a day for 10 consecutive days. Immunoadsorption plasmapheresis (IAP) [114] Immunoadsorption plasmapheresis (IAP) is an autologous plasma exchange, which separates plasma from blood cells as described about for TPE. However, in IAP antibodies are selectively removed from the plasma, and the antibody depleted plasma is then returned to the subject. In IAP the removal of antibodies results in also removing protective antibodies; however, this technique also reduces the risk. IAP removes about ^80% of total Ig in plasma after one session, increasing to ~98% after multiple sessions. IAP exchanges about 2-3 plasma volumes per treatment session. [115] Multiple studies have supported the use of plasma filtering methods for the removal of anti-AAV antibodies in vitro (in non-clinical species including mice, rats and monkeys) as well as clinically (Kaspryk et al. Mol. Ther.2022, Majowicz et al., Mol. Ther.14:27-38, 2017, Orlowski et al., Mol. Ther.2020, Bertin et al., Nat. Sci. Reports 10:264, 2020; Monteilhet et al. Mol. Ther. 2011). UniQure presented a study in 2017 wherein immune adsorption in NHP resulted in the depletion of high-titer anti-AAV5 antibodies by >90%, allowing successfully redosing with a second AAV vector (Majowicz et al., Mol. Ther.14:27-38, 2017). Bertin et al. demonstrated that plasmapheresis allows for AAV vector readministration in non-human primates and efficient removal of capsid-specific antibody through use of Sepharose matrix crosslinked to AAV8 capsids (Bertin et al., Nat. Sci. Reports 10:264, 2020). [116] In order to selectively remove the antibodies from the plasma of a subject, the plasma is filtered through an affinity column that binds immunoglobulins. For example, the affinity columns may be a porous matrix coated with recombinant camelid Ig which will remove all subtypes of human antibodies. The disclosed methods may be carried out with a column that removes IgG, IgM, IgA, IgGE or a combination therefor. Exemplary porous matrix of the column may be Sepharose, silica, polyacrylate, or polyvinyl alcohol. Exemplary columns include THERASORB Ig column which comprises polyclonal sheep anti-human IgG, or column comprising protein A. [117] For example, methods of subjecting a subject’s plasma to IAP removes at least about 50% of anti-AAV antibodies of the subject, or removes at least about 55% of anti-AAV antibodies, or removes at least about 60% of anti-AAV antibodies, or removes at least about 70% of anti-AAV antibodies or removes at least about 80% of anti-AAV antibodies, or removes at least about 90% of anti-AAV antibodies, or removes at least about 95% of anti-AAV antibodies in the plasma of the subject or removes at least about 99% of anti-AAV antibodies in the plasma of the subject, this includes removal of FVIII inhibitors when the FVIII inhibitor is an antibody. [118] The disclosed methods comprising subjecting the subject’s plasma to at least one IAP session, or at least two IAP sessions, or at least three IAP sessions, or at least four IAP sessions. For an IAP session, 2-3 plasma volumes are exchanged per session. In addition, the IAP sessions are carried out once a day over about 1 to 3 days, or 1 to 4 day or 1 to 5 days, or about 1 to 10 days, or about 5 to 10 days, or about 5 to 7 days or about 7 to 10 days. The IAP sessions are carried out once a day for two consecutive days, or once a day for three consecutive days or once a day for four consecutive days for 5 consecutive days, or once a day for 6 consecutive days, or once a day for 7 consecutive days, or once a day for 7 consecutive days, or once a day for 8 consecutive days, or once a day for 9 consecutive days or once a day for 10 consecutive days. The IAP sessions are carried out 2, 3 or 4 times a day for two consecutive days, or 2, 3 or 4 times a day for three consecutive days or 2, 3 or 4 times a day for four consecutive days or 2, 3 or 4 times a day for 5 consecutive days, or 2, 3 or 4 times a day for 6 consecutive days, or 2, 3 or 4 times a day for 7 consecutive days, or 2, 3 or 4 times a day for 7 consecutive days, or 2, 3 or 4 times a day for 8 consecutive days, or 2, 3 or 4 times a day for 9 consecutive days or 2, 3 or 4 times a day for 10 consecutive days. Immunosuppressive Agents [119] The disclosure also provides for carrying out any of the disclosed methods using an alternative immunosuppressive agent instead of or in combination with a corticosteroid. The immunosuppressive agent is any agent that inhibits the subject’s immune system, reduces the effectiveness of the subject’s immune system or modulates the activity or effectiveness of the subject’s immune system. The immunosuppressive agent may be administered prophylactically at the same time as administration of the FVIII AAV or administered prior to an elevation of ALT levels after administration of the FVIII AAV. In other embodiments, the immunosuppressive agent is administered therapeutically. For example, the immunosuppressive agent is administered after elevated levels of ALT are detected in the subject after administration of the FVIII AAV. [120] Exemplary immunosuppressive agents include glucocorticosteroids, janus kinase inhibitors, calcineurin inhibitors, mTOR inhibitors, cyctostatic agents such as purine analogs, methotrexate and cyclophosphamide, inosine monophosphate dehydrogenase (IMDH) inhibitors and biologics such as monoclonal antibodies or fusion proteins and polypeptides. [121] Janus kinase inhibitors are inhibitors of the JAK/STAT signaling pathway by targeting one or more of the Janus kinase family of enzymes. Exemplary janus kinase inhibitors include tofacitinib, baricitinib, upadacitinib, peficitinib, and oclacitinib. Calcineurin inhibitors bind to cyclophilin and inhibits the activity of calcineurin Exemplary calcineuine inhibitors includes cyclosporine, tacrolimus and picecrolimus. mTOR inhibitors reduce or inhibit the serine/threonine-specific protein kinase mTOR. Exemplary mTOR inhibitors include sirolimus, everolimus, and temsirolimus. Additional immunosuppressive agents include matacrolimus, pimecrolimus, and sirolimus. [122] Purine analogs block nucleotide synthesis and include IMDH inhibitors. Exemplary purine analogs include azathioprine, mycophenolate and lefunomide. [123] Exemplary immunosuppressing biologics include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, toccilizumab, ustekinenumab, vedolizumab, basiliximab, belatacep, and daclizumab, ocrelizumab, ofatumumab, otelixizumab, teplizumab and visilizumab, and alemtuzumab. Examples Example 1 Methods Anti-AAV5 capsid TAb Assay [124] A detailed description of the anti-AAV5 TAb method has been previously reported (long 2019). Briefly, meso scale discovery (MSD) plates were coated with AAV5 and incubated at room temperature for one hour with 400 rpm shaking. Plates were washed and then blocked with tris-buffered saline (TBS) with 1% casein (TBS-c) (1% casein in 20 mm TRIS and 500 mm NaCl [ph 7.4]) for one hour at room temperature with 400 rpm shaking. Samples and controls were diluted at 1:20 in blocking buffer, added to plates and incubated at room temperature for one hour with 400 rpm shaking. Plates were washed and ruthenylated protein a/g/l was added to each well. Plates were incubated at room temperature for 30 minutes with 400 rpm shaking. Plates were washed and then 1x MSD read buffer added and read on MSD sector imager. Sample data were considered acceptable if duplicate wells were ^ 25% cv. FVIII-SQ protein assay [125] A sandwich electrochemiluminescence (ECL) assay was performed on the MSD QuickPlex SQ 120 imager (QuickPlex imager) to measure the concentration of hFVIII in sodium- citrated normal pooled cynomolgus monkey plasma. A monoclonal antibody to the a2 domain of hFVIII was conjugated to an extra-long-chain amine-reactive n-hydroxysulfosuccinimide (lc-lc- NHS) biotin, and a sheep polyclonal antibody to hFVIII was conjugated to a ruthenium NHS (sulfo-NHS) tag. Standard calibrators and quality controls (QCS) were prepared with xyntHA (clinical-grade hFVIII-SQ) in 100% pooled cynomolgus monkey plasma, ranging from 301 to 0.294 ng/ml (a total of 11 points), with the bottom three designated as anchor points, making the range of quantitation (RoQ) from 301 to 2.35 ng/ml FVIII-SQ. High-, mid-, and two LQC samples were tested at concentrations of 226, 60.3, 5.00, and 3.00 ng/ml FVIII-SQ, respectively. The standard calibrators, QCS, and study samples were diluted to a minimum residual disease (MRD) factor of 1:10 in assay diluent (Cedarlane, catalog number cl2003sk- diluent) prior to addition to the MSD plate wells. Samples and combined labeled anti-FVIII detection reagents were incubated for 2 hours at room temperature with shaking. Simultaneously, an MSD plate coated with streptavidin was blocked with 6% BSA in TBST for 2 hours at room temperature with shaking. At the end of the blocking step, the blocking buffer in the wells of the MSD plate was removed without washing. The mixture of the labeled antibodies and plasma samples was then incubated for 1 hour at room temperature with shaking on the blocked MSD plate to capture the FVIII-SQ-antibody complexes via the biotin label. After a triple wash with TBST, 1x MSD read buffer containing the substrate tripropylamine (TPA) was added to react chemically with ruthenium in the presence of applied voltage. The FVIII-SQ complexes bound to both the biotinylated and ruthenylated antibodies generate an ECL signal detected by the QuickPlex imager. Standard curve regression analysis using a 4-parameter logistic algorithm with 1/y weighting in Watson Laboratory Information Management System (LIMS) version 7.4.2 was used to report concentrations, percent coefficient of variation (CV), and percent relative error (RE) of back-calculated unknown qc and study samples. The lower limit of quantitation for the assay was 2.35 ng/ml FVIII-SQ. FIX protein assay [126] Factor IX protein levels were assessed by a fluorescence assay. Nunc MaxiSorb Black Opaque plates were coated with anti-FIX capture antibody (gma002, green mountain antibodies) at 4°c overnight. Plates were washed three times with TBS-t20 and then blocked with 6% BSA-0.05%tween with incubation at 37°c for 1.5 hours. Benefix FIX (recombinant FIX, Wyeth) was used for standards and QCS. Samples and standards were diluted at 1:5 MRD in green sample diluent (Affinity Biologicals) and added to the plate. After incubation at room temperature for 1 hour with shaking, plates were washed. The anti-FIX detection antibody (FIX- EIA-d, Affinity Biologicals) was added and plates were incubated at room temperature for 1 hour with shaking. Plates were washed and QuantaBlu reagent added to wells. Plates were incubated at room temperature for 10 to 15 minutes with shaking. QuantaBlu stop solution was added and plates read in fluorescence mode, ex325nm/em425nm, with cutoff at 420nm. SoftMaxPro was used for data analysis with a 5-parameter curve fit, no weighting. Standard curve and QC data were acceptable if accuracy ^ 20% relative error (re) [25% re at limit of quantitation (loqs)] and duplicate wells had precision ^ 20% coefficient variation (CV) (25% CV at LOQS). Sample testing data were acceptable if duplicate wells were ^ 20% CV. Immunophenotyping by flow cytometry [127] Blood was collected by venipuncture on days -14, 15, 43, 71, and 84. The whole blood samples were checked for clots and transferred to the appropriate laboratory at the testing facility. Upon receipt, the samples were stored at ambient temperature. Absolute cell counts were determined using BD TRUCOUNT™ tubes per testing facility standard operating procedure (SOP). Calculation of absolute counts for each cell population was performed using the relative percentages of each cell population and the corresponding lymphocyte or lymphocyte/monocyte/granulocyte count obtained using BD TRUCOUNT™ tubes with CD45 (SSC/CD45+). The cellular antigens and cell populations identified were quantified according to testing facility validated methods. Longitudinal plots of immunophenotyping data were generated using GRAPHPAD PRISM™ software version 8.4.2. Cellular Immune Response IFN-^ ELISAspot Assay [128] Blood was collected by venipuncture on days -10, 15, 43, 71, and 85. Samples were mixed gently and kept at room temperature. The peripheral blood mononuclear cells (PBMC) samples were transferred to the testing facility’s laboratory sciences department at ambient condition for subsequent processing utilizing testing facility sop. PBMCs were frozen at 5-10 × 106 cells/ml/cryovial. Short term (1-3 days) storage of frozen PBMCs was in a freezer set to maintain -80°c while long term storage (> 3 days) was in a liquid nitrogen tank. PBMCs were assessed for ex-vivo cytokine release in response to staphylococcal enterotoxin b (seb), anti- CD3 (positive controls), DMSO (negative control), or two sponsor-derived peptide pools according to the testing facilities analytical procedure. Cytokine Sample Collection, Processing, and Analysis [129] Blood was collected by venipuncture and resultant plasma was divided (approximately equal volumes were visually estimated), transferred to 2 appropriately labeled polypropylene tubes, and frozen immediately in a freezer set to maintain -80°c until transferred to the appropriate laboratory at the testing facility. The samples were analyzed using a validated luminex method (ap.i-001489.im.06) for the detection of IL-1^, IL -1ra, IL-2, IL -4, IL-5, IL -6, IL- 8, IL -10, IL-12/23 (p40), IL-13, IL-17a, MCP-1, MIP-1^, IFN-^, TNF-^, G-CSF, and gm-CSF. Longitudinal plots of cytokine data were generated using GRAPHPAD PRISM™ software version 8.4.2. Example 2 Safety Study in Nonhuman Primates [130] The objective of the present study was to determine the pharmacodynamics and safety following a single bolus injection of AAV-FVIII-SQ into cynomolgus monkeys (nonhuman primates or NHP) with varying pre-existing levels of neutralizing AAV5 antibodies (referred to as total antibody (TAb)/transduction inhibition (ti) titers) and non-antibody inhibitors (AAV5 TI assay). The experimental design is presented in Table 2. Table 2: Group (n) Immune status AAV5: TI range Dose of AAV- TAb/TI status FVIII-SQ (vg/kg) 1 (3) Control TAb-/TI- Neg 6e13 2 (4) Non-antibody TAb-/TI- 2 to <5 6e13 inhibitor 3 (3) Non-antibody TAb-/TI- 5 to 10 6e13 inhibitor 4 (5) Neutralizing TAb+/TI- >10 6e13 AAV5 antibodies [131] AAV-FVIII-SQ, (4.17e13 vg/ml), was stored at -80°c until use. AAV-FVIII-SQ was equilibrated at room temperature for approximately 1 hour on the day of use, prepared for administration under a laminar flow hood, and administered within 5 hours after preparation. AAV-FVIII-SQ was administered as a single slow intravenous bolus injection on study day 1. Detection of pre-existing AAV5 immunity in monkeys (screening phase): [132] To study the impact of pre-existing AAV5 immunity on AAV-FVIII-SQ-mediated gene transfer, this study aimed to specifically enroll cynomolgus monkeys that met pre-defined criteria for AAV5 TAb/TI status. Additional specific details regarding the cell-based transduction inhibition (TI) and total binding antibody (TAb) assays are published elsewhere (Long et al., 2019). Briefly, 60 cynomolgus monkeys (Macaca fascicularis) were screened during the pre- treatment phase, of which 15 monkeys were subsequently enrolled in one of four groups as set out in Table 2. These males were between 2.5 to 4.4 years of age and weighed between 2.4 to 3.3 kg prior to treatment. Group 1 contained animals without AAV5 TAb and without detectable transduction inhibition (TAb-/TI-; control group). Groups 2 (N=4) and 3 (N=3) contained animals without detectable AAV5 tab, but with detectable transduction inhibition (TAb-/ti+; non-antibody inhibitors); lower TI titers (2-4) were enrolled in Group 2, moderate TI titers (5-10) were enrolled in Group 3. Group 4 (N=5) contained animals with both AAV5 TAb and detectable transduction inhibition (TAb+/TI+; neutralizing AAV5 antibodies). Dosing and In-Life Phase: [133] AAV-FVIII-SQ was administered as a single, slow intravenous bolus injection on study day 1. Blood was obtained by venipuncture for routine hematology throughout the study at designated time points (week -1 and days 29 and 56). Coagulation parameters (activated partial thromboplastin time, fibrinogen and prothrombin time) were assessed at week -1 and days 29 and 56, and fasting clinical chemistry studies were performed at week -1 and on days 15, 29, 43, and 56. NHPs were euthanized by exsanguination on study day 56. At necropsy, a complete set of tissues was collected for histopathology. A standard list of protocol-required tissues was processed for routine light microscopic evaluation. In-life procedures and necropsies were conducted at Charles River Laboratories (Reno, Nevada). [134] Human FVIII-SQ levels in cynomolgus monkey plasma group mean data (sd) across three different time points are listed in Table 3. Table 3 Mean (sd) FVIII concentration (ng/ml) Group (n) Day 22 Day 29 Day 36 Group 1 (3) Control 25.1 (8.77) 22.2 (9.92) 24.6 (13.5) Group 2 (5) Non-antibody inhibitor 45.0 (32.8) 50.1 (42.8) 53.7 (43.6) Group 3 (3) Non-antibody inhibitor 27.3 (11.0) 24.6 (12.6) 27.6 (14.9) Group 4 (5) Neutralizing AAV5 antibodies 8.01 (11.5) 6.16 (9.08) 7.46 (11.6) [135] At baseline (day -7), FVIII-SQ levels in all animals were below the lower limit of quantitation (lloq), confirming that the assay has no cross-reactivity for monkey FVIII. After administering AAV-FVIII-SQ, all animals showed FVIII-SQ levels above the LLOQ, with the exception of 2 of the 5 animals in Group 4 (TAb+/TI+; neutralizing AAV5 antibodies with screening TI titers of 6-10059). Peak levels (cmax) in all animals with quantifiable FVIII-SQ fell between days 22 and 36. Even though animals in all groups received the same dose level (4.17e13 vg/kg), the mean FVIII-SQ concentration in group 4, which included anti-AAV5 TI+ TAb+ animals, was lower than that in group 1, which included anti-AAV5 TI- TAb- animals (control group) with no evidence of pre-existing AAV5 immunity. The lower levels of FVIII-SQ in group 4 were observed across all three (day 22, 29, and 36) time points, suggesting that anti- AAV5 TAb+/TI+ positivity diminished the pharmacodynamic effectiveness of gene therapy administration. Levels of hFVIII-SQ in cynomolgus monkey plasma mean data across three different time points are presented in Table 3. [136] Plasma samples from all animals were tested in the AAV5 TAb assay at baseline and post-treatment on days 8, 15, 22, 29, and 56. By day 8, all dosed animals were AAV5 antibody-positive, indicating that the onset of the AAV5 antibody response occurred rapidly after AAV-FVIII-SQ injection and with similar kinetics across all four study groups, regardless of the presence of pre-existing AAV5 immunity. Plasma from all dosed animals remained positive for AAV5 antibodies throughout the study until day 56, without any apparent effect of pre-existing AAV5 immunity (Long, 2019). [137] There were no clinical observations or body weight changes associated with the administration of AAV-FVIII-SQ to NHPs either with or without pre-existing TAb or TI titers. NHPs in group 4 (TAb+ and TI titers of 6-100) administered AAV-FVIII-SQ had a statistically significant increase (1.5x, data not shown) in lymphocyte counts on day 56 compared to group 1 (TAb- and TI-). There were no changes in the coagulation parameters or clinical chemistry including serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST), Table 4]. Table 4: Male NHPs Administered AAV-FVIII-SQ with Various Baseline Titers Alt (u/l) Group Day 6 Day 15 Day 29 Day 43 Day 56 1 (n=3) 47.3 48 54.7 47.3 44.3 2 (n=5) 47.8 44 49.8 51.5 49.5 3 (n=3) 38.7 46 40.7 46.7 42 4 (n=5) 34.8 32.4 36.6 29.8 31.6 Ast (u/l) Group Day 6 Day 15 Day 29 Day 43 Day 56 1 (n=3) 61.3 47.7 85 40.3 41.7 2 (n=5) 41.3 38.5 42.8 40.8 36.5 3 (n=3) 37 35 37.3 34.7 37.3 4 (n=5) 47.6 35.4 45 33.2 34.6 [138] Group mean splenic weights were slightly higher (not statistically significant) in group 4 animals compared to Group 1 (data not shown). However, in the absence of a true naïve/untreated control group, the splenic weight change was considered incidental with no relationship to TAb/TI status or to the administration of the test articles. Histopathologic examination of livers from nhps from all groups revealed no test article-related or adverse findings. A few scattered foci of mixed inflammatory cell infiltrates observed across all treatment groups were considered incidental and normal background findings of cynomolgus monkeys (Sato et al 2012; Chamanza et al., 2010). Overall, there were no microscopic changes in the spleen. Example 3 Safety and Efficacy of Vector Redosing in Non-Human Primates [139] The objective of this study was re to assess the safety (and efficacy) of vector re-dosing in NHPs previously exposed to same serotype (AAV5). A key objective of this study was to evaluate transduction efficacy and safety of vector re-administration with high capsid titers for the same serotype. The experimental design is presented in Table 5. Frozen test articles [AAV5-cgb (batch no.17-754) and AAV5-hFIX (batch no.17-738)] were stored at -80°c until use and were thawed on the day of dose administration. The dose formulations were equilibrated at room temperature for approximately 0.5 hours prior to dosing and administered within 4 hours after thawing. Table 5. Experimental study design Group (n) Purpose Day (S -7 Q d )ose Day 1 dose (iv) Day 29 dose (iv) 1 (3) Control Na Na 3e13 vg/kg AAV5- fix 5e12 v 3e13 vg/kg AAV5- 3e13 vg/kg AAV5- 2 (3) Re-dosing g AAV5- bCG bCG fix [140] Cynomolgus monkey (macaca fascicularis, denoted as NHPs) were received from Charles River Laboratories, Houston, TX. The animals were between 2.5 to 3.0 years of age and weighed between 2.1 and 2.3 kg on study day 1. Prior to enrollment in this study, male NHPs were screened for the presence of antibodies against the AAV5 capsid (see screening phase in Example 2). Anti-AAV5 capsid antibody negative male NHPs were enrolled and assigned to one of two treatment groups (Table 5). [141] Briefly, NHPs in group 1 served as positive controls and were dosed once on day 29 with an AAV5 vector expressing human FIX [AAV5-hFIX]. Following dose administration, group 1 was expected to achieve maximal expression of the FIX transgene (FIX plasma protein concentration) since these NHPs pre-screened negative for AAV5 TAb and also did not receive prior gene therapy dose administrations). [142] NHP in groups 2 were dosed on study day -7 with a subcutaneous administration of 5e12 vg AAV5-bCG and a second administration of 3e13 vg/kg AAV5-bCG IV at day 1. Group 2 animals were expected to mount an AAV5 TAb response following administration of AAV5-bCG. The same animals in this group (group 2) were then administered 3e13 vg/kg AAV5-fix at day 29 to evaluate the safety and pharmacodynamic effect of gene therapy administration in the presence of a high titer AAV5 TAb. [143] Blood was collected by venipuncture on days -14, 1 (predose), 15, 29 (predose), 43, 57, 71, and 84 for hematology, clinical chemistry, coagulation, and anti-AAV5 capsid antibodies. Plasma levels of the transgene product (hFIX) were measured as well. NHPs were euthanized by exsanguination on study day 85. At necropsy, a complete set of tissues was collected for histopathology and for DNA/RNA-qPCR analysis. A standard list of protocol-required tissues was processed for routine light microscopic evaluation. In-life procedures and necropsies were conducted at Charles River Laboratories (Reno, Nevada). [144] All animals developed antibodies to AAV5 capsid following dosing with AAV5-hfix (group 1) and AAV5-cgb (group 2) (Table 6). Means in the table, individual lines in plot). Group 1 animals were dosed with AAV5-hfix on day 29 and had detectable titers on day 43. Group 2 animals received a subcutaneous injection of AAV5-cgb on day -7 followed by intravenous doses of AAV5-CGB on day 1 and AAV5-hFIX on day 29. Very low titers were detectable in some of the group 2 animals on day 1 of the study and a robust response developed in all animals by day 43. Notably, the purpose of the subcutaneous injection was to target the vector capsids to the draining lymph nodes in an attempt to elicit a more localized immune response, which would not have been achieved as efficiently with an IV or systemic administration. Table 6 Group N Day 1 Day 29 Day 43 1 3 <20 <20 12500 2 3 <20 62500* 312500 *plasma samples were collected at day -7 (baseline) and at days 1, 15, 29, 43, 57, 71, and 84 (study end) and were assessed for AAV5 TAb. Vertical lines indicate time of AAV dose administrations and all samples were collected. [145] Human FIX was observed only in AAV5-hFIX animals (group 1) that were not previously sensitized to AAV5 prior to challenge dose administration. hFIX plasma protein concentrations ranged from 5636.6-11355.5 mIU/mL on Days 57 and 84. Human FIX plasma protein expression was not detected in the animals administered AAV5-CGB + AAV5-hFIX (Group 2; Table 7) suggesting the anti-AAV5 capsid TAb response following the prior sensitizing dose administration was capable of neutralizing transduction by the second dose (data not shown). Table 7 Day -14 Day 1 Day 29 Day 57 Day 84 Group Mean (sd) Mean (sd) Mean (sd) Mean (sd) Mean (sd) 1975.34 1 0.59 (0.06) 0.37 (0.04) 0.57 (0.29) 1816.44 (5.68)* (64.18)* 2 0.45 (0.02) 0.45 (0.02) 0.59 (0.04)* 0.69 (0.11) 0.38 (0.00)* *Indicates one or more group subject tested either blq or alq. For these subjects, the lloq (0.381 miu/ml) or uloq (2500 miu/ml) concentration was used to determine group mean ± sd, respectively. Group 1 had two alq subjects at day 57 and day 84, and group 2 had one blq subject at day 29 and three at day 84. [146] NHPs in both treatment groups had no test article-related clinical observations, body weight changes, or food consumption changes during the course of the study. There were no changes in the coagulation or clinical chemistry parameters, including serum transaminases (ALT and AST, Table 4). Similar to study described in Example 2, histopathologic examination of livers from NHPs from all groups revealed no test article-related or adverse findings. A few scattered foci of mixed inflammatory cell infiltrates observed across all treatment groups were considered incidental and normal background findings of cynomolgus monkeys (Sato et al., 2012; Chamanza et al., 2010). Immunophenotyping of Peripheral Blood Mononuclear Cells and Evaluation of Plasma Cytokines [147] Peripheral blood samples were drawn at baseline (day -14) and days 15, 43, 71 and 84 and PBMC populations were immunophenotyped by flow cytometry for enumeration of T-cells (CD4+ Th subsets and CD8+ CTL and Foxp3+ T-regs), B-cell, NK-cells and CD14+ monocytes. The percentage change in absolute counts over baseline is shown in Figure 2. There were few notable differences in percentage change from baseline measures between groups 1 and 2, however AAV5-CBG administration on days -7 and 1 in group 2 resulted in a mean 2-fold increase (220% increase over baseline) in circulating cd3-/cd14+ monocytes on day 15 the mean at the day 15 time point was increased by a single animal (2003), with a 301% increase over baseline. A less robust increase in monocytes (approximately 1.5-fold) was also observed on days 71 (144% over baseline) and 84 (154% over baseline) in the same group (Group 2). By comparison, group 1 mean percentage change from baseline were 118% at days 15 and 71 and 99% at day 84 respectively. [148] Consistent with the elevated whole blood monocyte counts, an increase in plasma monocyte chemoattractant protein-1 (MCP-1) concentrations (3.176, 7.005, and 6.564-fold relative to pre-study) was present at day 1: 6 hours post-dose in all AAV5 (group 2) animals (Figure 3). One control (Group 1) animal (male no.1003) yielded detectable mcp-1 values, but as this value was only 1.133-fold above baseline, it was considered to be within the range of normal variability observed at the testing facility. No further increases in this analyte were detectable following the day 29 challenge dose. Plots of fold-change over baseline in individual animal cytokine data are shown in Figure 3. There were no test article related changes observed for interleukin-1 receptor antagonist (IL -1Ra), IL -4, IL-6, IL -8, IL-12/23(p40), granulocyte-colony stimulating factor (g-CSF), or tumor necrosis factor alpha (TNF-^). While detectable levels were observed for each of these analytes, these changes were not considered to be test article related as they were not observed in all group members and were generally within the range of pre-study responses. There were no test article related changes observed for granulocyte-macrophage colony-stimulating factor (gm-CSF), interferon gamma (IFN-^), IL- 10, IL-13, IL-17a, IL-1β, IL-2, IL -5, or macrophage inflammatory protein-1^ (MIP-1^) as all samples were below the LLOQ. [149] AAV5 capsid-specific cellular immune responses were measured by ELIspot assay for secreted IFN-^ from cryopreserved cynomolgus monkey PBMCS collected at days -10, 15, 43, 71, and 85 and stimulated with AAV5 peptide pools. Based on the PBMC responses to control stimulations, the method performed within acceptable parameters. No IFN-^ secretion in response to stimulation with AAV5 peptide pools was measured above the LOD for any animal at any time point. While all PBMC samples passed formal sample acceptance criteria, several samples (n=4) showed a decreased response to stimulation with the positive control, phytohaemagglutinin lectin (PHA-L), indicating that the PBMC sample collection or immune responses in these samples may not have been optimal (data not shown). Overall, expression of hFIX was observed only in AAV5-HFIX animals (Group 1) that were not previously sensitized to AAV5 prior to the challenge dose administration. Example 4 Immunoadsorption Plasmapheresis for the Removal of Plasma Immunoglobulins [150] The presence of pre-existing anti-AAV total binding antibodies (AAV TAb) and in vitro neutralizing antibodies (AAV NAb) may limit the efficacy of gene therapy. Moreover, a first administration of an AAV vector induces high titers of treatment emergent AAV NAb, which may compromise repeat dose administration with the same vector. This experiment investigates if depletion of AAV NAb by immunoadsorption plasmapheresis (IAP) is a strategy that could allow successful vector administration in recipients with either pre-existing or treatment-emergent antibodies. The objective of this study was to evaluate the effectiveness of IAP to remove AAV serotype 5 (AAV5) NAb from animals sensitized by an initial gene therapy dose. This allows for further optimization of the safety and efficacy of the IAP procedure in NHP and administration of a repeat (challenge) dose of gene therapy in animals sensitized to AAV5. [151] Multiple rounds of IAP over multiple days greatly reduced but did not eliminate sensitized antibody titers in hon human primates. Figure 4 shows the results from one NHP after receiving a single does of AAV5-bCG (6E13 vg/kg). Two plasma volumes of IAP per day resulted in an 83% decrease in AAV5 TAb titer after 1 day, and a 95% reduction in AAV5 TAb titer after two days (Figure 5). [152] To further investigate, five cynomolgus macaques (Macaca fascicularis) were included in this study; four were sensitized by administration of an AAV5 capsid encoding for the beta subunit of cynomolgus chorionic gonadotropin (AAV5-^CG) at a dose of 6E13vg/kg, and one control animal was naïve. All were subjected to IAP for a minimum of 1 day of 4 runs (plasma volume exchanges) to a maximum of 3 consecutive days of 3 runs. The IAP were carried out using Miltenyi Biotec apheresis equipment paired with THERASORBTM affinity columns (CE marked in the EU) to support use in clinical patients. THERASORB columns utilize a porous matrix coated with recombinant Camelid Ig to remove all subtypes of human antibodies (regardless of specificity). [153] All 5 animals were challenged with the same AAV5 capsid encoding a different protein, human coagulation factor IX (AAV5-hFIX) at a dose of 6E13 vg/kg, administered within 10 minutes of the last run IAP. Efficacy of the IAP procedure was functionally evaluated by laboratory measures of plasma IgG and AAV5 total binding antibody (AAV5 TAb) titer, hFIX plasma protein concentration, and quantitation of vector genomes and transcripts in liver tissue. The design of the study is summarized in Table 8 below.
Table 8 Group Gender ID Approx. Weight AAV5 Antibody Age Group 1 Female Ne Cg S C 3o 6n 5trol 7 years 3.99 kg Negative NHP1 11 Positive (BA958G) years 7.2 kg (Previously Sensitized) NHP 2 EA009) 7 ye Positive (C ars 8.07 kg (Previously Sensitized) Group 2 Male NHP 3 P 593F) 11 ye ositive (BB ars 8.7 kg (Previously Sensitized) NHP 4 10 yea Positive (CBL002) rs 10.6 kg (Previously Sensitized) [154] As shown in Figures 6A-6B, maximal depletion of AAV5 TAb titer (>99%) was achieved in two animals resulting in a nadir titer of 61 and 59. The highest precent decrease in pre- existing AAV5 TAb was achieved over multiple days of plasmapheresis. The number of days and plasmapheresis runs achieved for each subject varied based on the health of each animal following each run. The data depicted in the graphs in Figure 6 is summarized below in Table 9.
Table 9 CS365 - Animal Control BA958G CEA009 BB593F CBL002 Number of Plasma Volumes/Day of IAP 4 3-4 4 4 4 Number of Days of IAP 2 3 2 1 1 Starting TAb Titer Neg 3714 43,406 52,945 42,181 TAb Titer on Day of Rechallenge Neg 59 158 599 2416 Percent TAb Titer Reduction NA 98.4% 99.6% 98.9% 94.3% [155] Human FIX transgene DNA and RNA was evaluated by ddPCR analysis from cynomolgus monkey liver samples collected at termination ~8 weeks following challenge dose administration. Plasma was collected at multiple time points for assessment of hFIX plasma protein concentration. Peak hFIX expression and area under the concentration time curve (AUC) are shown from the time of challenge dose administration through 4 weeks post challenge. As shown in Figures 7A-7B, the two animals which achieved maximum depletion of AAV TAb titer (>99%) also achieved approximately 25% and 50% of reference hFIX plasma protein levels, respectively, compared to the naïve animal (0.8 IU/mL), and a proportional percentage of vector genome copies measured in liver tissue compared to the naïve animal (1.6E7 cp/mg DNA). Following a variable number of IAP sessions (plasma volume exchanges over consecutive days) and administration of the AAV5-hFIX challenge dose, there was significant perturbation of hematological and biochemical blood parameters; however, all parameters returned to baseline levels within hours or days of the procedure. [156] In this study, the number of successful IAP runs vary between animals and would be dependent on animal health. Thus, a decision tree was implemented as show in Figure 8. According to this decision tree, administration of gene therapy will be performed after the 4th run on Day 4. Gene therapy item may be injected as soon as the end of 2 runs on the first day if an IAP issue is anticipated for the next days, according to scheme set out in Figure 8. [157] This study demonstrates that multiple sessions (days) and plasma volume (runs) of IA- plasmapheresis brought antibody titers down below 100 in a subset of previously sensitized NHP. In addition, increasing the number of sessions and plasma volumes reduced antibody titers more effectively. Achieving an anti-AAV5 TAb titer below 100 was associated with an improved level of efficacy following repeat dose administration. [158] Overall, these results demonstrate the viability of IAP as an immune modulation procedure to deplete AAV5 capsid-specific antibody titers sufficient to allow repeat dose administration. As such, IAP may enable AAV-based vector gene therapy in patients currently excluded from gene therapy clinical trials or commercial product use due to pre-existing antibodies. Furthermore, additional evaluation of the efficacy of this procedure may be worthwhile in subjects with pre-existing antibody titers resulting from natural exposure to AAV infections, which result in lower antibody titers than the treatment-emergent titers observed here. Example 5 Seroprevalence Study in Human Hemophilia A Patients [159] A global clinical AAV seroprevalence study (referred to the 270-901 study) that enrolled 547 (478 adults and 69 adolescents) participants from the United States, United Kingdom, France, Russia, Germany, Italy, Japan, South Africa and Brazil was carried out (Hayes, 2019). It compared seroprevalence and antibody titers against multiple AAV serotypes to provide epidemiological data characterizing pre-existing AAV immunity among hemophilia A patients. Regional variability was observed in the percentage of hemophilia A subjects with pre-existing antibodies to AAV5 and other serotypes across countries. The percentage of total antibody (TAb)-positive hemophilia A subjects and titer range are lowest for AAV5 (33%) as compared to other serotypes (44-54%). Rates of seroprevalence for each capsid increase with age for all serotypes tested but remain the lowest for AAV5. The AAV5 TAb result and titers remain ed consistent over 24-weeks’ time for subjects returning at 12-weeks and 24-weeks for follow-up testing. [160] There are multiple methods for measuring pre-existing AAV immunity that may impact efficacy. The anti-AAV TAb assay appears to be more discriminating than transduction inhibition (TI) in pre-clinical studies, with regards to the ability to detect low titers (Falese, 2017; Sun, 2013). In pre-clinical evaluation, the AAV5 TAb assay better predicted AAV-FVIII-SQ efficacy, whereas TI titer in tab-negative non-human primates were not associated with reduced transduction or efficacy (Long, 2019). Therefore, the AAV5 TAb assay has been chosen as the diagnostic to screen potential subjects in the AAV-FVIII-SQ clinical studies and is intended as a companion diagnostic for the program. [161] To focus on the global hemophilia A patients, AAV seropositivity using the global ha weighted average was calculated by multiplying the percentage of participants who tested positive in each country by the number of people with ha in that country, divided by the total number of people with ha in all countries in the study. The values were based on individual participant titers for individual participants in the global population. Participants with negative titers plotted as a value of 1. Participants with positive titer results and a titer <20, the MRD, are shown as 20. Width is representative of the number of points at a particular value (see Klamroth et al. Hum Gene Ther.2022 apr;33(7-8):432-441). This analysis indicated that about 30% of persons with hemophilia A are positive for AAV5 antibody (see Figure 9). In addition, the pre- existing immunity titers are significantly lower than treatment-emergent titers with a pre-existing immunity (seroprevalence) titer range with a minimal residual disease (MRD) of 1913 (see Figure 10). The treatment-induced immunity impacts the ability to re-dose with AAV5 gene therapy vectors, while the pre-existing immunity impacts the administration of the first dose of AAV5 gene therapy vectors. Figure 11 demonstrates that about 65% of participants in the seroprevalence study with pre-existing immunity would be potentially addressable in day 1 of IAP treatment (2 cycles), and as a result about 97% of the hemophilia patients may be transduced after 2 days of IAP (4 cycles). Clinical Study [1] The present study builds on the 270-901 global study to further describe the seroprevalence and rate of seroconversion of subjects with hemophilia A, with a focus on the US population. Seroprevalence and rate off seroconversion of AAV5, AAV6, AAV8, as well as seroprevalence of exploratory vectors are evaluated and characterized through analysis of vector titer measurements over time within and across subjects. Although treatment decisions based on companion diagnostics outcomes have a qualitative positive or negative test outcome, detection of antibody titers over the full range is an essential endpoint for the study. As such, this study aims to describe the antibody titers around the cut point as well as to fully understand antibody titer variability over time. This study also investigates factors that may influence antibody titers and seroconversion, including physiological, demographic, and geographic. [2] In interim results from the 270-901 study (n=47 subjects), 21.3% of hemophilia A subjects in the United States with residual FVIII levels ^ 2 IU/dL were seropositive for AAV5. Assuming the same seroprevalence is observed in the 270-701 study, a sample size of 255 subjects is required to estimate AAV5 seroprevalence with a 95% confidence interval (CI) that has a precision of ± 5% of the observed seroprevalence in the US hemophilia A population (estimated to be 18,434 patients). [3] While a sample size of 255 provides the specified level of precision for the point prevalence estimate, the present study also evaluates the seroprevalence in different geographic regions of the United States. With the assumption that recruited subjects are distributed equally geographically and analyzed in four regions consistent with US census regions, a total sample size of approximately 1000 subjects would be needed for the regional level estimation of seroprevalence within the precision as in the calculation above (2010 Census Regions and Divisions of the United States). Thus, approximately 1000 subjects are planned to be enrolled in study 270-701. Additionally, a sample size of 1000 represents approximately 5% of the US hemophilia A population. [4] After baseline testing, re-testing will be performed on all subjects to further explore changes in titer measurements over time. Additionally, the study aims to describe seroprevalence among subgroups of the US hemophilia A population, including evaluation of regional and demographic associations. [162] AAV5, AAV6, and AAV8 WERE elected for the study as they represent the serotypes being evaluated in several late-stage gene therapy trials for hemophilia patients, and the data generated by this study may facilitate development of these therapeutic options. Exploratory vectors are included as potential viral delivery forms being explored as a delivery option for future gene therapies. [163] This is a single-center, decentralized, patient-centered, prospective, observational study utilizing biospecimen samples collected from hemophilia A subjects across the United States to evaluate and characterize seroprevalence and the rate of seroconversion of antibodies against AAV serotypes and exploratory vectors, and to investigate the associated factors that may influence the vector titers. Relevant medical findings will also be collected from the subject, which may include age at initial diagnosis of hemophilia, specific information concerning prior or existing medical conditions, history of inhibitor usage, coinfection with human immunodeficiency virus (HIV)/Hepatitis C/Hepatitis B, as well as symptoms related to hemophilia A. The collection of medical history may include major illnesses, diagnoses, and surgeries. [164] The primary objection of the study is to quantify the seroprevalence of antibodies to AAV5, AAV6, and AAV8 and the seroconversion rate over varying follow-up intervals in subjects with hemophilia A. The secondary objections are i) To describe and characterize AAV5, AAV6, and AAV8 titer values in subjects with hemophilia A. ii) To identify and characterize the distribution of titer values around the lower level of detection, and across the full range of values, in subjects with hemophilia A. iii) To explore factors associated with seroprevalence and seroconversion, including potential regional and demographic influences, in subjects with hemophilia A. iv) To evaluate cross-reactivity of antibodies across selected AAV serotypes. The tertiary objection is to describe and characterize exploratory vector titer values in subjects with hemophilia A. [165] The primary end point is to determine seroprevalence and the seroconversion rate. The secondary end points are i) to determine AAV5, AAV6 and AAV8 absolute titer levels, ii) to determine correlation between seroprevalence, seroconversion rate at specified time points and factors of interest (e.g., regions, certain demographic and physiologic), and iii) determine the cross-reactivity rates of antibodies across AAV serotypes. The tertiary end point is to determine exploratory vector titer values. Seroconversion [166] To evaluate antibody level consistency over time, a re-test procedure will be requested at either 12 or 24 weeks (± 2 weeks) after initial testing (baseline). This re-test will follow the same biospecimen collection procedures as the initial testing. After the initial baseline measurement has become available, subjects will be randomized in a 1:1 ratio for the timing of re-testing at either 12 or 24 weeks (± 2 weeks) after initial testing (baseline). Subjects who are exposed to AAV vector gene therapy during the course of the study will be discontinued from the study. Subjects are allowed to have blood re-drawn to obtain a valid seroprevalence measurement. Study Duration [167] Each subject may be in the study for up to 28 weeks. The initial testing for antibodies will be performed within 4 weeks of signed consent, and re-testing is either 12 or 24 weeks (± 2 weeks) after initial testing (baseline) which will determine the total length of participation. Number of Subjects and Subject Selection [168] This study will enroll approximately 1000 subjects with hemophilia A across the United States. Subjects deemed potentially eligible for the study will be invited to participate in the study via email or push notification. After providing consent, subjects who fulfil the requirements of the inclusion and exclusion criteria will be accepted for the study. Subjects will be assigned a unique identifier by the electronic data capture system used for the study. [5] The inclusion criteria include i) subjects previously diagnosed with hemophilia A, ii) Subjects ^ 18 years of age, iii) Subject (or legally authorized representative) is willing and able to provide electronic informed consent after the nature of the study has been explained and prior to any data collection. iv) Subject is willing and able to comply with all study procedures, including blood sampling and follow up for adverse reactions. [169] The exclusion criteria include i) legal incapacity or limited legal capacity without a legally authorized representative and ii) Currently participating in an interventional study of any investigational product, device or procedure. Seroconversion Testing (Initial Testing and Re-Testing) [170] To evaluate antibody level consistency over time, the biospecimen collection will be conducted at initial testing (baseline), followed by re-testing at either 12 or 24 weeks (± 2 weeks) The re-test will follow the same biospecimen collection and other assessment procedures as the initial testing. Subjects who are exposed to AAV vector gene therapy during the course of the study will be discontinued from the study. Randomization [171] Subjects are randomized in a 1:1 ratio for the timing of re-testing [either 12 or 24 weeks (± 2 weeks) after initial testing (baseline)]. Randomization is performed through the electronic data capture system. Additional details will be available in a separate plan outlining randomization requirements and system function. [172] In general, subjects who enter the study with an available seroprevalence measurement at baseline but missing (or having a non-analyzable test outcome for) the re-test 12- or 24-week measurement will not be replaced. These subjects will be included in the database and in the denominator for the seroprevalence calculation. However, they will be excluded for the seroconversion calculation due to a missing re-test value. Analysis for Primary Endpoints [173] Seroprevalence for AAV5, AAV6 and AAV8 is summarized. For each AAV serotype, the number of subjects is tabulated by their seroprevalence status at Baseline, Week 12 or Week 24, the corresponding proportion, presented as a percentage, and the 95% CI of the proportion will be provided in the overall population as well as by subgroups of interest. [174] Seroconversion rate by AAV serotypes (AAV5, AAV6, AAV8) is summarized. For each AAV serotype, the number of subjects whose seropositivity changes between baseline to Week 12 or Week 24 will be tabulated (positive to negative, or negative to positive) along with the number who do change status. The corresponding proportions out of patients with an available baseline and re-test measure, and 95% CI will be calculated. Analysis for Secondary Endpoints [175] The absolute titer levels of the antibodies against AAV serotypes (AAV5, AAV6, AAV8), among those who are seropositive, will be graphically summarized. [176] Titer values of the antibodies at each visit (Baseline, Week 12 or Week 24) may also be presented with summary statistics. To evaluate titer level consistency over time for each AAV type, change of the titer level (increased, stable, decreased) will be provided as a percentage at Week 12 or Week 24 in the overall population and by subgroups of interest. [177] Correlations between seroprevalence, seroconversion rate at specific time points and other factors of interest (eg, regions, certain demographic and physiologic) will be explored by tabulation and graphic tools. Statistical methods for tertiary endpoints will be in line with above analyses of AAV5, AAV6, and AAV8. Example 6 Clinical Study Investigating Clinical Phenotype Hemophilia A Patients with FVIII Activity [178] Three-year results from a previous clinical study (referred to herein as “270-201 study”) demonstrated that following gene transfer, mean and median FVIII activity levels increased above 15% (15 IU/dl), as measured by a chromogenic substrate assay, were achievable and sustained following a single infusion of 6e13 vg/kg of AAV-FVIII-SQ, with an acceptable safety profile (Pasi, 2020). Preliminary results from optional liver biopsies (in subjects receiving lower doses of AAV-FVIII-SQ) confirm pan-lobular and otherwise healthy liver transduction at 2.5 years. In addition, an interim analysis of an ongoing phase 3 study designed to assess the efficacy and safety of AAV-FVIII-SQ at a dose of 6e13 vg/kg (referred to “270-301 study”), demonstrated FVIII activity levels that were also well above 15 IU/dl, albeit lower than what was observed for the 6e13 vg/kg cohort in 270-201 (Pasi, 2020). [179] Subjects receiving 6e13 vg/kg in 270-201 study received a different corticosteroid regimen than subjects in 270-301 study; in 270-201, subjects were started on corticosteroids by week 3 (either therapeutically, in response to an ALT elevation, or prophylactically), whereas in 270-301 subjects received corticosteroids only in response to an ALT elevation. Possibly as a result of this difference, subjects receiving 6e13 vg/kg in 270-201 started corticosteroids at an earlier date in reference to the date of AAV-FVIII-SQ infusion, showed later advent of first alt elevations, and were also less likely to experience a significant decline in FVIII activity concurrently with an ALT elevation when compared with subjects in a recent study (270-301) (20% of subjects in 270-201 vs.58% of subjects in 270-301). In 270-301, alt elevation within the first 26 weeks was associated with decreased FVIII activity. Recently published data from 270- 201 suggests that corticosteroids may have assisted in rescue or protection of FVIII levels during elevations of alt and in resolution of elevated alt levels in some subjects (Pasi, 2020). [180] The present study is a phase 1/2, two-part, open-label, multi-center study designed to assess whether AAV-FVIII-SQ can safely alter the clinical phenotype of HA patients with FVIII activity ^ 1 IU/dl at the time of detected active inhibitors, who have developed FVIII neutralizing antibodies (inhibitors) during HA treatment. For HA patients with inhibitors, the potential benefits of AAV-FVIII-SQ could include eradication of inhibitors by attaining immunological tolerance to FVIII, and/or achievement of hemostasis with either endogenous production of hFVIII or prophylactic FVIII treatment. In addition, since HA patients with active inhibitors, or a history of prior inhibitors (either because they have previously been successfully treated with immune tolerance induction (ITI) to eradicate inhibitors or have expressed inhibitors only transiently) are excluded from many gene therapy trials, this study provides an opportunity for patients to access this novel, potentially transformative therapeutic platform. [181] The primary objective of the study is to assess the safety of a single IV administration of AAV-FVIII-SQ in HA subjects with active inhibitors, or prior inhibitors. The secondary objectives of the study are i) to assess the efficacy of AAV-FVIII-SQ as measured by FVIII activity together with the level of inhibitor titer and the recurrence of inhibitors, ii) to assess the impact of AAV- FVIII-SQ on the use of emicizumab and FVIII prophylaxis, and iii) to assess the impact of AAV- FVIII-SQ on the number of bleeding episodes requiring pharmacologic intervention. The tertiary efficacy objective of the study is to assess the impact of AAV-FVIII-SQ on quality of life as measured by patient-reported outcome (pro) instruments. Activate Inhibitor Population (Part A) [182] Subjects enrolling in Part A must have inhibitors detectable at screening and at least 6 months use of emicizumab prior to study entry, as well as at least 12 months of well-documented bleeding events and hemophilia treatment. In order to be eligible for treatment with AAV-FVIII-SQ, subjects must have a positive inhibitor titer at screening: the first 3 subjects enrolling in Part A must have high-titer inhibitors at screening (> 5 BU in the chromogenic Nijmegen Bethesda assay), while the remaining subjects may have a lower titer (> 0.6 Bu). [183] Approximately 10 subjects will be enrolled in part A, dosed sequentially. The first subject is enrolled in part A is administered AAV-FVIII-SQ at a dose of 6e13 vg/kg. The next subject can be dosed at least one week after the first subject, if there are no precluding safety findings in the immediate post-infusion period. The initial 2 subjects will then be followed up for a minimum of 12 weeks, at which point the accrued safety and efficacy data will be reviewed, to determine the appropriate does for subject 3. Twelve weeks of post-infusion data is considered to provide an appropriate timeframe to evaluate FVIII activity after gene transduction, any potential changes in inhibitor titers subsequent to endogenous FVIII production, as well as any development of any potential delayed hypersensitivity reaction (e.g., serum sickness). After subject 3 has reached a minimum of 6 weeks follow-up, the totality of the data in all three subjects is reviewed to determine whether to expand Part A (i.e. to recruit up to 7 additional subjects to be dosed in parallel). After Part A expansion, the investigators will continue to assess subject data every 12 weeks at a minimum to establish the eradication of inhibitors, stability of FVIII activity levels, and a tolerable safety profile. Prior inhibitor population (Part B) [184] After 3 subjects have been dosed in Part A, subject 3 has been followed for a minimum of 6 weeks, and after review of the data from those 3 subjects, the investigators may recommend dosing to start in Part B (regardless of whether part a is expanded). For Part B, subjects must have a documented history of a positive inhibitor titer but a current negative inhibitor titer (< 0.6 Bu) and been receiving FVIII replacement therapy for at least 12 months prior to study entry, as well as at least 12 months of well-documented bleeding events and FVIII usage. Approximately 10 subjects will be enrolled in Part B. [185] The dosing scheme in Part B is similar to Part A: the first 2 subjects will be enrolled sequentially by at least one week apart, with a review of the data after a minimum follow-up of 12 weeks for each participant prior to enrolling the third subject. After subject 3 has completed at least 6 weeks of post-infusion follow-up, the investigator will assess the data and determine whether the Part B cohort should be expanded to include up to 7 additional subjects to be dosed in parallel, with ongoing review of safety and efficacy data. After Part B expansion, the investigator will continue to assess subject data every 12 weeks to confirm the continued absence of inhibitors, stability of FVIII activity levels, and a tolerable safety profile. [186] To avoid breakthrough bleeding in both parts of the study: Subjects in Part A will discontinue their emicizumab treatment only after reaching FVIII activity levels > 5 IU/dL following AAV-FVIII-SQ infusion; and Subjects in Part B will discontinue their regular FVIII treatment regimen starting 4 weeks after the day of infusion and switch to an “on-demand” schedule. [187] In subjects who experience recurring bleeding episodes, the decision on whether to resume prior treatment regimen will be discussed between Investigator and Medical Monitor. Upon review of the data, it may be recommended that additional subjects be enrolled, up to a total of approximately 40 subjects in the study. Subjects in both parts will be followed post- infusion for 5 years. [188] Subjects in Part B who do not respond to AAV-FVIII-SQ treatment (i.e., treatment failure, manifesting as either failure to achieve FVIII activity > 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment of the Investigator may follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year visits during Years 2-5. [189] All subjects will be started on prophylactic corticosteroids: For Part A subjects, prophylactic corticosteroids will be started at the Week 2 visit (Day 15). If clinically indicated (e.g., ALT elevation, rising inhibitor titers), corticosteroids may be started earlier than Week 2. For Part B subjects, prophylactic corticosteroids will be started on Study Day 1. In addition, therapeutic oral corticosteroids may be initiated when a subject’s ALT values are elevated, and subsequent dosage adjustments made, after consultation between Investigator and the Medical Monitor. Treatment [190] AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. The IP is labelled according to the particulars approved by the relevant regulatory agencies. [191] AAV-FVIII-SQ will be administered at a qualified dosing site, and subjects will be monitored for at least 24 hours (for subjects in Part A) or 8 hours (for subjects in Part B) post- infusion for any immediate hypersensitivity or adverse drug reaction. In case of a suspected Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory cytokine bead array (CBA) to assess inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be collected if deemed necessary at the discretion of the Investigator and Medical Monitor. [192] On the day of infusion, the subject will come to the infusion site, where a physical examination will be performed by the Investigator or designee. If the subject is found to have an active acute illness at the time of planned infusion, then the infusion should be deferred until the illness has resolved; screening procedures may require repetition if outside the specified window. An IV catheter will be inserted into a suitable peripheral vein (e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will not be given since venipuncture is a minimally invasive procedure in these individuals under ordinary conditions. [193] AAV-FVIII-SQ will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at room temperature prior to administration. Refer to the Pharmacy Manual for IP administration instructions. [194] AAV-FVIII-SQ will be infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase. Of note, the IP has been shown to be stable at room temperature for 10 hours following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals throughout the time period of the infusion. [195] As with any infused biological product, there is a potential risk of acute, systemic hypersensitivity reactions (including anaphylaxis) with AAV-FVIII-SQ. Dosing will be administered at a qualified infusion site, with appropriate resuscitation equipment and medication available and easily accessible. [196] Should symptoms of potential hypersensitivity occur, the infusion may be slowed or halted at the Investigator’s discretion, with consideration of the subject’s clinical condition. If the infusion is halted, it should only be restarted if the Investigator considers it safe and appropriate to do so. Antihistamines, anti-pyretic, and/or corticosteroid administration is permitted prior to restarting an interrupted infusion after an infusion-related reaction. At the restart, the infusion rate may be adjusted (ie, to a slower rate [minimum of 1 mL/min], with the rate increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min, if the subject’s clinical condition permits such an increase) with careful monitoring of the subject. In the event of an infusion rate reaction with more than one dosing interruption, the infusion rate would not go beyond 1mL/min. [197] In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory CBA to assess inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be collected if deemed necessary at the discretion of the Investigator and Medical Monitor. Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions. [198] Following completion of the infusion, vital signs will be monitored hourly (± 5 minutes). If the vital signs are stable the catheter will be removed 8 hours after the infusion. Hemostasis at the puncture site will be established by applying pressure according to standard protocol for infusing FVIII concentrates. Subjects will remain in the clinic for at least 24 hours (for subjects in Part A) or 8 hours (for subjects in Part B) to observe for any immediate toxicity of the procedure; inpatient observation can be extended beyond 24 hours (for subjects in Part A) or 8 hours (for subjects in Part B) if needed per Investigator discretion. After the observation period, subjects will be discharged from the clinic unless toxicity has been observed in which case the stay in the clinic may be extended or the subject may transfer to a separate facility based on the evaluation and judgment of the Principal Investigator after consultation with the Medical Monitor. [199] Prior to discharging subjects from the clinic, the Investigator or designee should instruct subjects how to recognize signs and symptoms of potential (delayed) hypersensitivity reactions and anaphylaxis, and to contact a medical practitioner or seek emergency care in case of such an event. [200] Exploratory biomarker samples at baseline and at post-infusion study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion- related hypersensitivity reactions. Any safety signal may trigger a review of the data and possible additional immunogenicity studies or other diagnostics deemed necessary to assess cellular immune responses using collected PBMCs. [201] At applicable sites for subjects enrolled in Part B (and starting in Year 2 for subjects enrolled in Part A), certain study assessments may be performed by a mobile nursing (MN) professional at the patient's home or another suitable location such as their school or office (if the subject has given written informed consent to participate in MN visits), or at the site of approved lab facility as a shortened lab draw-only visit, to improve access and convenience for patients participating in the study, as indicated in the protocol. The Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor). The MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed. If the investigator at a participating site determines that MN services are appropriate for a patient and the patient gives written informed consent to participate in MN visits, the MN network will communicate with the patients and the patient’s visit. Inclusion Criteria [202] Individuals eligible to participate in this study must meet all of the following inclusion criteria: i) Males 18 years of age with hemophilia A and documented prior residual FVIII activity ^ 1 IU/dL including, but not limited to, at the time of detected inhibitors, at the time of signing the informed consent, ii) Documented history of a prior positive inhibitor result (results from a Bethesda Assay or Nijmegen Bethesda Assay > 0.6 BU), with the first detection of the inhibitor at least 12 months prior to Screening. iii) For Part A: Positive FVIII inhibitor test per central lab at Screening, defined as inhibitor titer > 0.6 BU from the chromogenic Nijmegen-Bethesda Assay (cNBA). The first 3 subjects enrolled in Part A must have an inhibitor titer > 5 BU. iv) For Part B: Negative FVIII inhibitor test per central lab at Screening, defined as inhibitor titer < 0.6 BU from cNBA. v) For Part A: Subject must be on emicizumab prophylaxis for at least 6 months prior to Screening. Subjects are required to be taking emicizumab at a maintenance dose of 1.5 mg/kg weekly, or be willing to switch to this regimen, prior to dosing with AAV-FVIII-SQ. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available. vi) For Part B: Subject must be on FVIII replacement prophylaxis therapy for at least 12 months prior to Screening. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available. vii) Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures. [203] Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier contraception (i.e. condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection. [204] Subjects must be willing to abstain from consumption of alcohol for at least the first 52 weeks following AAV-FVIII-SQ infusion. Exclusion Criteria [205] Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Detectable pre-existing antibodies to the AAV5 capsid.2. Any evidence of active infection or any immunosuppressive disorder, including HIV infection.3. Currently undergoing, or plan to receive during the study, immune tolerance induction therapy or prophylaxis with FVIII (Part A only). [206] The subject must not have significant liver dysfunction with any of the following abnormal laboratory results: ALT (alanine aminotransferase) > 1.25x ULN; AST (aspartate aminotransferase) > 1.25x ULN;GGT (gamma-glutamyltransferase) > 1.25x ULN; Total bilirubin > 1.25x ULN; Alkaline phosphatase > 1.25x ULN; or INR (international normalized ratio) ^ 1.4. Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing of the entire liver test panel within the same Screening window and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor. [207] Subject’s most recent, prior FibroScan or prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used. [208] Additional exclusion criteria include : evidence of any bleeding disorder not related to hemophilia A, Platelet count of < 100 x 109/L, significant renal dysfunction with any of the following abnormal laboratory results: serum creatinine >1.5 mg/dL, estimated glomerular filtration rate (eGFR) <90 mL/min by the Modification of Diet in Renal Disease (MDRD) equation hematuria or proteinuria as indicated by urine dipstick test at screening, liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan. [209] Further exclusion criteria include chronic or active hepatitis B as evidence by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy. Active malignancy, except non-melanoma skin cancer. History of hepatic malignancy. History of arterial or venous thromboembolic events (e.g. deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), except for catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation. A history of known inflammatory, connective tissue, or autoimmune disorders (e.g. vasculitis). [210] Subjects must not have received treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study. [211] Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including corticosteroid treatment outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result. [212] Additional exclusion criteria include prior treatment with any vector or gene transfer agent. Major surgery planned in the 26-week period following the infusion with AAV-FVIII-SQ. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the AAV-FVIII-SQ infusion. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of safety and efficacy of AAV-FVIII-SQ and with prior consultation with the Medical Monitor. Known allergy or hypersensitivity to investigational product formulation. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed. Corticosteroid Usage During Study [213] Refer to steroid prescription guidelines to determine eligibility, monitoring and managing of side effects during steroid treatment. Prior to dosing, all subjects must be screened per steroid prescription guidelines to ensure the subject is eligible to receive corticosteroid treatment as outlined in the protocol. Refer to corticosteroid prescription guidelines for recommended monitoring for, and management of, potential side effects of corticosteroids, including guidance on medications that should be avoided during corticosteroid treatment. Prophylactic Corticosteroids [214] All subjects will be started on prophylactic corticosteroids: For Part A subjects, prophylactic corticosteroids will be started at the Week 2 visit (Day 15). If clinically indicated (eg, ALT elevation, rising inhibitor titers), corticosteroids may be started earlier than Week 2. [215] For Part B subjects, prophylactic corticosteroids will be started on Study Day 1. The first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, or an equivalent dose of another corticosteroid) should be taken at least 3 hours prior to the start of the AAV- FVIII-SQ infusion and continued on a daily basis. Figure 12A (for Part A) and Figure 12B (for Part B) provide an example of a possible prophylactic corticosteroid course for each study part, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses. Discussions between the Investigator and Medical Monitor are advised for any questions or concerns. [216] If clinically indicated, corticosteroids may be started earlier than Week 2 (eg, in the event of an ALT increase, increasing inhibitor titers, etc.). Following initiation or completion of corticosteroid regimen, if a recurrence of ALT VALUES > ULN or ^ 1.5x baseline value is reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation, relationship between increases in ALT and FVIII activity, ALT levels/FVIII activity post-corticosteroid initiation, and adverse events related to corticosteroid dosing. After discontinuation of oral corticosteroids, weekly labs for ALT levels and FVIII activity will be measured once a week for 4 weeks to ensure stability in values. Test for hepatitis B or Hepatitis C should only be performed in subjects with a history of these diseases prior to study entry. [217] Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (eg, ^ 1.5x baseline value or > ULN) and alternative etiologies have been ruled out, and/or if FVIII activity levels significantly decline, prompt institution of newly administered or an increased dose of therapeutic or on-demand oral corticosteroids (prednisone or an equivalent dose of another corticosteroid) should be considered after consultation with the Medical Monitor. [218] Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids. Newly administered corticosteroids or dose increased are not indicated if elevations in ALT are clearly not related to AAV-FVIII-SQ (eg, elevated in ALT with concurrent increase in CPK due to intensive exercise) although this should be discussed with the Medical Monitor. [219] Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. If the ALT level immediately returns to ^ 1.5x baseline and FVIII activity levels continue to rise and/or remain within or above the normal range in the 2 weeks following corticosteroid initiation, on- demand corticosteroids can be discontinued. However, if this is not the case, therapeutic corticosteroids should be tapered over a longer period of time. At minimum, the recommended duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter. Should a scenario arise in which a deviation from the minimum recommended dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. [220] After discontinuation of oral corticosteroids, labs for ALT levels and FVIII activity will be measured once a week for 4 weeks to ensure stability in values. [221] Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels (eg, > ULN or ^ 1.5x baseline value) are reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression. [222] Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if possible. Practical management to prevent complications related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, hyperlipidemia etc.). Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start of oral corticosteroid treatment and then 1 week and 13 weeks after the completion of oral corticosteroid treatment in subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse events suspected to be caused by or related to corticosteroid use) should be reported. [223] Subjects on corticosteroids should receive appropriate counselling and support regarding side effects from the Investigator or the treating institution (eg, listings of side effects and when to notify carers, wallet card for emergencies if on steroids, etc.). Additional management, including the co-prescription of additional medications to prevent complications related to corticosteroid therapy, may be undertaken at the discretion of the investigator, including, but not limited to, prophylaxis against the occurrence of gastric ulcers, osteoporosis, and infections. All adverse events (including any adverse events suspected to be caused by or related to corticosteroid use) should be reported. Efficacy Variables FVIII Activity [224] The efficacy variable of primary interest for Part A and Part B is hFVIII activity, as measured by chromogenic substrate assay. The efficacy goal is to establish the timing to FVIII activity > 5 IU/dL post-AAV-FVIII-SQ infusion. [225] If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; the 72-hour wash-out period is only intended for subjects who have achieved FVIII > 5 IU/dL after AAV-FVIII-SQ infusion, discontinued prophylaxis, and who have not resumed FVIII replacement therapy or use of emicizumab. [226] In the event of an FVIII activity level decline during the study: If FVIII activity has declined at least 20% from the peak but less than 35% and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 7 days until FVIII activity is stable or increasing. If FVIII activity has declined >35% from the eh peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [227] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred (upon consultation between the Investigator and the Medical Monitor) until either a clearer trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase. [228] Subjects in Part B who do not respond to AAV-FVIII-SQ treatment (i.e., treatment failure, manifesting as either failure to achieve FVIII activity ^ 5 IU/dL by Week 52 or iNAbility to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the Medical Monitor or Sponsor-designated Data Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year visits during Years 2-5. Anti-FVIII Inhibitor Titer Changes [229] For Part A, decrease in anti-FVIII inhibitor titer post-infusion will be measured. For Part B, the absence of recurrence of anti-FVIII inhibitors ^ 0.6 BU post-infusion will be assessed. Hemophilia Treatment/Bleeding Episodes [230] The change in the annualized number of bleeding episodes requiring BPA in Part A or exogenous FVIII replacement treatment in Part B (annualized bleeding rate, ABR) post-AAV- FVIII-SQ infusion will be assessed, as will the change in the annualized utilization of emicizumab (Part A) or (IU/kg) exogenous FVIII replacement therapy (Part B) post- AAV-FVIII- SQ infusion from the baseline utilization of those therapies. [231] Subjects must have high quality documented historical data available concerning previous bleeding episodes and hemophilia treatment over the previous 12 months in order to be eligible to enroll in the study. During the study, subjects will be asked at each study visit to report the use of factor replacement therapy and the number of bleeding episodes since the previous visit. This information will be captured on the subject’s diary or other subject records. [232] Subjects are strongly encouraged to immediately consult Investigator for guidance regarding management of suspected bleeds or bleeding episodes within the first 30 days post AAV-FVIII-SQ infusion. [233] In subjects who experience recurrent bleeding episodes, the Investigaor and Medical Monitor will discuss whether to resume prior FVIII prophylaxis or use of emicizumab. Immunogenicity [234] Immunogenicity assays will be performed on plasma and PBMCs. The assays will include detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (Transduction Inhibitors, TI). FVIII Inhibitors will be assessed using the cNBA for both local and centralized testing. Any abnormality of the liver parameters will lead to a retrospective - immunogenicity assessment to evaluate FVIII and capsid-specific cellular immunogenicity. FVIII- and capsid-specific cellular immunity will be assessed by stimulated cytokine secretion using an interferon gamma (IFNg) ELISpot assay performed on collected PBMCs. Activation of complement will be evaluated by measuring plasma levels of C3, C3a, C4, Bb, and sC5b-9. Exploratory immunophenotyping of patients PBMC by flow cytometry will investigate changes over time in cellular immune responses, regulatory T-cell populations, and their relationship to FVIII inhibitor titers. Pharmacodynamics [235] The FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters. Pharmacokinetics [236] For Part B, sparse FVIII activity assessments, prior to AAV-FVIII-SQ administration, will be collected to estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours post-FVIII infusion. If supported by the data, sparse samples together with established population pharmacokinetic models will be used to estimate an individual subject’s FVIII activity clearance (CL) value. Individual subject CL estimates may then be evaluated against post- AAV-FVIII-SQ FVIII activity levels to determine if an association exists between an individual’s FVIII activity CL value and FVIII activity levels achieved with AAV-FVIII-SQ. Exploratory Assessments [237] Blood samples will be collected from subjects at the time points indicated in the Schedules of Events to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A. [238] All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol. In addition, samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed. Safety Variables [239] Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. Clinical Laboratory Assessments [240] The scheduled clinical laboratory tests are listed in Table 11.
Table 11 a Coagulation Screen Blood Chemistry Hematology Urine Tests including: activated partial Albumin Hemoglobin Appearance thromboplastin time (APTT) blood urea nitrogen prothrombin time/ (BUN) Hematocrit Color international normalized ratio (PT/INR) Calcium White Blood Cell pH thrombin time (TT) (WBC) count Chloride Red Bloo cd ou C ne tll (RBC) Specific gravity Total cholesterol Platelet count Ketones creatinine phosphokinase Differential cell count Protein (CPK) RBC indices mean corpuscular volume (MCV) and mean Creatinine corpuscular Glucose Other Tests: hemoglobin (MCH) CRP Bilirubin ABO blood typing* Glucose Nitrite Phosphorus Urobilinogen Potassium Hemoglobin Total protein UACR Sodium Uric Acid [241] For Part A, a local urine dipstick will be performed initially at all timepoints where urine tests are scheduled to be assessed. If the dipstick shows evidence of proteinuria or hematuria, or any other abnormalities deemed clinically significant by the Investigator, the urine sample should be sent for additional laboratory testing as outlined in the table. [242] In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) and fasting FibroTest will be assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. [243] In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour and 8-24 hours following the hypersensitivity reaction for assessment of complement and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points, if possible, 1 week after the event for an optional exploratory CBA to assess inflammatory biomarkers and plasma cytokine levels. [244] At applicable sites for subjects in Part B (and starting in Year 2 for subjects enrolled in Part A), certain study assessments may be performed by a MN professional at the patient's home or another suitable location, such as their school or office, to improve access and convenience for patients participating in the study. The Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor). The MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed. If the investigator at a participating site determines that MN services are appropriate for a patient and the patient gives written informed consent to participate in MN visits, the MN network will communicate with the patient and the patient’s site. MN visits will be allowed at the visits indicated in the Schedules of Events. Unscheduled visits may also be conducted by MN as appropriate. Liver and Hepatitis Testing [245] Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb. Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period. [246] Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening and will be tested for hepatitis B and hepatitis C reactivation. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening. [247] A liver ultrasound/FibroScan and LTs during Screening will identify any significant hepatic dysfunction. LTs will be monitored on a regular basis; at each time point, the following LTs should be assessed: alkaline phosphatase, ALT (SGPT), AST (SGOT), direct bilirubin, total bilirubin, CGT and LDH. Elevated ALT levels (above the upper limit of normal range) should be evaluated according to the following plan: Table 12 ALT Level Work-Up ^1.5x • Continue to monitor LTs and FVIII per protocol (repeat within 24-72 Bas -e <lin2ex p hrooutrosco ifl n secxhteduled visit is >24-72 hours from the time of the reported Baseline • ALT elevation) Consider evaluation to rule out alternative etiology (eg, concomitant medications, viral or autoimmune hepatitis, alcohol use, recreational drug use, special diets, strenuous exercise, prior and/or concurrent illnesses, exposure to environmental and/or industrial chemicals, etc.) • If ALT is > ULN or > 2x baseline in 2 consecutive assessments within 24-72 hours and alternative etiologies have been ruled out, start oral corticosteroids upon consultation with the Medical Monitor ^2x • Repeat LTs and FVIII within 24-72 hours or > Ba UsLeNlin -e <3x ULN • Continue to monitor LTs weekly until ALT is stable or improving • Evaluate and rule out alternative etiologies (as above) • Consult with Medical Monitor • If ALT is ^ 2x baseline or > ULN - < 3x ULN in 2 consecutive a 7s2se hsosumrsen atsnd wi athltienrnative etiologies have been ruled out, start oral corticosteroids upon consultation with the Medical Monitor (refer to Section 9.4.8.2) • Obtain other possibly relevant laboratory evaluations (albumin, PT/INR, • C ORbtPa,in et cco.)mplete blood count with differential to assess for eosinophilia • Obtain PBMC to evaluate potential immune response (prior to starting oral corticosteroids) • If no improvement in 14 days, consider gastroenterology and/or hepatology consult, abdominal workup, imaging (including MRI or ultrasound), and/or liver biopsy as appropriate ^3x ULN • Consult with Medical Monitor • Evaluate and rule out alternative etiologies (as above) • Repeat LTs and FVIII within 24-48 hours, and continue with monitoring of LTs at least twice weekly for as long as the subject’s • A IfL ^T3x re UmLaNin isn ^ 23 cxon UsLeNcutive assessments within 48 hours, start oral corticosteroids • Obtain other possibly relevant laboratory evaluations (albumin, PT/INR, • C ORbtPa,in et cco.)mplete blood count with differential to assess for eosinophilia • Obtain PBMC to evaluate potential immune response (prior to starting oral corticosteroids) • If no improvement in 14 days, consider gastroenterology and/or hepatology consult, abdominal workup, imaging (including MRI or ultrasound), and/or liver biopsy as appropriate Adverse Effects [248] An adverse effect (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. [249] Events meeting the AE definition include Exacerbation of a chronic or intermittent pre- existing condition including either an increase in frequency and/or intensity of the condition. New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study. Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. [250] Events not meeting the AE definition include: Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition. The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition. Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the AE. Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). Anticipated day- to-day fluctuations of pre-existing disease(s) or conditions(s) present or detected at the start of the study that do not worsen. Efficacy Analyses [251] For Part A and Part B, the efficacy variable of primary interest, hFVIII activity levels, as measured by chromogenic substrate assay (bovine), will be summarized descriptively by visit. The number and proportion of subjects with hFVIII activity > 5 IU/dL by visit as well as time to first achieving hFVIII > 5 IU/dL will also be summarized. Values for hFVIII activity will be excluded if obtained within 72 hours since the last infusion of exogenous FVIII protein concentrates. [252] For Part A, decrease in anti-FVIII inhibitor titer post-infusion, change in ABR requiring BPA post-AAV-FVIII-SQ infusion from baseline, and change in the annualized utilization of emicizumab post-AAV-FVIII-SQ infusion from baseline will be summarized. [253] For Part B, absence of anti-FVIII inhibitors < 0.6 BU post-infusion, change in ABR requiring exogenous FVIII replacement treatment post-AAV-FVIII-SQ infusion from baseline, and change in the annualized utilization of exogenous FVIII replacement therapy (IU/kg) post- AAV-FVIII-SQ infusion from baseline will be summarized. Safety Analysis [254] All AEs will be coded to system organ class and preferred term using the current version of MedDRA. The incidence of AEs will be summarized by system organ class, preferred term, relationship to study drug, and severity. A by-subject listing will be provided for those subjects who experience an SAE, including death, an EOSI, or an AE resulting in early withdrawal from the study. [255] Clinical laboratory data will be summarized by the type of laboratory test. For each clinical laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent visits. Descriptive statistics for physical examination results and vital signs will also be provided. Immunogenicity Analysis [256] Anti-AAV5 capsid and anti-FVIII total antibodies, as well as neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (Transduction Inhibitors, TI) will be summarized. Pharmacodynamic Analyses [257] Plasma profiles will utilize the FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively. PD parameters determined using FVIII protein and activity will be summarized with descriptive statistical measures (e.g. mean, standard deviation, CV%, min, median, max). Example 7 Endopeptidase cleavage of IgG to remove circulating antibody. [258] A pilot study was conducted in non-human primates (NHPs) that demonstrated a single dose of Imlifidase (IdeS) reduced pre-existing antibody titers and enabled successful transduction of the liver. Four NHPs were included in the study, Animal P0201 had pre-existing AAV5 antibodies, and Animals P0001, P0002 & P0003 were AAV5 negative and served as positive controls. The NHP with pre-existing AAV5 TAbs was administered 5 mg/kg IV of IdeS 48 hrs prior to challenge with 6E13 vg/kg of an AAV5-Factor IX (FIX) vector. IdeS was well tolerated with no safety observations. The single dose of IdeS administered to Animal P0201 with pre-existing antibodies (plotted in black through all three panels) reduced TAb titer below MRD and FIX level was greater than controls (Figure 13 A-D). [259] A rabbit model system was developed to evaluate immunogenicity and AAV5 vectored gene therapy that adopted a low dose AAV sensitization model, to induce immunity, followed by rechallenge with AAV to assess effectiveness of IdeS in overcoming anti-AAV antibodies. IdeS was also well tolerated in rabbits with no safety observations. The rabbit IdeS study design is depicted in Figure 14A. Animals sensitized in with AAV5-bCG produced a range of NAb and TAb titers and were evenly distributed into IdeS-treated and Control groups. (Figure 14B). A single dose of 1 mg/kg IdeS reduced treatment induced AAV5 TAb titers by >99% in 11/11 animals (Figure 15A), and also enabled successful transgene expression in all sensitized animals (Figure 15B and 15C). Taken together, IdeS treatment enabled efficacious gene therapy dose administration in a redosing scenario where animals were sensitized to have physiologically meaningful TAb and NAb titers. [260] A 99% decrease would reduce TAb titers in all hemophilia A patients from the study described above (Example 7) to below the AAV 5 companion diagnostic cut-point, assuming IdeS was equally efficacious in human patients (Figure 16). A 1 mg/kg dose in rabbits has a human equivalent dose of 0.3 mg/kg (based on body surface area) which is comparable to 0.25 mg/kg approved clinical dose of IdeS. While pre-existing antibody titers are lowered and more manageable than treatment emergent titers, sequential IdeS dosing or combination with plasmpaheresis could allow redosing as well. [261] Patients that test positive for AAV5 TAb in the CDx are ineligible for AAV-FVIII-SQ treatment (~30% of the population). The IgG degrading enzyme approach for seropositive people to access gene therapy will unlock additional patients for AAV-FVIII-SQ gene therapy and other gene therapies. A single dose of an IgG cleaving enzyme, IdeS, could address essentially all patients with pre-existing immunity, is easy to administer and is well tolerated and could also provide a potential path to redosing patients when FVIII levels wane. EXAMPLE 8 Preliminary Results from Clinical Study Investigating Clinical Phenotype Hemophilia A Patients with FVIII Activity [262] The following is data obtained in the clinical study described above in Example 6 to assess the safety of a single IV administration of AAV-FVIII-SQ (valoctocogene roxaparvovec) for individuals with severe hemophilia A and active (part A) or prior (part B) FVIII inhibitors. The primary outcome was safety, and the secondary outcomes were efficacy as indicted by a change in baseline for FVIII activity and antibody titer, annualized bleeding rate, annualized utilization of hemophilia therapy and hemophilia-specific quality of life questionnaire for adults (Haemo-Qol-A). The study schedule is provided in Figure 17. In Part A (active FVIII inhibitors), data for two patients is provided herein. Participant 1 was a 30 year old male, who received emicizumab prior to and throughout the study. This participant received prophylactic corticosteroids from week 2 to week 21, then received reactive corticosteroids from week 24 to week 31 and from week 34 to week 42. The inhibitor titer level at screening was 3.5 BU, with a peak inhibitor titer of 200 BU for participant 1. Participant 2 was a 27 year old male, who received emicizumab before and throughout the time of the trial. This participant received prophylactic corticosteroids from week 2 to week 21. For participant 2, the inhibitor level at screening was 2.2 BU with a peak inhibitor titer of 72 BU. The normal ALT range is 5-48 U/L. [263] Figures 18A and 18B provide the inhibitor levels, FVIII activity levels, FVIII antigen levels and ALT levels over 52 weeks. In this figure, FVIII activity levels of <1.5 IU/dL were imputed as 0 and FVIII antigen levels of <4.7 ng/mL were imputed as 1. The FVIII inhibitor titers increased as expected, and the rise in FVIII inhibitor levels suggest FVIII is being produced in the liver although it was undetectable by chromogenic substrate assay (CSA). Participant 1 exhibited fluctuation in FVIII inhibitor titers. Participant 2 exhibited a decrease in FVIII inhibitor titers and a decrease in detectable FVIII activity by week 28. [264] In Part B (prior FVIII inhibitors), data for two patients is provided herein. Participant 1 was a 33 year old male, who received FVIII prophylaxis from week 1 through week 4. This participant received prophylactic corticosteroids from week 1 to week 6, and received immunosuppressive agent mycophenolate mofetil (1000 mg 2x a day) from week 11 to week 18 and again from week 20 to week 26. For participant 1, the inhibitor titer level at screening was <0.6 BU, with a peak inhibitor titer of 20 BU. Participant 2 was a 26 year old male, who received FVIII prophylaxis from week 1 through week 5. This participant received prophylactic corticosteroids from week 1 to week 8, and then reactive corticosteroids from week 8 to week 18, from week 21 to week 26 and then again from week 26 to week 34. For participant 2, the inhibitor level at screen was <0.6 BU with a peak inhibitor titer of 20 BU. [265] Figures 19 A and B provide the inhibitor levels, FVIII activity levels and ALT levels over 36 weeks. The normal ALT range is 5-48 U/L. This data demonstrated that both participants demonstrated an increase in FVIII activity levels by week 4. [266] All of the participants in the study showed a similar safety profile. The most common adverse event was ALT elevation. There were not serious or severe adverse events reported related to administration of valoctocogene roxaparvec or IS therapy. There were no thromboembolic events or malignancy. No FVIII inhibitor recurrence in the prior inhibitor population (part B). EXAMPLE 9 Clinical Study To Evaluate Efficacy And Safety Of Administration Of AAV-FVIII-SQ And Prophylactic Corticosteroids [267] In the study described above in Example 6, subjects were started on corticosteroids by Week 3 (either therapeutically, in response to an alanine aminotransferase (ALT) elevation, or prophylactically), and in another clinical study (referred to the 270-301 study) subjects received corticosteroids only in response to an ALT elevation. Possibly as a result of this difference, subjects receiving 6E13 vg/kg in the 270-201 study started corticosteroids at an earlier date in reference to the date of AAV-FVIII-SQ infusion, showed later advent of first ALT elevations, and were also less likely to experience a significant decline in FVIII activity concurrently with an ALT elevation when compared with subjects in 270-301 (20% of subjects in 270-201 vs.58% of subjects in 270-301). In the 270-301 study, ALT elevation within the first 26 weeks was associated with decreased FVIII activity. Recently published data from 270-201 suggests that corticosteroids may have assisted in rescue or protection of FVIII levels during elevations of ALT and in resolution of elevated ALT levels in some subjects. [268] The current study is a Phase 3b, single arm, open-label study designed to assess whether AAV-FVIII-SQ, at a dose of 6E13 vg/kg with prophylactic corticosteroids, can safely and effectively improve the FVIII activity profiles and alter the clinical phenotype of hemophilia A patients with residual FVIII activity ^ 1 IU/dL. Subjects are enrolled at approximately 10 sites worldwide. Subjects must have high-quality, well-documented historical data available concerning previous bleeding episodes and exogenous FVIII usage over the previous 12 months in order to be eligible to enroll in the study. [269] AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. [270] On the day of infusion, the subject will come to the infusion site, where a physical examination is performed. If the subject is found to have an active acute illness at the time of planned infusion, then the infusion should be deferred until the illness has resolved; screening procedures may require repetition if outside the specified window. An IV catheter will be inserted into a suitable peripheral vein (e.g. the median cubital vein) and flushed with saline. FVIII replacement therapy will not be given since venipuncture is a minimally invasive procedure in these individuals under ordinary conditions. AAV-FVIII-SQ is prepared and infused as a pure solution over a dose-dependent time. Prepared drug is kept at room temperature prior to administration. [271] AAV-FVIII-SQ is infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min. The infusion rate is increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase. Of note, the IP has been shown to be stable at room temperature for 10 hours following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and temperature) are monitored at 15 minute (±5 minutes) intervals throughout the time period of the infusion. Therapeutic Corticosteroid Treatment and/or Alternative Immunosuppressive Agent Treatment of Elevated Hepatic Transaminases [272] Refer to steroid prescription guidelines to determine eligibility, monitoring and managing of side effects during steroid treatment. Prior to dosing, all subjects are screened per steroid prescription guidelines to ensure the subject is eligible to receive corticosteroid treatment as outlined in the protocol. Refer to corticosteroid prescription guidelines for recommended monitoring for, and management of, potential side effects of corticosteroids, including guidance on medications that should be avoided during corticosteroid treatment. [273] All subjects are started on prophylactic corticosteroids starting on the day of infusion (Day 1). The first dose of prophylactic corticosteroids (40 mg of prednisone or prednisolone, or an equivalent dose of another corticosteroid) is taken at least 3 hours prior to the start of the AAV-FVIII-SQ infusion and continued on a daily basis. See Figure 12B provides an example of a possible prophylactic corticosteroid course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses. [274] Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (e.g. ^ 1.5x baseline value or > ULN) and alternative etiologies have been ruled out, prompt institution of newly administered or an increased dose of therapeutic or on-demand oral corticosteroids (prednisone or an equivalent dose of another corticosteroid) should be considered. i) Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids. ii) Newly administered corticosteroids or dose increases are not indicated if elevations in ALT are clearly not related to AAV-FVIII-SQ (e.g., elevated ALT with concurrent increase in CPK due to intensive exercise). iii) Alternative immunosuppressive agents may also be considered for use on a case-by-case basis (e.g., if prolonged corticosteroid use is contraindicated). [275] Unless otherwise indicated, therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. If the ALT level immediately returns to ^ 1.5x baseline and FVIII activity levels continue to rise and/or remain within or above the normal range in the 2 weeks following corticosteroid initiation, on-demand corticosteroids can be discontinued. However, if this is not the case, therapeutic corticosteroids should be tapered over a longer period of time. At minimum, the recommended duration of on-demand corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter. Should a scenario arise in which a deviation from the minimum recommended dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. Tapering of corticosteroid dosages should be guided as set out in the following Table 13. Table 13 Adjustments to Corticosteroid Regimen Corticosteroids may be tapered if: Corticosteroids should be tapered on an individual • ALT ^ 1.5x baseline value; and subje thcet b foalsloisw winigth guiding • FVIII activity levels > 90% of the pre-decline FVIII principles: activity levels; and • There is no concern for adrenal insufficiency post- withdrawal If ALT level is increasing or FVIII activity level is decreasing Increasing Corticosteroid o wrhaille c o rnticosteroids, any increases in oral corticosteroid Dose dosing should be made only upon consultation with the Medical Monitor For any scenarios that are not accounted for in the above table, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. [276] After discontinuation of on-demand oral corticosteroids, labs for ALT and FVIII levels are measured once a week for 4 weeks to ensure stability in values. [277] Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels (eg, > ULN or ^ 1.5x baseline value) are reported, corticosteroid management decisions will be based on discussions with the Investigator. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression. [278] Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if possible. Practical management to prevent complications related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (e.g., evaluation of glucose intolerance, hyperlipidemia etc.). Alternative, non-steroidal systemic immunosuppressive agents may be used should corticosteroid use be deemed by an Investigator to be clinically ineffective, not tolerated, and/or contraindicated. Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start of oral corticosteroid/immunosuppressive agent treatment in corticosteroid/immunosuppressive agent treatment and then 1 week and 13 weeks after the completion of oral corticosteroid/immunosuppressive agent subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse events suspected to be caused by or related to corticosteroid/immunosuppressive agent use) should be reported. Subjects [279] Approximately 20 adult subjects with severe HA (e.g. residual FVIII levels ^ 1 IU/dL) will receive a 6E13 vg/kg dose of AAV-FVIII-SQ as a single intravenous infusion in conjunction with receipt of a 19-week prophylactic corticosteroid regimen starting on the day of the AAV-FVIII-SQ infusion. Post-infusion, subjects are eligible to receive on-demand corticosteroids. [280] The final analysis for the study is performed after all subjects have been followed for 52 weeks post- AAV-FVIII-SQ infusion (or have discontinued study participation prior to Week 52). After the final analysis, safety and efficacy will then continue to be assessed long-term for a total of approximately 5 years for each subject. [281] To avoid breakthrough bleeding, subjects will only discontinue exogenous prophylactic FVIII replacement therapy 4 weeks following infusion of AAV-FVIII-SQ or if FVIII activity has consistently increased above 5 IU/dL, whichever is earlier. Four weeks represents the time by which endogenous production of FVIII following gene transfer is expected to be efficacious, based on prior study results. Subjects previously receiving emicizumab, given its approximate 1- month half-life, will remain on emicizumab prophylaxis until AAV-FVIII-SQ infusion, with their final dose administered prior to Day 1. [282] In subjects who experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume prior FVIII prophylaxis. Subjects who do not respond to AAV-FVIII-SQ treatment (ie, treatment failure, manifesting as either failure to achieve FVIII activity ^ 5 IU/dL by Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the Medical Monitor or Sponsor- designated Data Monitor, follow an abbreviated visit schedule after Week 52 of the study by attending only the Q12W and End of Year visits during Years 2-5. [283] An optional liver biopsy is performed (in subjects who consent to do so) at or around Week 26, Week 52, and/or during Years 2-5 following AAV-FVIII-SQ infusion. Subjects who consent to the liver biopsy will have additional assessments, including a liver ultrasound and FibroScan, and will receive prophylactic FVIII prior to the procedure, as indicated in the judgment of the Investigator, to minimize the risk of bleeding. Outcomes [284] The primary efficacy objective of the study is to assess the efficacy of AAV-FVIII-SQ with prophylactic corticosteroids defined as FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52, following intravenous infusion of AAV-FVIII-SQ. [285] The secondary efficacy objectives of the study are to assess the impact of AAV-FVIII- SQ with prophylactic corticosteroids on the use of exogenous FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving prior emicizumab prophylaxis. ii) Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on the number of bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to Week 52 for subjects receiving prior FVIII prophylaxis or on use of emicizumab from Week 27 to Week 52 for subjects receiving prior emicizumab prophylaxis. iii) Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on quality of life as measured by the Haemo-QoL-A questionnaire at Week 52 of the study compared to baseline. [286] The tertiary efficacy objective of the study is to Assess the impact of AAV-FVIII-SQ with prophylactic corticosteroids on patient-reported outcomes (PROs) (other than Haemo-QoL-A) at Week 52 of the study compared to baseline. [287] The exploratory efficacy objective of the study is to assess the efficacy of AAV-FVIII-SQ with prophylactic corticosteroids defined as FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52, following intravenous infusion of AAV-FVIII-SQ for subjects with detectable AAV5 total antibodies below the minimum required dilution at Screening. [288] The safety objectives of the study are to evaluate the safety of AAV-FVIII-SQ with prophylactic corticosteroids during the first 52 weeks following intravenous infusion of AAV- FVIII-SQ and to assess the long-term safety of AAV-FVIII-SQ with prophylactic corticosteroids. Inclusion and Exclusion Criteria [289] Individuals eligible to participate in this study must meet all of the following inclusion criteria: 1. Males ^ 18 years of age with hemophilia A and residual FVIII levels ^ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent. 2. Must have been on prophylactic hemophilia therapy for at least 12 months prior to study entry. High-quality, well-documented historical data concerning bleeding episodes and hemophilia therapy usage over the previous 12 months must be available. 3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs). 4. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures. 5. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 6. 0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart within the past 12 months (at least one of which should be tested at the central laboratory). 7. Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection. 8. Willing to abstain from alcohol consumption for at least the first 52 weeks following AAV-FVIII-SQ infusion. [290] Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Detectable pre-existing antibodies to the AAV5 capsid. Up to 25% of subjects may have detectable pre-existing AAV5 capsid antibodies, so long as the titer level is below the minimum required dilution (< 20). Any evidence of active infection or any immunosuppressive disorder, including HIV infection. Significant liver dysfunction with any of the following abnormal laboratory results: ALT (alanine aminotransferase) > 1.25x ULN; AST (aspartate aminotransferase) > 1.25x ULN; GGT (gamma-glutamyltransferase) > 1.25x ULN; Total bilirubin > 1.25x ULN; Alkaline phosphatase > 1.25x ULN; or INR (international normalized ratio) ? 1.4. Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing of the entire liver test panel within the same Screening window and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor. FibroScan or prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts, 1995) or METAVIR (Bedossa, 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used. Evidence of any bleeding disorder not related to hemophilia A. Platelet count of < 100 x 109/L. Creatinine > 1.5 mg/dL. Liver cirrhosis of any etiology as assessed by FibroScan or liver ultrasound. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results in the Laboratory Manual. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy. Active malignancy, except non-melanoma skin cancer. History of hepatic malignancy. 20. History of arterial or venous thromboembolic events (e.g., deep vein thrombosis, non- hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing. 21. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation. 22. Treatment with any investigational product within 30 days or 5 half-lives of the investigational product prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study. 23. Any condition that, in the opinion of the Investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including possible corticosteroid treatment outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result. 24. Prior treatment with any vector or gene transfer agent. 25. Major surgery planned in the 52-week period following the infusion with AAV-FVIII-SQ. 26. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the AAV-FVIII-SQ infusion. 27. Concurrent enrollment in another clinical study, unless it is an observational (non- interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of efficacy and safety of AAV- FVIII-SQ and with prior consultation with the Medical Monitor. 28. Known allergy or hypersensitivity to AAV-FVIII-SQ investigational product formulation. 29. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleeding episode. [291] Individuals eligible for the optional liver biopsy must meet the following inclusion criterion: 1. Able to sign informed consent and comply with requirements for the optional liver biopsy. 2. Documentation of FVIII activity ^ 50 IU/dL (or higher, depending on local guidelines and/or Investigator discretion) within 24 hours prior to the liver biopsy being performed (FVIII activity levels should be assessed at the local laboratory). Subjects may be treated with additional exogenous FVIII replacement products in order to increase their FVIII levels activity to an appropriate level, under the supervision/instruction of the Investigator. [292] Individuals who meet any of the following exclusion criteria are not eligible for the optional liver biopsy: Any condition that, in the opinion of the Investigator or a hepatologist/radiologist would make liver biopsy contraindicated. This includes (but is not limited to) abnormalities detected on liver ultrasound performed within 28 days of procedure, or prior liver ultrasound result within 90 days that would preclude safe performance of the biopsy. Study Safety Evaluation Criteria [293] If any of the following events occur in a subject in the study who has received AAV- FVIII-SQ infusion, an urgent evaluation by the DMC will be required and further enrollment into the trial will be temporarily put on hold. i) Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic etiology): ALT > 5x ULN, for more than 2 weeks, ALT > 3x ULN and (total bilirubin > 2x ULN or INR >1.5) or ALT > 3x ULN with signs and symptoms of liver dysfunction. ii) The occurrence of Grade 4 or Grade 5 adverse events assessed as related to study drug (events of liver dysfunction are defined above). iii) The occurrence of an AE of hepatic failure. iv) The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in two subjects. v) The occurrence of any cancer (except non-melanoma skin cancer) at any point after AAV-FVIII-SQ infusion. vi) The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one subject. [294] If any of the following events occurs in a subject in the study who has received AAV- FVIII-SQ infusion, an urgent evaluation is required. Further enrollment into the trial will continue while DMC evaluation is ongoing, unless deemed otherwise by the DMC: i) The detection of high-titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in one subject or ii) occurrence of a thromboembolic event in one subject. Primary Efficacy Variable – FVIII Activity [295] The primary efficacy variable is change of the hFVIII activity, as measured by chromogenic substrate assay during Weeks 49-52 post-AAV-FVIII-SQ infusion from baseline. [296] If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; The 72-hour wash-out period is only intended for subjects who have achieved FVIII ^ 5 IU/dL at the end of 16 weeks after AAV-FVIII-SQ infusion and who have not resumed FVIII replacement therapy. [297] In the event of an FVIII activity level decline during the study: i) If FVIII activity has declined at least 20% from the peak but less than 35% and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 7 days until FVIII activity is stable or increasing. Ii) If FVIII activity has declined ^ 35% from the peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [298] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred until either a clearer trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase. Secondary Efficacy Variables FVIII Replacement Therapy/Bleeding Episodes [299] Secondary efficacy variables include: i)·Change in the annualized utilization (IU/kg/year) and infusion (number/year) rates of exogenous FVIII replacement therapy during Week 5 to Week 52 post-AAV-FVIII-SQ infusion from the baseline number and utilization of exogenous FVIII replacement therapy, for subjects receiving FVIII prophylaxis during the 12 months prior to study entry, or change in administration of exogenous FVIII replacement therapy Week 27 to Week 52 post-AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis. ii) ·Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 post- AAV-FVIII-SQ infusion for subjects receiving prior FVIII prophylaxis, or Week 27 to Week 52 post-AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis, from the baseline ABR during the 12 months prior to study entry. [300] Subjects must have high quality documented historical data available concerning previous bleeding episodes and hemophilia treatment over the previous 12 months in order to be eligible to enroll in the study. During the study, subjects will be asked at each study visit to report the use of factor replacement therapy and the number of bleeding episodes since the previous visit. This information will be captured on the subject’s diary or other subject records. [301] Subjects are strongly encouraged to immediately consult Investigator for guidance regarding exogenous FVIII administration for suspected bleeds or bleeding episodes within the first 30 days post-AAV-FVIII-SQ infusion. In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume prior FVIII prophylaxis or use of emicizumab. Patient-Reported Outcomes (PRO) [302] The Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality of life questionnaire for adults (Rentz, 2008). It consists of 41 questions covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns). Items are answered on a 6-point Likert-type scale, ranging from 0 (None of the time) to 5 (All of the time). Higher scores mean better health-related quality of life or less impairment for a particular subscale (Haemo-QoL Study Group, 2017). [303] The EQ-5D-5L instrument is a self-reported questionnaire designed to measure general health status (The EuroQol Group, 1990) (Brooks, 1996). The EQ-5D-5L is composed of 2- parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual analogue scale (EQ VAS) assessment for overall health. [304] The Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of disease symptom severity on work productivity and classroom productivity (if applicable) (Recht, 2014). The WPAI+CIQ:HS questionnaire yields scores related to work/classroom absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and activity impairment. WPAI+CIQ:HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (Reilly, 2002). [305] The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is designed to investigate and directly probe patient perspectives on outcomes they deem relevant to their life and care. PROBE aims to develop a new global tool to enhance the direct patient- voice in health care decision-making (Chai-Adisaksopha, 2017). Immunogenicity [306] Immunogenicity assays will be performed on plasma and PBMCs. The assays will include detection of anti-AAV5 capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 capsid (transduction inhibitors, TI). FVIII inhibitors are assessed using the chromogenic Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will lead to a retrospective immunogenicity assessment to evaluate FVIII- and capsid-specific cellular immunogenicity. FVIII- and capsid-specific cellular immunity is assessed by stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs. [307] The FVIII protein concentration and activity level is measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters. Pharmacokinetics [308] Sparse FVIII activity assessments, prior to AAV-FVIII-SQ administration, is collected to estimate each subject’s half-life of replacement FVIII concentrate used for prophylaxis. Samples will be drawn immediately prior to recombinant FVIII concentrate infusion (between Day -2 and Day -7), 3 hours (+/- 30 minutes) post-FVIII infusion, and 24-52 hours post-FVIII infusion. If supported by the data, sparse samples together with established population pharmacokinetic models is used to estimate an individual subject’s FVIII activity clearance (CL) value. Individual subject CL estimates are then evaluated against post-AAV-FVIII-SQ FVIII activity levels to determine if an association exists between an individual’s FVIII activity CL value and FVIII activity levels achieved with AAV-FVIII-SQ. For subjects receiving emicizumab, pharmacokinetics assessment is optional. Exploratory Assessments [309] Blood samples are collected from subjects at particular time points to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV gene transfer, and to develop assays used for these evaluations. Subjects may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A. [310] All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol. In addition, samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed. Optional Liver Biopsy [311] Subjects electing to undergo an optional liver biopsy are required to consent to the procedure and collection of tissue in the study ICF. The analysis of the optional liver biopsy is considered exploratory. Patients who elect to proceed will have a liver biopsy performed around Week 26, Week 52, and/or during Years 2-5. Additional liver biopsies at times deemed to be clinically relevant (e.g., decreasing FVIII at a time of increased ALT) may be pursued. Subjects will be asked to consent to the procedure for each liver biopsy performed during the study. [312] Subjects who consent to the procedure will have a liver biopsy via either transjugular or percutaneous (ultrasound-guided) route, according to the standard procedures of the institution. Two tissue cores will be harvested in the context of the optional liver biopsy. Subjects will be required to observe an 8-hour fasting period before the procedure. [313] Within 24 hours prior to the biopsy being performed, subjects must have a documented FVIII activity level of ^ 50 IU/dL (or higher, depending on local guidelines and/or investigator discretion). FVIII activity levels for this purpose should be assessed at the local laboratory within 7 days before the biopsy and again on the day the biopsy, prior to the procedure. As needed, subjects may be treated with additional exogenous FVIII replacement products in order to increase their FVIII activity levels to an appropriate level, under the supervision/instruction of the investigator, to ensure the safety of the subject during the procedure. [314] Subjects consenting to participate to the optional liver biopsy will undergo pre-biopsy assessments at least 7 days before the procedure, as follows: Local FVIII activity level assessment and/or Pre-biopsy consultation (with hepatologist and/or radiologist). [315] On the day of the biopsy, brief physical examination and liver and blood tests should be performed before the procedure (including hematology, coagulation, and chemistry). FVIII activity assessment should also be performed to ensure the subject has sufficient FVIII activity to protect against procedure-related bleeding (as discussed above). LT assessment and a whole blood draw for PBMC collection should be performed on the biopsy day or ± 1 week from the biopsy day. [316] The optional liver biopsy is performed in the morning if feasible, and the biopsy procedure and follow-up care should be done according to the local standard of care. Following completion of the biopsy, the subject should remain under observation in the clinic for at least 4- 6 hours. Overnight post-procedure observation may be done at the investigator’s discretion and/or according to local guidelines. Safety Variables [317] Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected at the same time as the local unscheduled sample. Clinical Laboratory Assessments [318] The scheduled clinical laboratory tests are listed in Table 11 (see Example 6 above). Any abnormal test results determined to be clinically significant by the Investigator should be repeated (at the Investigator’s discretion) until: (1) the cause of the abnormality is determined; (2) the value returns to baseline or to within normal limits; or (3) the Investigator determines that the abnormal value is no longer clinically significant. [319] In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) and Fibrotest will be assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. [320] In case of a Grade 2 or higher hypersensitivity or adverse drug reaction, a safety assessment including physical examination and vital signs will be performed and additional blood samples will be collected within 1 hour, and 8-24 hours following the hypersensitivity reaction for assessment of complement (C3, C3a, C4, Bb, and sC5b-9) and tryptase. Additional samples will be collected at the 1 hour and 8-24 hour time points and, if possible, 1 week after the event for an optional, exploratory CBA to assess inflammatory biomarkers and plasma cytokine levels. Inpatient observation can be extended and additional blood samples can be collected if deemed necessary. Liver and Hepatitis Testing [321] Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb. Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period. [322] Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with a history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B and hepatitis C reactivation at the timepoints. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening. Liver tests are summarized in Table 14 below: TABLE 14 LIVER TESTS (LTS) ALKALINE AST (SGOT) TOTAL BILIRUBIN LDH PH AOLSTP (SHGATPATS)E DIRECT BILIRUBIN GGT ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma- glutamyltransferase; LDH, lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase [323] Elevated ALT levels (above the upper limit of normal range) should be evaluated according to the plan set out in Table 12 (in Example 6 above). [324] When ruling out alternative viral or autoimmune hepatitis as part of the elevated ALT workup, the following tests as set out in Table 15 should be performed. Table 15 Viral Hepatitis Workup Testing Autoimmune Hepatitis Workup Testing Hepatitis A Smooth muscle antibody Hepatitis B Mitochondrial antibody Hepatitis C Liver/kidney microsomal antibodies Hepatitis E Antinuclear antibody (ANA) HEP-2 Cytomegalovirus (CMV) Epstein-Barr virus (EBV) Herpes simplex virus (HSV) 1 & 2 HIV Testing [325] HIV testing will be performed at Screening. Subjects with documented negative results within the last 30 days prior to screening do not need to be retested. Vital Signs, Physical Examinations and Other Observations Related to Safety [326] Vital signs will include seated systolic and diastolic blood pressure, heart rate, respiration rate, and temperature. Any clinically significant change in vital signs will be recorded as an AE. [327] Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature will be assessed at the time points indicated in the schedules of events. On the day of the AAV-FVIII-SQ infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Any abnormal vital sign assessments should be repeated, and both values should be recorded in the eCRF. [328] A complete physical examination should be performed during Screening/Baseline, at Week 26 (± 2 weeks) and 52 and every 52 weeks thereafter; at other visits, brief physical examinations may be performed at the discretion of the Investigator based on the subject’s clinical condition. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses. [329] A complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. A brief physical examination will include general appearance, cardiovascular, dermatologic, respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. Height will be recorded at Screening only. Weight will be recorded at Screening and then at the timepoints indicated in the Schedules of Assessments. Vector Shedding [330] During the Post-Infusion Follow-Up period, subjects will undergo testing of various bodily samples to look for evidence of vector shedding for possible viral transmission. Bodily fluids will be tested by polymerase chain reaction (PCR). Fluids tested will include: blood, saliva, semen, urine and/or stool. [331] Vector shedding will also be extensively studied in the present clinical trial. Testing will continue until at least 3 consecutive results below the limit of detection are obtained; additional collection and testing may be performed based on batch testing schedules, result turnaround times, or discussions between Medical Monitor and Investigator. Testing of semen will continue at least through Week 12, even if 3 consecutive results below the limit of detection have been recorded in that compartment prior to that time point. Subjects who have not had 3 consecutive semen samples below the limit of detection by Week 52 should continue to have PCR testing in semen every 4 weeks (during Year 2) or every 6 weeks (during Years 3-5) until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and Medical Monitor). [332] Samples may be fractionated prior to shedding analysis in order to better characterize the presence, structure, and location of vector DNA and/or vector capsid within each matrix. If needed, the fractionation may be performed with samples collected specifically for shedding analysis (saliva, blood, semen, urine, stool). Alternatively, the vector DNA characterization during shedding analysis may utilize already fractionated exploratory samples obtained from the above biofluids, such as exploratory plasma samples, exploratory PBMC samples, and red blood cells recovered during PBMC/plasma isolations. [333] Fractionation of semen to collect purified sperm separately from non-sperm cells may be performed, after consultation between the Medical Monitor and the Investigator, in parallel at any visit where semen samples are collected. The shedding analysis of a fractionated semen sample will only be performed if vector DNA was detected in the whole semen sample for the same visit. Fractionation of semen during shedding analysis may be stopped if purified sperm tested positive for vector DNA on at least three visits, or if purified sperm tested below the limit of detection for vector DNA on at least three consecutive visits. [334] Contraception use may need to be extended beyond 12 weeks in individual subjects based on observed vector shedding in semen. After 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples below the limit of detection (upon consultation between the Investigator and Medical Monitor). Primary Efficacy Endpoint [335] For the primary efficacy endpoint at Week 52 (i.e., the change in the hFVIII activity during Weeks 49-52 post-AAV-FVIII-SQ infusion from baseline, as measured by chromogenic substrate assay), a one-sample t-test will be used to test the null hypothesis that the change is 0 or less against the alternative hypothesis that the change is greater than 0 at the 1-sided significance level of 0.025 (or equivalently, at the 2-sided significance level of 0.05). Baseline value of 1 IU/dL (eligible subjects must have residual FVIII levels ^ 1 IU/dL as evidenced by medical history) will be used in the calculation of change from baseline since all the subjects will be on prophylactic hemophilia therapy prior to AAV-FVIII-SQ infusion where the FVIII activity level cannot be reliably measured. Descriptive summaries of the proportions of subjects whose hFVIII activity during Weeks 49-52 is greater than or equal to select thresholds, such as 5, 15, 25, 30, and 40 IU/dL, and the confidence intervals of the proportions will also be provided. [336] For a subject with a missing value of the primary endpoint, the median value in the subject’s last 4-week window containing a valid observation will be used. Additional analyses will be conducted to examine the sensitivity of the results to the handling of missing data, including analysis using observed cases, and a mixed model for repeated measures (MMRM) approach. Further detail will be provided in the SAP. [337] The analyses for the primary endpoint will be performed using the analysis populations as defined above. Secondary Efficacy Endpoints [338] The analyses of the secondary efficacy endpoints will be descriptive. Mean and associated 95% confidence interval will be provided for the following secondary endpoints, where the baseline value will be derived from the data in the approximately 12-month period prior to AAV-FVIII-SQ infusion: i) Change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy during Weeks 5-52 post-AAV-FVIII-SQ infusion, for subjects receiving FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 post- AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis. ii) Change from baseline in the annualized infusion rate (number/year) of exogenous FVIII replacement therapy during Weeks 5-52 post- AAV-FVIII-SQ infusion, for subjects receiving FVIII prophylaxis during the 12 months prior to study entry, or change from baseline in the annualized utilization (mg/kg/year) of emicizumab during Week 27 to Week 52 post- AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis. iii) Change from baseline in the annualized number of bleeding episodes (number/year) requiring exogenous FVIII replacement treatment during Weeks 5-52 post-AAV-FVIII-SQ infusion for subjects receiving prior FVIII prophylaxis, or Weeks 27-52 post- AAV-FVIII-SQ infusion for subjects receiving prior emicizumab prophylaxis. [339] Mean change from baseline and associated 95% confidence interval will be calculated for the total score of Haemo-QoL-A at Week 52 post-AAV-FVIII-SQ infusion as well. [340] The missing value of the change for annualized utilization and annualized infusion rate will be imputed as 0. The missing value of the change for annualized number of bleeding episodes will be imputed using the median value of the changes of all observed cases. [341] A sensitivity analysis is planned to analyze ABR using a generalized linear mixed model assuming negative binomial as the underlying distribution. The model will include period (pre- to post-AAV-FVIII-SQ infusion) as the only factor, repeated within subject. The actual number of bleeding episodes will be used as the dependent variable with the time period adjustment (annualization) being implemented as the offset. [342] To assess the impact of missing data, analyses using observed case are planned as sensitivity analyses for the secondary endpoints. Multiple imputation methods may also be performed. Tertiary Efficacy Endpoints [343] The analyses of the tertiary efficacy endpoints will be descriptive. Mean change from baseline and associated 95% confidence interval will be provided for EQ-5D-5L, WPAI+CIQ: HS and PROBE scores at Week 52 post- AAV-FVIII-SQ infusion. Immunogenicity [344] Analysis of total and neutralizing antibody response and other immunological parameters will be primarily descriptive and involve both inter-subject and intra-subject comparisons. Pharmacodynamic Analyses [345] Plasma FVIII protein concentrations and FVIII activities determined over the course of the study will primarily be evaluated and summarized with descriptive statistical measures (eg, mean, standard deviation, CV%, min, median, max). Safety Analysis [346] All AEs will be coded to system organ class and preferred term using the current version of MedDRA. The incidence of AEs will be summarized by system organ class, preferred term, relationship to study drug, seriousness, and severity. A by-subject listing will be provided for those subjects who experience an SAE, including death, EOSI, or an AE resulting in early withdrawal from the study. [347] Clinical laboratory data will be summarized by the type of laboratory test. For each clinical laboratory test, descriptive statistics will be provided on Baseline as well as all subsequent visits. Descriptive statistics for physical examination results and vital signs will also be provided. Example 10 Safety, Tolerability, and Efficacy Study of AAV-FVIII-SQ in Hemophilia A Patients with Pre-existing Antibodies Against AAV5 [348] AAV-FVIII-SQ is being evaluated in clinical study 270-201, an ongoing first-in-human, phase 1/2 dose escalation study in subjects with severe HA designed to assess the safety and efficacy of AAV-FVIII-SQ at various dose levels (6E12 vg/kg, 2E13 vg/kg, 4E13 vg/kg, 6E13 vg/kg). Specifically, 270-201 explores the relationship of vector dose to the augmentation of residual FVIII activity and whether these levels are sufficient to alter the clinical phenotype. Three-year results from 270-201 have demonstrated that following gene transfer, mean and median FVIII activity levels above 15% (15 IU/dL), as measured by a chromogenic substrate assay, are achievable and sustained following a single infusion of 6E13 vg/kg of AAV-FVIII-SQ, with administration of prophylactic corticosteroids and an acceptable safety profile (Pasi, 2019). In addition, an interim analysis of clinical study. [349] This study (referred to the 270-301 study) is an ongoing phase 3 study designed to assess the efficacy and safety of AAV-FVIII-SQ at a dose of 6E13 vg/kg and administration of therapeutic corticosteroids (i.e. in response to ALT elevations), demonstrated FVIII activity levels that were also well above 15%, albeit lower than what was observed for the 6E13 vg/kg cohort in 270-201 at 26 weeks (Pasi, 2019). [350] Subjects enrolled and infused in the 270-201 study screened negative for AAV5 antibodies, as the prevailing expectation has been that vector-specific antibodies could interfere with receptor binding and effectively neutralize efficient transduction of the target cell population. As this was the first FVIII gene therapy with AAV5 in humans, this criterion was adopted out of an abundance of caution. These pre-existing vector-specific antibodies are thought to arise from previous exposure to AAV, with seroprevalence varying across human populations and across studies. AAV5 has consistently been shown to have the lowest seroprevalence among the common AAV serotypes (Boutin, 2010; Hayes, 2019). [351] Current data describing the extent of neutralization or inhibited transduction has been inconsistent across studies, each employing one of several varying methodologies to evaluate both vector-specific antibodies and transduction inhibition (TI). Early studies using AAV2 for the treatment of hemophilia B described inhibited transduction in patients with neutralizing antibody titers of 2 or 3 (Manno, 2006), but more recent studies have described successful transduction in patients who, in retrospect, were determined to have pre-existing antibody to the vector capsid (Majowicz, 2017). Importantly, no drug-related adverse events were described in these patients. As the sensitivity of assays used to detect pre-existing antibody has increased greatly in recent years, the biological relevance of any given titer determination, and comparisons across studies using assays with differing titer sensitivities, requires additional study. [352] In this study, patients with severe HA and pre-existing antibodies against AAV5 will be enrolled to evaluate the clinical response to AAV-FVIII-SQ gene therapy. The aim is to evaluate the safety, tolerability, and efficacy of AAV-FVIII-SQ in patients with severe HA and pre-existing antibodies against AAV5 vector capsid at various levels of AAV5 antibody titers. [353] This is a Phase 1/2, single-arm, open-label study in severe HA patients (FVIII < 1 IU/dL), with a history of at least 150 exposure days to FVIII concentrates/cryoprecipitates, with pre-existing antibodies to the AAV5 vector capsid as measured by total antibody [TAb] assay. Approximately 10 subjects may be enrolled at 5-6 sites in 2 cohorts (5 subjects in each cohort) and will receive a single dose of 6E13 vg/kg AAV-FVIII-SQ as an IV infusion. Subjects in Cohort 1 will have a Screening AAV5 TAb titer < 500, while subjects in Cohort 2 will have a Screening AAV5 TAb titer > 500. Choosing a titer cutoff of 500 reflects the observed distribution of existing titer data with the BioMarin titer assay seen to date. [354] The primary objection of this study is to assess the safety of a single intravenous administration of AAV-FVIII-SQ in severe HA subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody. The secondary objectives are i) Assess the efficacy of AAV-FVIII-SQ defined as FVIII activity at or above 5 IU/dL at Week 26. ii) Assess the impact of AAV-FVIII-SQ on usage of exogenous FVIII replacement therapy. iii) Assess the impact of AAV-FVIII-SQ on the number of bleeding episodes requiring exogenous FVIII therapy. iv) Evaluate the pharmacodynamics of FVIII expression following IV infusion of AAV-FVIII-SQ and v) Assess the impact of AAV-FVIII-SQ on patient-reported outcomes (PROs). [355] Subjects will be dosed sequentially in Cohort 1 or Cohort 2, based on the results of their Screening AAV5 TAb titers. Subjects in Cohort 2 can be dosed after a minimum of 3 and a maximum of 5 subjects have been dosed in Cohort 1 and had their safety and efficacy data (from a minimum of6 weeks post-infusion) reviewed. FVIII activity ^ 5% after six weeks post- infusion is expected to be the earliest differentiating time point for the majority of subjects dosed with 6E13 vg/kg who later achieved normal FVIII activity levels, compared with the one subject who had a slightly lower response, based on data from 270-201. Up to 6 weeks post-infusion will provide an appropriate timeframe to evaluate the development of any potential delayed hypersensitivity reaction (eg, serum sickness). [356] Data from 270-201 suggest that achievement of therapeutic FVIII levels > 5 IU/dL occurs approximately 4 weeks after AAV-FVIII-SQ infusion, although the FVIIII PD in AAV+ subjects is unknown and requires close monitoring. As such, in order to provide adequate FVIII protection while subjects are projected to reach clinically relevant FVIII levels > 5 IU/dL, prior FVIII prophylaxis for each subject will be continued at the discretion of the DMC based on individual subject status and data review or when FVIII activity has reached at least 5 IU/dL. In subjects who experience recurring bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume prior FVIII prophylaxis. [357] The study analysis will be performed after all subjects have been followed for 26 weeks post-AAV-FVIII-SQ infusion, with presentation of safety, efficacy, and FVIII PD assessments. After the safety, efficacy, and FVIII PD analyses at 26 weeks post-AAV-FVIII-SQ infusion, long- term safety and efficacy will be assessed in all subjects for up to a total of 5 years post-infusion. During the trial, additional subjects may be recruited into each cohort at any time, if deemed necessary. Diagnosis And All Criteria For Inclusion And Exclusion: [358] Individuals eligible to participate in this study must meet all of the following criteria: 1. Males >18 years of age with hemophilia A and residual FVIII levels ^ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent. 2. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total antibody ELISA. 3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs) 4. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. 5. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures. 6. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart within the past 12 months (at least one of which should be tested at the central laboratory) 7. Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection. 8. Willing to abstain from consumption of alcohol for at least the first 52 weeks following AAV-FVIII-SQ infusion. [359] Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Any evidence of active infection or any immunosuppressive disorder, including HIV infection. Significant liver dysfunction with any of the following abnormal laboratory results: ALT (alanine aminotransferase) > 1.25x ULN; AST (aspartate aminotransferase) > 1.25x ULN; GGT (gamma-glutamyltransferase) > 1.25x ULN; Total bilirubin > 1.25x ULN; Alkaline phosphatase > 1.25x ULN; or INR (international normalized ratio) ^ 1.4 Prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used. Evidence of any bleeding disorder not related to hemophilia A Platelet count of < 100 x 109/L Creatinine ^ 1.5 mg/dL Liver cirrhosis of any etiology as assessed by liver ultrasound Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results . Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy Active malignancy, except non-melanoma skin cancer History of hepatic malignancy History of arterial or venous thromboembolic events (eg, deep vein thrombosis, non- hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis). Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study 16. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including possible corticosteroid treatment outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result. 17. Prior treatment with any vector or gene transfer agent 18. Major surgery planned in the 52-week period following the infusion with AAV-FVIII-SQ 19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the AAV-FVIII-SQ infusion 20. Concurrent enrollment in another clinical study, unless it is an observational (non- interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of safety and efficacy of AAV- FVIII-SQ and with prior consultation with the Medical Monitor 21. Known allergy or hypersensitivity to investigational product formulation 22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed Study Safety Evaluation Criteria [360] If any of the following events occur in a subject in the study who has received AAV- FVIII-SQ infusion, further enrollment into the trial will be temporarily put on hold pending prompt evaluation: i) 1. Liver dysfunction (criteria do not apply to ALT elevations with an extra-hepatic etiology): ALT >5x ULN, for more than 2 weeks, ALT >3x ULN and (total bilirubin >2x ULN or INR >1.5), ALT >3x ULN with signs and symptoms of liver dysfunction, ii) The occurrence of an AE of hepatic failure, or iii) The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in two subjects. iii) The occurrence of any cancer (except non- melanoma skin cancer) at any point after AAV-FVIII-SQ infusion. iv) The occurrence of a thromboembolic event with FVIII activity > 150 IU/dL in one subject. [361] If any of the following events occurs in a subject in the study who has received AAV- FVIII-SQ infusion, a prompt evaluation will be required. Further enrollment into the trial will continue while evaluation is ongoing, unless deemed otherwise: i) 1. Acute hypersensitivity assessed as related to AAV-FVIII-SQ, ii) The detection of high titer neutralizing antibodies (>5 BU) to hFVIII following AAV-FVIII-SQ infusion in one subject. iii) Occurrence of a thromboembolic event. Product Characteristics and Administration [362] AAV-FVIII-SQ is a sterile, clear, colorless-to-pale yellow solution for IV infusion and is supplied in a 10 mL Crystal Zenith® (CZ) vial. Each CZ vial contains 8.5 mL (extractable volume 8 mL) of AAV5-hFVIII-SQ at a concentration of 2E13 vector genomes per mL in a pH 7.4 phosphate buffer. [363] On the day of infusion, the subject will come to the infusion site, where a physical examination will be performed by the Investigator or designee. If the subject is found to have an active acute illness at the time of planned infusion, then the infusion should be deferred until the illness has resolved; screening procedures may require repetition if outside the specified window. An IV catheter or butterfly needle will be inserted into a suitable peripheral vein (eg, the median cubital vein) and flushed with saline. FVIII replacement therapy will not be given since venipuncture is a minimally invasive procedure in these individuals under ordinary conditions. [364] AAV-FVIII-SQ will be prepared and infused as a pure solution over a dose-dependent time. Prepared drug will be kept at room temperature prior to administration. An electric syringe pump will be used to infuse through an in-line, low protein binding 0.22 micron filter. AAV-FVIII- SQ will be infused through the catheter using an appropriate infusion pump at an initial rate of 1 mL/min. The infusion rate should be increased every 30 minutes by 1 mL/min up to a maximum of 4 mL/min, provided that the subject’s clinical condition permits such an increase. Of note, the IP has been shown to be stable at room temperature for approximately 10 hours following completion of product thaw. Vital signs (pulse, blood pressure, respiration rate and temperature) should be monitored at 15 minute (±5 minutes) intervals throughout the period of the infusion. [365] As with any infused biological product, there is a potential risk of acute, systemic hypersensitivity reactions (including anaphylaxis) with AAV-FVIII-SQ. Dosing will be administered at a qualified infusion site, with appropriate resuscitation equipment and medication available and easily accessible. [366] Data from an ongoing first in human study (270-201) indicates that following single escalated doses of AAV-FVIII-SQ (6E12, 2E13, 4E13, 6E13 vg/kg), dose-related increases in FVIII activity were observed, with concurrent improvements in bleeding episodes and exogenous FVIII utilization, particularly at the 4E13 and 6E13 vg/kg dose levels. At all dose levels, AAV-FVIII-SQ is considered to be well-tolerated with mild increases in ALT as the most common adverse event. The 6E13 vg/kg dose has been selected for this study to maximize the likelihood of transduction in the face of pre-existing AAV5 antibodies. Concomitant Hemophilia Treatments [367] Subjects on prophylactic FVIII therapy will discontinue their regular treatment regimen starting 4 weeks after the day of infusion and switch to an “on-demand” schedule. FVIII replacement therapy can always be taken as needed by the subject for treatment of an acute bleeding episode; the subject must carefully record his treatment and bleeding episodes in his diary. Prophylactic FVIII can be used on a case-by-case basis and in consultation with the Medical Monitor to prevent bleeding in extenuating circumstances (eg, peri-operative). Therapeutic Corticosteroid Treatment of Elevated Hepatic Transaminases [368] All subjects will be started on prophylactic corticosteroids starting on the day of infusion (Day 1). Figure 12A (as described in Example 4) provides an example of a possible prophylactic corticosteroid course, including taper and post-corticosteroid additional monitoring of FVIII activity, LTs, and hepatitis B/hepatitis C reactivation. Clinical judgment, weighting the potential risks and benefits of corticosteroid treatment, should always be exercised when considering adjustment of corticosteroid doses. [369] Following initiation or completion of the prophylactic corticosteroid regimen, if ALT levels become increased (eg, > ULN or > 2x baseline value) and alternative etiologies have been ruled out, prompt institution of therapeutic or on-demand oral corticosteroids (prednisone or converted equivalent) should be considered. Whenever possible, a confirmatory lab draw for ALT should be performed within 72 hours, along with FVIII activity, prior to initiating oral corticosteroids. Corticosteroids may be delayed if elevations in ALT are clearly not related to AAV-FVIII-SQ (e.g., elevated in ALT with concurrent increase in CPK due to intensive exercise). [370] Therapeutic corticosteroid treatment should be initiated at a dose of 60 mg/day. At minimum, the recommended duration of therapeutic corticosteroids is 60 mg/day for 3 weeks, 40 mg/day for 4 weeks, and 30 mg/day for 4 weeks, followed by a gradual taper thereafter. Should a scenario arise in which a deviation from the minimum recommended dose and/or duration of therapeutic corticosteroids may be clinically indicated, a discussion should take place between the Investigator and Medical Monitor regarding corticosteroid dose adjustments. Tapering of corticosteroid dosages should be guided as set out in Table 16. Table 16 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^!^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^ • ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^ ^ • ^^^^^^^^^^^^^^^^^^^^^^^^ !" ^^#^^$^^^^^% ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ • &$^^^^^^^^^^^^^^^^^^#^^^^^^^^^^^ ^^^^##^^^^^^^^^^^^%' ^^$^^^' ^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^"^^^ ^ ^#^^(&^^^^^^^^^^^^^^^^^^^)^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^)^' $^^^^^^^^^^^^^^^^^^^^^^^^*^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^)^^$^^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^' ^^$^^$^^ ^ ^^^^^^^^ ^^^^^^^ [371] After discontinuation of oral corticosteroids, labs for ALT and FVIII levels will be measured once a week for 4 weeks to ensure stability in values. [372] Following initiation or completion of therapeutic oral corticosteroids, if increased ALT levels (eg, > ULN or > 2x baseline value) are reported, corticosteroid management decisions will be based on discussions between the Investigator and Medical Monitor. Modification of the corticosteroid regimen may take into consideration possible confounders for the ALT elevation and impact on FVIII expression. [373] Management and monitoring of reactions to corticosteroids should be determined by the Investigator’s clinical judgment in consultation with the Sponsor’s Medical Monitor. This includes the contraindicated use of NSAIDs during corticosteroid treatment and specific monitoring not already covered by the SoA. The use of COX-2 inhibitors, while not contraindicated during corticosteroid treatment, should be limited, if possible. Practical management to prevent complications related to oral corticosteroid therapy may be undertaken at the discretion of the Investigator (eg, evaluation of glucose intolerance, hyperlipidemia etc.). Hepatitis B status and HCV viral load will be rechecked 6 weeks after the start of oral corticosteroid treatment and then 1 week and 13 weeks after the completion of oral corticosteroid treatment in subjects with a history of hepatitis B or hepatitis C. All adverse events (including any adverse events suspected to be caused by or related to corticosteroid use) should be reported as outlined in Section 10 of the protocol. [374] Subjects on corticosteroids should receive appropriate counselling and support regarding side effects from the Investigator or the treating institution (e.g., listings of side effects and when to notify carers, wallet card for emergencies if on steroids, etc.). Efficacy Variables FVIII Activity [375] Efficacy (response to treatment) will be defined as FVIII activity > 5 IU/dL at Week 26 following AAV-FVIII-SQ infusion. [376] Values for FVIII activity will be excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII protein concentrates. If a subject has used FVIII within 72 hours of a measurement day, all efforts should be made to obtain FVIII activity measurements when a 72-hour interval without FVIII use is achieved; The 72-hour wash-out period is only intended for subjects who have achieved FVIII > 5 IU/dL at 16 weeks after AAV-FVIII-SQ infusion and who have not resumed FVIII replacement therapy. [377] In the event of an FVIII activity level decline during the study: i) If FVIII activity has declined at least 20% from the peak but less than 35% and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 7 days until FVIII activity is stable or increasing. ii) If FVIII activity has declined >35% from the peak and has declined for at least 2 consecutive assessments, FVIII activity and LTs should be repeated every 72 hours until FVIII activity is stable or increasing. [378] Note that fluctuations in FVIII activity are common, and if no clear trend indicating a decline in FVIII activity is observed, then this additional testing may be deferred (upon consultation between the Investigator and the Medical Monitor) until either a more clear trend of decline has been demonstrated or until the FVIII activity levels stabilize or increase. [379] Subjects who do not respond to AAV-FVIII-SQ treatment (i.e., treatment failure, manifesting as either failure to achieve FVIII activity > 5 IU/dL by either Week 26 or Week 52 or inability to maintain independence from prophylactic FVIII replacement therapy due to joint bleeding episodes, in the judgment of the Investigator) may, at the Investigator’s discretion and after discussion with the Medical Monitor. Factor VIII Replacement Therapy/Bleeding Episodes [380] Additional efficacy variables are: i) Change of annualized utilization (IU/kg) of exogenous FVIII replacement therapy during Week 5 to Week 26 post AAV-FVIII-SQ infusion from the baseline utilization of exogenous FVIII replacement therapy. ii) Change of ABRs requiring exogenous FVIII replacement treatment during Week 5 to Week 26 of the study post AAV-FVIII-SQ infusion from the baseline ABR. [381] During the study, subjects will be asked at each study visit to report the use of factor replacement therapy and the number of bleeding episodes since the previous visit. This information will be captured on the subject’s diary or other subject records. [382] Subjects are strongly encouraged to immediately consult Investigator for guidance regarding exogenous FVIII administration for suspected bleeds or bleeding episodes within the first 6 weeks post AAV-FVIII-SQ infusion. [383] In subjects who experience recurrent bleeding episodes, the Investigator and Medical Monitor will discuss whether to resume prior FVIII prophylaxis. Patient-Reported Outcomes (PRO) [384] The Haemo-QoL-A questionnaire is a validated hemophilia-specific health-related quality of life questionnaire for adults (Rentz, 2008). It consists of 41 questions covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns). Items are answered on a 6-point Likert-type scale, ranging from 0 (None of the time) to 5 (All of the time). Higher scores mean better health-related quality of life or less impairment for a particular subscale (Haemo-QoL Study Group, 2017). Details regarding the Haemo-QoL-A assessment will be included in the Study Reference Manual. [385] The EQ-5D-5L instrument is a self-reported questionnaire designed to measure general health status (The EuroQol Group, 1990) (Brooks, 1996). The EQ-5D-5L is composed of 2- parts: a descriptive system that assesses 5 levels of perceived problems (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) in 5 dimensions and the EQ visual analogue scale (EQ VAS) assessment for overall health. [386] Haemophilia Activities List (HAL) measures the impact of hemophilia on self-perceived functional abilities in adults (van Genderen, 2006). The instrument consists of multiple domains including lying/sitting/kneeling/standing, leg and arm function, use of transportation, self-care, household tasks, and leisure activities where subjects are asked to rate their level of difficulty with activities of daily living on a 6-point Likert-type scale from 1 (Impossible) to 6 (Never). For some items, subjects are given the choice to answer ‘Not applicable’. [387] The Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) instrument is designed to measure the effect of disease symptom severity on work productivity and classroom productivity (if applicable) (Recht, 2014). The WPAI+CIQ:HS questionnaire yields scores related to work/classroom absenteeism, reduced on-the-job effectiveness, overall work/classroom impairment, and activity impairment. WPAI+CIQ:HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (Reilly, 2002). Immunogenicity [388] Immunogenicity assays will be performed on plasma and PBMCs. The assays will include detection of anti-AAV5 vector capsid and anti-FVIII total antibodies, as well as determination of neutralizing antibodies against FVIII (FVIII inhibitors) and against the AAV5 vector capsid (Transduction Inhibitors, TI). FVIII Inhibitors will be assessed using the Bethesda assay with Nijmegen modification. Any abnormality of the liver parameters will lead to a retrospective immunogenicity assessment to evaluate FVIII-and vector capsid-specific cellular immunogenicity. FVIII- and vector capsid-specific cellular immunity will be assessed by stimulated cytokine secretion using an ELISpot assay performed on collected PBMCs. [389] Pharmacodynamics [390] The FVIII protein concentration and activity level as measured by a validated immunoassay and by a validated FVIII activity assay, respectively, will be used for plasma profiles; FVIII protein and activity will be used to determine PD parameters. Exploratory Assessments [391] A cytokine bead array assay assessment will be performed at Baseline and then weekly through Week 26. [392] In addition, blood samples will be collected from subjects at particular time points to evaluate biochemical, molecular, cellular, and genetic/genomic aspects relevant to hemophilia A, coagulation, and/or AAV5 gene transfer, and to develop assays used for these evaluations. Subject may choose to opt out of the exploratory genetic/genomic research being done to study or try to discover genes that are not yet known to be associated with hemophilia A. [393] All biomarker samples collected in this study may be used for exploratory biomarker research, including evaluation of additional biomarkers not specifically listed in the protocol. In addition, samples collected for other purposes in this study may be used for exploratory research once testing for the primary purpose has been completed. Safety Variables [394] Safety in this study will be determined from evaluation of AEs, clinical laboratory assessments with a particular attention to the liver function, vital signs assessments, physical examinations, and immunogenicity. Clinical Laboratory Assessments [395] The scheduled clinical laboratory tests are listed in Table 11 (provided in Example 6) Urine tests will be performed locally and centrally; all other laboratory assessments will be performed at the central laboratory. In case of a safety concern, additional unscheduled laboratory tests may be performed locally (at the Investigator’s discretion) in order to facilitate timely and appropriate clinical management decisions; where possible, a matched sample for testing at the central laboratory should be collected (using the Unscheduled Visit lab kit) at the same time as the local unscheduled sample. [396] Any abnormal test results determined to be clinically significant by the Investigator should be repeated (at the Investigator’s discretion) until: (1) the cause of the abnormality is determined; (2) the value returns to baseline or to within normal limits; or (3) the Investigator determines that the abnormal value is no longer clinically significant. [397] All abnormal clinical laboratory results should be initialed and dated by an Investigator, along with a comment regarding whether or not the result is clinically significant. Each clinically significant laboratory result should be recorded as an adverse event. [398] The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are considered clinically significant by the Investigator will be recorded on the AE eCRF. [399] In addition to scheduled clinical laboratory assessments, a fasting blood lipid panel (including triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) is assessed at the AAV-FVIII-SQ infusion visit. Subjects will fast for at least 8 hours prior to pre-infusion laboratory sampling on the day of the infusion visit. [400] In case of hypersensitivity or adverse drug reaction, safety assessment, including physical examination and vital signs, will be done and additional blood samples will be collected within 1 hour of the hypersensitivity reaction (eg, tryptase, C3, C3a, C4, C5, C5a, and cytokine bead array, as well as possible additional exploratory testing) and samples for IgE and cytokine bead array (and possible additional exploratory testing) between 8-24 hours after the reaction. In addition, a blood sample should be taken 1 week after the hypersensitivity reaction for assessment of the cytokine bead array. Exploratory biomarker samples at baseline and at post- infusion study visits may also be used to assess changes in these biomarkers to better elucidate the mechanisms of infusion-related hypersensitivity reactions" as described in the rationale of changes. [401] At applicable sites, certain study assessments may be performed by a mobile nursing (MN) professional at the patient's home or another suitable location, such as their school or office, to improve access and convenience for patients participating in the study. The Sponsor may select a healthcare company that will be responsible for providing MN services for participating sites (the MN vendor). The MN vendor is responsible for ensuring that all MN professionals are licensed, qualified, and in good standing, as per applicable regulations, and that appropriate background checks have been performed. If the investigator at a participating site determines that MN services are appropriate for a patient and the patient gives written informed consent to participate in MN visits, the MN network will communicate with the patient and the patient’s site. Liver and Hepatitis Testing [402] Subjects will be screened for evidence of previous or active hepatitis B or hepatitis C infection at Screening; hepatitis B screening should include HBsAg, HBsAb, and HBcAb. Subjects with documented results showing an absence of active hepatitis B or hepatitis C infection (as measured by negative surface antigen or DNA for hepatitis B or negative RNA testing for hepatitis C) 30 days prior to providing signed informed consent do not need to repeat those tests during the screening period. [403] Evidence of ongoing hepatitis B or hepatitis C infection is exclusionary. Subjects with history of hepatitis B or hepatitis C infection prior to study entry will be tested for hepatitis B and hepatitis C reactivation at Week 16. Subjects with a history of hepatitis B or hepatitis C will be asked for information about the treatments received as part of their medical history assessment at Screening. [404] Subjects with a previous history of hepatitis B or hepatitis C who receive therapeutic oral corticosteroids prior to Week 16 do not need to complete the Week 16 reactivation assessment; instead, they will be tested for hepatitis B and hepatitis C reactivation at the required time points. [405] A liver ultrasound and liver tests (LTs) during Screening will identify any significant hepatic dysfunction. Liver tests will be monitored on a regular basis; at each time point specified in the SoA, the following LTs should be assessed as set out in Table 17. Table 17 LIVER TESTS (LTS) ALKALINE AST (SGOT) TOTAL BILIRUBIN LDH PH AOLSTP (SHGATPATS)E DIRECT BILIRUBIN GGT [406] Elevated ALT levels should be evaluated according to the plan as set out in Table 12 (see Example 6). HIV Testing [407] HIV testing is performed at Screening. Subjects with documented negative results within the last 30 days prior to screening do not need to be retested. Vital Signs, Physical Examinations and Other Observations Related to Safety [408] Vital signs include seated systolic and diastolic blood pressure, heart rate, respiration rate, and temperature. Any clinically significant change in vital signs will be recorded as an AE. [409] Systolic blood pressure, diastolic blood pressure, heart rate, respiration rate, and temperature will be assessed at Screening, Baseline, and at the beginning of each visit during the Post-Infusion Follow-Up and Long-Term Follow-Up periods. On the day of the AAV-FVIII-SQ Infusion, vital signs will be monitored prior to infusion, during the infusion every 15 minutes (± 5 minutes), following the infusion hourly (± 5 minutes) for at least 8 hours during the subject’s stay in the clinic. Any abnormal vital sign assessments should be repeated, and both values should be recorded in the eCRF. [410] A complete physical examination should be performed at Screening, Week 26, Week 52, and at the End of Year visits. A complete physical examination will include general appearance (head, eyes, ears, nose, and throat), cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, and neurologic systems. [411] At other visits, brief physical examinations may be performed at the discretion of the Investigator based on the subject’s clinical condition. A brief physical examination will include general appearance, cardiovascular, dermatologic, respiratory, gastrointestinal, musculoskeletal, and neurologic assessments. Particular attention should be given to signs of bleeding, as well as assessing possible hemarthroses. [412] Height will be recorded at Screening only. Weight will be recorded at Screening and then every 4 weeks thereafter through Week 20, at Week 26, every 4 weeks through Week 52, and then at the second Q12W visit each year and at every End of Years visit during Years 2-5. [413] At visits where the MN services are used or shortened lab draw-only visits are conducted at the sites, the physical examination and vital signs assessments indicated in the Schedule of Events will not be performed. Vector Shedding [414] During the Post-Infusion Follow-Up period, subjects undergo testing of various bodily samples to look for evidence of vector shedding for possible viral transmission. Bodily fluids will be tested by polymerase chain reaction (PCR). Fluids tested will include: blood, saliva, semen, urine and stool. [415] Vector shedding will also be extensively studied in the present clinical trial, at particular time points. Testing will continue until at least 3 consecutive results below the limit of detection are obtained. Testing of semen will continue at least through Week 12, even if 3 consecutive results below the limit of detection have been recorded in that compartment prior to that time point. Subjects who have not had 3 consecutive semen samples below the limit of detection by Week 26 should continue to have PCR testing in semen every 4 weeks until 3 consecutive samples below the limit of detection are documented (or upon consultation between the Investigator and Medical Monitor). Subjects who meet the definition of treatment failure and wish to follow an abbreviated schedule (refer to Section 12.5.3) but who have not cleared vector shedding from all fluids must still provide samples for assessment until vector shedding has cleared: at Weeks 32, 36, 40, 44, 48, and 52 (during Year 1) and every 4 weeks during Years 2- 5. Such subjects may provide samples on the designated study visit dates either at the sites or through use of a MN professional. [416] Samples may be fractionated prior to shedding analysis in order to better characterize the presence, structure, and location of vector DNA and/or vector capsid within each matrix. If needed, the fractionation may be performed with samples collected specifically for shedding analysis (saliva, blood, semen, urine, feces). Alternatively, the vector DNA characterization during shedding analysis may utilize already fractionated exploratory samples obtained from the above biofluids, such as exploratory plasma samples, exploratory PBMC samples, and red blood cells recovered during PBMC/plasma isolations. [417] Fractionation of semen to collect purified sperm separately from non-sperm cells may be performed in parallel at any visit where semen samples are collected. The shedding analysis of a fractionated semen sample will only be performed if vector DNA was detected in the whole semen sample for the same visit. Fractionation of semen during shedding analysis may be stopped if purified sperm tested positive for vector DNA on at least three visits, or if purified sperm tested below the limit of detection for vector DNA on at least three consecutive visits. 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Sequences SEQ ID NO: 1 <211> 4374 <212> DNA <400> 1 ATGCAGATTGAGCTGAGCACCTGCTTCTTCCTGTGCCT GCTGAGGTTCTGCTTCTCTGCCACCAGGAGATACTACCTGGGGGCTGTGGAGCTGAGCTG GGACTACATGCAGTCTGACCTGGGGGAGCTGCCTGTGGATGCCAGGTTCCCCCCCAGAGT GCCCAAGAGCTTCCCCTTCAACACCTCTGTGGTGTACAAGAAGACCCTGTTTGTGGAGTT CACTGACCACCTGTTCAACATTGCCAAGCCCAGGCCCCCCTGGATGGGCCTGCTGGGCCC CACCATCCAGGCTGAGGTGTATGACACTGTGGTGATCACCCTGAAGAACATGGCCAGCCA CCCTGTGAGCCTGCATGCTGTGGGGGTGAGCTACTGGAAGGCCTCTGAGGGGGCTGAGTA TGATGACCAGACCAGCCAGAGGGAGAAGGAGGATGACAAGGTGTTCCCTGGGGGCAGCCA CACCTATGTGTGGCAGGTGCTGAAGGAGAATGGCCCCATGGCCTCTGACCCCCTGTGCCT GACCTACAGCTACCTGAGCCATGTGGACCTGGTGAAGGACCTGAACTCTGGCCTGATTGG GGCCCTGCTGGTGTGCAGGGAGGGCAGCCTGGCCAAGGAGAAGACCCAGACCCTGCACAA GTTCATCCTGCTGTTTGCTGTGTTTGATGAGGGCAAGAGCTGGCACTCTGAAACCAAGAA CAGCCTGATGCAGGACAGGGATGCTGCCTCTGCCAGGGCCTGGCCCAAGATGCACACTGT GAATGGCTATGTGAACAGGAGCCTGCCTGGCCTGATTGGCTGCCACAGGAAGTCTGTGTA CTGGCATGTGATTGGCATGGGCACCACCCCTGAGGTGCACAGCATCTTCCTGGAGGGCCA CACCTTCCTGGTCAGGAACCACAGGCAGGCCAGCCTGGAGATCAGCCCCATCACCTTCCT GACTGCCCAGACCCTGCTGATGGACCTGGGCCAGTTCCTGCTGTTCTGCCACATCAGCAG CCACCAGCATGATGGCATGGAGGCCTATGTGAAGGTGGACAGCTGCCCTGAGGAGCCCCA GCTGAGGATGAAGAACAATGAGGAGGCTGAGGACTATGATGATGACCTGACTGACTCTGA GATGGATGTGGTGAGGTTTGATGATGACAACAGCCCCAGCTTCATCCAGATCAGGTCTGT GGCCAAGAAGCACCCCAAGACCTGGGTGCACTACATTGCTGCTGAGGAGGAGGACTGGGA CTATGCCCCCCTGGTGCTGGCCCCTGATGACAGGAGCTACAAGAGCCAGTACCTGAACAA TGGCCCCCAGAGGATTGGCAGGAAGTACAAGAAGGTCAGGTTCATGGCCTACACTGATGA AACCTTCAAGACCAGGGAGGCCATCCAGCATGAGTCTGGCATCCTGGGCCCCCTGCTGTA TGGGGAGGTGGGGGACACCCTGCTGATCATCTTCAAGAACCAGGCCAGCAGGCCCTACAA CATCTACCCCCATGGCATCACTGATGTGAGGCCCCTGTACAGCAGGAGGCTGCCCAAGGG GGTGAAGCACCTGAAGGACTTCCCCATCCTGCCTGGGGAGATCTTCAAGTACAAGTGGAC TGTGACTGTGGAGGATGGCCCCACCAAGTCTGACCCCAGGTGCCTGACCAGATACTACAG CAGCTTTGTGAACATGGAGAGGGACCTGGCCTCTGGCCTGATTGGCCCCCTGCTGATCTG CTACAAGGAGTCTGTGGACCAGAGGGGCAACCAGATCATGTCTGACAAGAGGAATGTGAT CCTGTTCTCTGTGTTTGATGAGAACAGGAGCTGGTACCTGACTGAGAACATCCAGAGGTT CCTGCCCAACCCTGCTGGGGTGCAGCTGGAGGACCCTGAGTTCCAGGCCAGCAACATCAT GCACAGCATCAATGGCTATGTGTTTGACAGCCTGCAGCTGTCTGTGTGCCTGCATGAGGT GGCCTACTGGTACATCCTGAGCATTGGGGCCCAGACTGACTTCCTGTCTGTGTTCTTCTC TGGCTACACCTTCAAGCACAAGATGGTGTATGAGGACACCCTGACCCTGTTCCCCTTCTC TGGGGAGACTGTGTTCATGAGCATGGAGAACCCTGGCCTGTGGATTCTGGGCTGCCACAA CTCTGACTTCAGGAACAGGGGCATGACTGCCCTGCTGAAAGTCTCCAGCTGTGACAAGAA CACTGGGGACTACTATGAGGACAGCTATGAGGACATCTCTGCCTACCTGCTGAGCAAGAA CAATGCCATTGAGCCCAGGAGCTTCAGCCAGAACCCCCCAGTGCTGAAGAGGCACCAGAG GGAGATCACCAGGACCACCCTGCAGTCTGACCAGGAGGAGATTGACTATGATGACACCAT CTCTGTGGAGATGAAGAAGGAGGACTTTGACATCTACGACGAGGACGAGAACCAGAGCCC CAGGAGCTTCCAGAAGAAGACCAGGCACTACTTCATTGCTGCTGTGGAGAGGCTGTGGGA CTATGGCATGAGCAGCAGCCCCCATGTGCTGAGGAACAGGGCCCAGTCTGGCTCTGTGCC CCAGTTCAAGAAGGTGGTGTTCCAGGAGTTCACTGATGGCAGCTTCACCCAGCCCCTGTA CAGAGGGGAGCTGAATGAGCACCTGGGCCTGCTGGGCCCCTACATCAGGGCTGAGGTGGA GGACAACATCATGGTGACCTTCAGGAACCAGGCCAGCAGGCCCTACAGCTTCTACAGCAG CCTGATCAGCTATGAGGAGGACCAGAGGCAGGGGGCTGAGCCCAGGAAGAACTTTGTGAA GCCCAATGAAACCAAGACCTACTTCTGGAAGGTGCAGCACCACATGGCCCCCACCAAGGA TGAGTTTGACTGCAAGGCCTGGGCCTACTTCTCTGATGTGGACCTGGAGAAGGATGTGCA CTCTGGCCTGATTGGCCCCCTGCTGGTGTGCCACACCAACACCCTGAACCCTGCCCATGG CAGGCAGGTGACTGTGCAGGAGTTTGCCCTGTTCTTCACCATCTTTGATGAAACCAAGAG CTGGTACTTCACTGAGAACATGGAGAGGAACTGCAGGGCCCCCTGCAACATCCAGATGGA GGACCCCACCTTCAAGGAGAACTACAGGTTCCATGCCATCAATGGCTACATCATGGACAC CCTGCCTGGCCTGGTGATGGCCCAGGACCAGAGGATCAGGTGGTACCTGCTGAGCATGGG CAGCAATGAGAACATCCACAGCATCCACTTCTCTGGCCATGTGTTCACTGTGAGGAAGAA GGAGGAGTACAAGATGGCCCTGTACAACCTGTACCCTGGGGTGTTTGAGACTGTGGAGAT GCTGCCCAGCAAGGCTGGCATCTGGAGGGTGGAGTGCCTGATTGGGGAGCACCTGCATGC TGGCATGAGCACCCTGTTCCTGGTGTACAGCAACAAGTGCCAGACCCCCCTGGGCATGGC CTCTGGCCACATCAGGGACTTCCAGATCACTGCCTCTGGCCAGTATGGCCAGTGGGCCCC CAAGCTGGCCAGGCTGCACTACTCTGGCAGCATCAATGCCTGGAGCACCAAGGAGCCCTT CAGCTGGATCAAGGTGGACCTGCTGGCCCCCATGATCATCCATGGCATCAAGACCCAGGG GGCCAGGCAGAAGTTCAGCAGCCTGTACATCAGCCAGTTCATCATCATGTACAGCCTGGA TGGCAAGAAGTGGCAGACCTACAGGGGCAACAGCACTGGCACCCTGATGGTGTTCTTTGG CAATGTGGACAGCTCTGGCATCAAGCACAACATCTTCAACCCCCCCATCATTGCCAGATA CATCAGGCTGCACCCCACCCACTACAGCATCAGGAGCACCCTGAGGATGGAGCTGATGGG CTGTGACCTGAACAGCTGCAGCATGCCCCTGGGCATGGAGAGCAAGGCCATCTCTGATGC CCAGATCACTGCCAGCAGCTACTTCACCAACATGTTTGCCACCTGGAGCCCCAGCAAGGC CAGGCTGCACCTGCAGGGCAGGAGCAATGCCTGGAGGCCCCAGGTCAACAACCCCAAGGA GTGGCTGCAGGTGGACTTCCAGAAGACCATGAAGGTGACTGGGGTGACCACCCAGGGGGT GAAGAGCCTGCTGACCAGCATGTATGTGAAGGAGTTCCTGATCAGCAGCAGCCAGGATGG CCACCAGTGGACCCTGTTCTTCCAGAATGGCAAGGTGAAGGTGTTCCAGGGCAACCAGGA CAGCTTCACCCCTGTGGTGAACAGCCTGGACCCCCCCCTGCTGACCAGATACCTGAGGAT TCACCCCCAGAGCTGGGTGCACCAGATTGCCCTGAGGATGGAGGTGCTGGGCTGTGAGGC CCAGGACCTGTACTGA SEQ ID NO: 2 <211> 4970 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 2 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG 180 GACACAGGAC GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA 240 GCCCCTGTTT GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC 300 CCCGTTGCCC CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA 360 GCTTCAGGCA CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC 420 ACCTGCTTCT TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG 480 GGGGCTGTGG AGCTGAGCTG GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT 540 GCCAGGTTCC CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG 600 AAGACCCTGT TTGTGGAGTT CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC 660 TGGATGGGCC TGCTGGGCCC CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC 720 CTGAAGAACA TGGCCAGCCA CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG 780 GCCTCTGAGG GGGCTGAGTA TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG 840 GTGTTCCCTG GGGGCAGCCA CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG 900 GCCTCTGACC CCCTGTGCCT GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC 960 CTGAACTCTG GCCTGATTGG GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG 1020 AAGACCCAGA CCCTGCACAA GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC 1080 TGGCACTCTG AAACCAAGAA CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC 1140 TGGCCCAAGA TGCACACTGT GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC 1200 TGCCACAGGA AGTCTGTGTA CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC 1260 AGCATCTTCC TGGAGGGCCA CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG 1320 ATCAGCCCCA TCACCTTCCT GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG 1380 CTGTTCTGCC ACATCAGCAG CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC 1440 AGCTGCCCTG AGGAGCCCCA GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT 1500 GATGACCTGA CTGACTCTGA GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC 1560 TTCATCCAGA TCAGGTCTGT GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT 1620 GCTGAGGAGG AGGACTGGGA CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC 1680 AAGAGCCAGT ACCTGAACAA TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG 1740 TTCATGGCCT ACACTGATGA AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC 1800 ATCCTGGGCC CCCTGCTGTA TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC 1860 CAGGCCAGCA GGCCCTACAA CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC 1920 AGCAGGAGGC TGCCCAAGGG GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG 1980 ATCTTCAAGT ACAAGTGGAC TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG 2040 TGCCTGACCA GATACTACAG CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG 2100 ATTGGCCCCC TGCTGATCTG CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG 2160 TCTGACAAGA GGAATGTGAT CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG 2220 ACTGAGAACA TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG 2280 TTCCAGGCCA GCAACATCAT GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG 2340 TCTGTGTGCC TGCATGAGGT GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC 2400 TTCCTGTCTG TGTTCTTCTC TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC 2460 CTGACCCTGT TCCCCTTCTC TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG 2520 TGGATTCTGG GCTGCCACAA CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA 2580 GTCTCCAGCT GTGACAAGAA CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT 2640 GCCTACCTGC TGAGCAAGAA CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA 2700 GTGCTGAAGA GGCACCAGAG GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG 2760 ATTGACTATG ATGACACCAT CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC 2820 GAGGACGAGA ACCAGAGCCC CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT 2880 GCTGTGGAGA GGCTGTGGGA CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG 2940 GCCCAGTCTG GCTCTGTGCC CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC 3000 AGCTTCACCC AGCCCCTGTA CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC 3060 TACATCAGGG CTGAGGTGGA GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG 3120 CCCTACAGCT TCTACAGCAG CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG 3180 CCCAGGAAGA ACTTTGTGAA GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC 3240 CACATGGCCC CCACCAAGGA TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG 3300 GACCTGGAGA AGGATGTGCA CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC 3360 ACCCTGAACC CTGCCCATGG CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC 3420 ATCTTTGATG AAACCAAGAG CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC 3480 CCCTGCAACA TCCAGATGGA GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC 3540 AATGGCTACA TCATGGACAC CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG 3600 TGGTACCTGC TGAGCATGGG CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT 3660 GTGTTCACTG TGAGGAAGAA GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG 3720 GTGTTTGAGA CTGTGGAGAT GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG 3780 ATTGGGGAGC ACCTGCATGC TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC 3840 CAGACCCCCC TGGGCATGGC CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC 3900 CAGTATGGCC AGTGGGCCCC CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC 3960 TGGAGCACCA AGGAGCCCTT CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC 4020 CATGGCATCA AGACCCAGGG GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC 4080 ATCATCATGT ACAGCCTGGA TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC 4140 ACCCTGATGG TGTTCTTTGG CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC 4200 CCCCCCATCA TTGCCAGATA CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC 4260 CTGAGGATGG AGCTGATGGG CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG 4320 AGCAAGGCCA TCTCTGATGC CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC 4380 ACCTGGAGCC CCAGCAAGGC CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC 4440 CAGGTCAACA ACCCCAAGGA GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT 4500 GGGGTGACCA CCCAGGGGGT GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG 4560 ATCAGCAGCA GCCAGGATGG CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG 4620 GTGTTCCAGG GCAACCAGGA CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG 4680 CTGACCAGAT ACCTGAGGAT TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG 4740 GAGGTGCTGG GCTGTGAGGC CCAGGACCTG TACTGAAATA AAAGATCTTT ATTTTCATTA 4800 GATCTGTGTG TTGGTTTTTT GTGTGAGGAA CCCCTAGTGA TGGAGTTGGC CACTCCCTCT 4860 CTGCGCGCTC GCTCGCTCAC TGAGGCCGGG CGACCAAAGG TCGCCCGACG CCCGGGCTTT 4920 GCCCGGGCGG CCTCAGTGAG CGAGCGAGCG CGCAGAGAGG GAGTGGCCAA 4970 SEQ ID NO: 3 <211> 4950 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 3 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG GACACAGGAC 180 GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT 240 GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC 300 CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA 360 CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT 420 TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG 480 AGCTGAGCTG GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC 540 CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT 600 TTGTGGAGTT CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC 660 TGCTGGGCCC CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA 720 TGGCCAGCCA CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG 780 GGGCTGAGTA TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG 840 GGGGCAGCCA CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC 900 CCCTGTGCCT GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG 960 GCCTGATTGG GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA 1020 CCCTGCACAA GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG 1080 AAACCAAGAA CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA 1140 TGCACACTGT GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA 1200 AGTCTGTGTA CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC 1260 TGGAGGGCCA CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA 1320 TCACCTTCCT GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC 1380 ACATCAGCAG CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG 1440 AGGAGCCCCA GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA 1500 CTGACTCTGA GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA 1560 TCAGGTCTGT GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG 1620 AGGACTGGGA CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT 1680 ACCTGAACAA TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT 1740 ACACTGATGA AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC 1800 CCCTGCTGTA TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA 1860 GGCCCTACAA CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC 1920 TGCCCAAGGG GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT 1980 ACAAGTGGAC TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA 2040 GATACTACAG CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC 2100 TGCTGATCTG CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA 2160 GGAATGTGAT CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA 2220 TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA 2280 GCAACATCAT GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC 2340 TGCATGAGGT GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG 2400 TGTTCTTCTC TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT 2460 TCCCCTTCTC TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG 2520 GCTGCCACAA CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT 2580 GTGACAAGAA CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC 2640 TGAGCAAGAA CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA 2700 GGCACCAGAG GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG 2760 ATGACACCAT CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA 2820 ACCAGAGCCC CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA 2880 GGCTGTGGGA CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG 2940 GCTCTGTGCC CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC 3000 AGCCCCTGTA CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG 3060 CTGAGGTGGA GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT 3120 TCTACAGCAG CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA 3180 ACTTTGTGAA GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC 3240 CCACCAAGGA TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA 3300 AGGATGTGCA CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC 3360 CTGCCCATGG CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG 3420 AAACCAAGAG CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA 3480 TCCAGATGGA GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA 3540 TCATGGACAC CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC 3600 TGAGCATGGG CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG 3660 TGAGGAAGAA GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA 3720 CTGTGGAGAT GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC 3780 ACCTGCATGC TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC 3840 TGGGCATGGC CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC 3900 AGTGGGCCCC CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA 3960 AGGAGCCCTT CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA 4020 AGACCCAGGG GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT 4080 ACAGCCTGGA TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG 4140 TGTTCTTTGG CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA 4200 TTGCCAGATA CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG 4260 AGCTGATGGG CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA 4320 TCTCTGATGC CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC 4380 CCAGCAAGGC CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA 4440 ACCCCAAGGA GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA 4500 CCCAGGGGGT GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA 4560 GCCAGGATGG CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG 4620 GCAACCAGGA CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT 4680 ACCTGAGGAT TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG 4740 GCTGTGAGGC CCAGGACCTG TACTGAAATA AAAGATCTTT ATTTTCATTA GATCTGTGTG 4800 TTGGTTTTTT GTGTGAGTGA TGGAGTTGGC CACTCCCTCT CTGCGCGCTC GCTCGCTCAC 4860 TGAGGCCGGG CGACCAAAGG TCGCCCGACG CCCGGGCTTT GCCCGGGCGG CCTCAGTGAG 4920 CGAGCGAGCG CGCAGAGAGG GAGTGGCCAA 4950 SEQ ID NO: 4 <211> 4983 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 4 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTGGGCG ACTCAGATCC CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC 180 TCCGATAACT GGGGTGACCT TGGTTAATAT TCACCAGCAG CCTCCCCCGT TGCCCCTCTG 240 GATCCACTGC TTAAATACGG ACGAGGACAG GGCCCTGTCT CCTCAGCTTC AGGCACCACC 300 ACTGACCTGG GACAGTGAAT CGCCACCATG CAGATTGAGC TGAGCACCTG CTTCTTCCTG 360 TGCCTGCTGA GATTCTGCTT TAGTGCCACC AGAAGATACT ACCTGGGTGC AGTGGAACTG 420 TCATGGGACT ATATGCAAAG TGATCTCGGT GAGCTGCCTG TGGACGCAAG GTAAATGCCC 480 TAAAATGGGC AAACATTGCA AGCAGCAAAC AACCTGGCTC AGAAACCACA GCGTCCTGTG 540 TCCATTCTAA TTTTTCCTTT CTTCACGCAG ATTTCCTCCT AGAGTGCCAA AATCTTTTCC 600 ATTCAACACC TCAGTCGTGT ACAAAAAGAC TCTGTTTGTA GAATTCACGG ATCACCTTTT 660 CAACATCGCT AAGCCCAGGC CCCCCTGGAT GGGCCTGCTG GGCCCCACCA TCCAGGCTGA 720 GGTGTATGAC ACTGTGGTGA TCACCCTGAA GAACATGGCC AGCCACCCTG TGAGCCTGCA 780 TGCTGTGGGG GTGAGCTACT GGAAGGCCTC TGAGGGGGCT GAGTATGATG ACCAGACCAG 840 CCAGAGGGAG AAGGAGGATG ACAAGGTGTT CCCTGGGGGC AGCCACACCT ATGTGTGGCA 900 GGTGCTGAAG GAGAATGGCC CCATGGCCTC TGACCCCCTG TGCCTGACCT ACAGCTACCT 960 GAGCCATGTG GACCTGGTGA AGGACCTGAA CTCTGGCCTG ATTGGGGCCC TGCTGGTGTG 1020 CAGGGAGGGC AGCCTGGCCA AGGAGAAGAC CCAGACCCTG CACAAGTTCA TCCTGCTGTT 1080 TGCTGTGTTT GATGAGGGCA AGAGCTGGCA CTCTGAAACC AAGAACAGCC TGATGCAGGA 1140 CAGGGATGCT GCCTCTGCCA GGGCCTGGCC CAAGATGCAC ACTGTGAATG GCTATGTGAA 1200 CAGGAGCCTG CCTGGCCTGA TTGGCTGCCA CAGGAAGTCT GTGTACTGGC ATGTGATTGG 1260 CATGGGCACC ACCCCTGAGG TGCACAGCAT CTTCCTGGAG GGCCACACCT TCCTGGTCAG 1320 GAACCACAGG CAGGCCAGCC TGGAGATCAG CCCCATCACC TTCCTGACTG CCCAGACCCT 1380 GCTGATGGAC CTGGGCCAGT TCCTGCTGTT CTGCCACATC AGCAGCCACC AGCATGATGG 1440 CATGGAGGCC TATGTGAAGG TGGACAGCTG CCCTGAGGAG CCCCAGCTGA GGATGAAGAA 1500 CAATGAGGAG GCTGAGGACT ATGATGATGA CCTGACTGAC TCTGAGATGG ATGTGGTGAG 1560 GTTTGATGAT GACAACAGCC CCAGCTTCAT CCAGATCAGG TCTGTGGCCA AGAAGCACCC 1620 CAAGACCTGG GTGCACTACA TTGCTGCTGA GGAGGAGGAC TGGGACTATG CCCCCCTGGT 1680 GCTGGCCCCT GATGACAGGA GCTACAAGAG CCAGTACCTG AACAATGGCC CCCAGAGGAT 1740 TGGCAGGAAG TACAAGAAGG TCAGGTTCAT GGCCTACACT GATGAAACCT TCAAGACCAG 1800 GGAGGCCATC CAGCATGAGT CTGGCATCCT GGGCCCCCTG CTGTATGGGG AGGTGGGGGA 1860 CACCCTGCTG ATCATCTTCA AGAACCAGGC CAGCAGGCCC TACAACATCT ACCCCCATGG 1920 CATCACTGAT GTGAGGCCCC TGTACAGCAG GAGGCTGCCC AAGGGGGTGA AGCACCTGAA 1980 GGACTTCCCC ATCCTGCCTG GGGAGATCTT CAAGTACAAG TGGACTGTGA CTGTGGAGGA 2040 TGGCCCCACC AAGTCTGACC CCAGGTGCCT GACCAGATAC TACAGCAGCT TTGTGAACAT 2100 GGAGAGGGAC CTGGCCTCTG GCCTGATTGG CCCCCTGCTG ATCTGCTACA AGGAGTCTGT 2160 GGACCAGAGG GGCAACCAGA TCATGTCTGA CAAGAGGAAT GTGATCCTGT TCTCTGTGTT 2220 TGATGAGAAC AGGAGCTGGT ACCTGACTGA GAACATCCAG AGGTTCCTGC CCAACCCTGC 2280 TGGGGTGCAG CTGGAGGACC CTGAGTTCCA GGCCAGCAAC ATCATGCACA GCATCAATGG 2340 CTATGTGTTT GACAGCCTGC AGCTGTCTGT GTGCCTGCAT GAGGTGGCCT ACTGGTACAT 2400 CCTGAGCATT GGGGCCCAGA CTGACTTCCT GTCTGTGTTC TTCTCTGGCT ACACCTTCAA 2460 GCACAAGATG GTGTATGAGG ACACCCTGAC CCTGTTCCCC TTCTCTGGGG AGACTGTGTT 2520 CATGAGCATG GAGAACCCTG GCCTGTGGAT TCTGGGCTGC CACAACTCTG ACTTCAGGAA 2580 CAGGGGCATG ACTGCCCTGC TGAAAGTCTC CAGCTGTGAC AAGAACACTG GGGACTACTA 2640 TGAGGACAGC TATGAGGACA TCTCTGCCTA CCTGCTGAGC AAGAACAATG CCATTGAGCC 2700 CAGGAGCTTC AGCCAGAACC CCCCAGTGCT GAAGAGGCAC CAGAGGGAGA TCACCAGGAC 2760 CACCCTGCAG TCTGACCAGG AGGAGATTGA CTATGATGAC ACCATCTCTG TGGAGATGAA 2820 GAAGGAGGAC TTTGACATCT ACGACGAGGA CGAGAACCAG AGCCCCAGGA GCTTCCAGAA 2880 GAAGACCAGG CACTACTTCA TTGCTGCTGT GGAGAGGCTG TGGGACTATG GCATGAGCAG 2940 CAGCCCCCAT GTGCTGAGGA ACAGGGCCCA GTCTGGCTCT GTGCCCCAGT TCAAGAAGGT 3000 GGTGTTCCAG GAGTTCACTG ATGGCAGCTT CACCCAGCCC CTGTACAGAG GGGAGCTGAA 3060 TGAGCACCTG GGCCTGCTGG GCCCCTACAT CAGGGCTGAG GTGGAGGACA ACATCATGGT 3120 GACCTTCAGG AACCAGGCCA GCAGGCCCTA CAGCTTCTAC AGCAGCCTGA TCAGCTATGA 3180 GGAGGACCAG AGGCAGGGGG CTGAGCCCAG GAAGAACTTT GTGAAGCCCA ATGAAACCAA 3240 GACCTACTTC TGGAAGGTGC AGCACCACAT GGCCCCCACC AAGGATGAGT TTGACTGCAA 3300 GGCCTGGGCC TACTTCTCTG ATGTGGACCT GGAGAAGGAT GTGCACTCTG GCCTGATTGG 3360 CCCCCTGCTG GTGTGCCACA CCAACACCCT GAACCCTGCC CATGGCAGGC AGGTGACTGT 3420 GCAGGAGTTT GCCCTGTTCT TCACCATCTT TGATGAAACC AAGAGCTGGT ACTTCACTGA 3480 GAACATGGAG AGGAACTGCA GGGCCCCCTG CAACATCCAG ATGGAGGACC CCACCTTCAA 3540 GGAGAACTAC AGGTTCCATG CCATCAATGG CTACATCATG GACACCCTGC CTGGCCTGGT 3600 GATGGCCCAG GACCAGAGGA TCAGGTGGTA CCTGCTGAGC ATGGGCAGCA ATGAGAACAT 3660 CCACAGCATC CACTTCTCTG GCCATGTGTT CACTGTGAGG AAGAAGGAGG AGTACAAGAT 3720 GGCCCTGTAC AACCTGTACC CTGGGGTGTT TGAGACTGTG GAGATGCTGC CCAGCAAGGC 3780 TGGCATCTGG AGGGTGGAGT GCCTGATTGG GGAGCACCTG CATGCTGGCA TGAGCACCCT 3840 GTTCCTGGTG TACAGCAACA AGTGCCAGAC CCCCCTGGGC ATGGCCTCTG GCCACATCAG 3900 GGACTTCCAG ATCACTGCCT CTGGCCAGTA TGGCCAGTGG GCCCCCAAGC TGGCCAGGCT 3960 GCACTACTCT GGCAGCATCA ATGCCTGGAG CACCAAGGAG CCCTTCAGCT GGATCAAGGT 4020 GGACCTGCTG GCCCCCATGA TCATCCATGG CATCAAGACC CAGGGGGCCA GGCAGAAGTT 4080 CAGCAGCCTG TACATCAGCC AGTTCATCAT CATGTACAGC CTGGATGGCA AGAAGTGGCA 4140 GACCTACAGG GGCAACAGCA CTGGCACCCT GATGGTGTTC TTTGGCAATG TGGACAGCTC 4200 TGGCATCAAG CACAACATCT TCAACCCCCC CATCATTGCC AGATACATCA GGCTGCACCC 4260 CACCCACTAC AGCATCAGGA GCACCCTGAG GATGGAGCTG ATGGGCTGTG ACCTGAACAG 4320 CTGCAGCATG CCCCTGGGCA TGGAGAGCAA GGCCATCTCT GATGCCCAGA TCACTGCCAG 4380 CAGCTACTTC ACCAACATGT TTGCCACCTG GAGCCCCAGC AAGGCCAGGC TGCACCTGCA 4440 GGGCAGGAGC AATGCCTGGA GGCCCCAGGT CAACAACCCC AAGGAGTGGC TGCAGGTGGA 4500 CTTCCAGAAG ACCATGAAGG TGACTGGGGT GACCACCCAG GGGGTGAAGA GCCTGCTGAC 4560 CAGCATGTAT GTGAAGGAGT TCCTGATCAG CAGCAGCCAG GATGGCCACC AGTGGACCCT 4620 GTTCTTCCAG AATGGCAAGG TGAAGGTGTT CCAGGGCAAC CAGGACAGCT TCACCCCTGT 4680 GGTGAACAGC CTGGACCCCC CCCTGCTGAC CAGATACCTG AGGATTCACC CCCAGAGCTG 4740 GGTGCACCAG ATTGCCCTGA GGATGGAGGT GCTGGGCTGT GAGGCCCAGG ACCTGTACTA 4800 ATAAAAGATC TTTATTTTCA TTAGATCTGT GTGTTGGTTT TTTGTGTGAG TGATGGAGTT 4860 GGCCACTCCC TCTCTGCGCG CTCGCTCGCT CACTGAGGCC GGGCGACCAA AGGTCGCCCG 4920 ACGCCCGGGC TTTGCCCGGG CGGCCTCAGT GAGCGAGCGA GCGCGCAGAG AGGGAGTGGC 4980 CAA 4983 SEQ ID NO: 5 <211> 4984 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 5 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTGGGCG ACTCAGATCC CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC 180 TCCGATAACT GGGGTGACCT TGGTTAATAT TCACCAGCAG CCTCCCCCGT TGCCCCTCTG 240 GATCCACTGC TTAAATACGG ACGAGGACAG GGCCCTGTCT CCTCAGCTTC AGGCACCACC 300 ACTGACCTGG GACAGTGAAT CGCCACCATG CAGATTGAGC TGAGCACCTG CTTCTTCCTG 360 TGCCTGCTGA GATTCTGCTT TAGTGCCACC AGAAGATACT ACCTGGGTGC AGTGGAACTG 420 TCATGGGACT ATATGCAAAG TGATCTCGGT GAGCTGCCTG TGGACGCAAG GTAAATGCCC 480 TAAAATGGGC AAACATTGCA AGCAGCAAAC ACCCTAAAAT GGGCAAACAT TGCAAGCAGC 540 AAACATTCTA ATTTTTCCTT TCTTCACGCA GATTTCCTCC TAGAGTGCCA AAATCTTTTC 600 CATTCAACAC CTCAGTCGTG TACAAAAAGA CTCTGTTTGT AGAATTCACG GATCACCTTT 660 TCAACATCGC TAAGCCCAGG CCCCCCTGGA TGGGCCTGCT GGGCCCCACC ATCCAGGCTG 720 AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC CAGCCACCCT GTGAGCCTGC 780 ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC TGAGTATGAT GACCAGACCA 840 GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG CAGCCACACC TATGTGTGGC 900 AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT GTGCCTGACC TACAGCTACC 960 TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT GATTGGGGCC CTGCTGGTGT 1020 GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT GCACAAGTTC ATCCTGCTGT 1080 TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC CAAGAACAGC CTGATGCAGG 1140 ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA CACTGTGAAT GGCTATGTGA 1200 ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC TGTGTACTGG CATGTGATTG 1260 GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA GGGCCACACC TTCCTGGTCA 1320 GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC CTTCCTGACT GCCCAGACCC 1380 TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT CAGCAGCCAC CAGCATGATG 1440 GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA GCCCCAGCTG AGGATGAAGA 1500 ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA CTCTGAGATG GATGTGGTGA 1560 GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG GTCTGTGGCC AAGAAGCACC 1620 CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA CTGGGACTAT GCCCCCCTGG 1680 TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT GAACAATGGC CCCCAGAGGA 1740 TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC TGATGAAACC TTCAAGACCA 1800 GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT GCTGTATGGG GAGGTGGGGG 1860 ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC CTACAACATC TACCCCCATG 1920 GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC CAAGGGGGTG AAGCACCTGA 1980 AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA GTGGACTGTG ACTGTGGAGG 2040 ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA CTACAGCAGC TTTGTGAACA 2100 TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT GATCTGCTAC AAGGAGTCTG 2160 TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA TGTGATCCTG TTCTCTGTGT 2220 TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA GAGGTTCCTG CCCAACCCTG 2280 CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA CATCATGCAC AGCATCAATG 2340 GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA TGAGGTGGCC TACTGGTACA 2400 TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT CTTCTCTGGC TACACCTTCA 2460 AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC CTTCTCTGGG GAGACTGTGT 2520 TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG CCACAACTCT GACTTCAGGA 2580 ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA CAAGAACACT GGGGACTACT 2640 ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG CAAGAACAAT GCCATTGAGC 2700 CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA CCAGAGGGAG ATCACCAGGA 2760 CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA CACCATCTCT GTGGAGATGA 2820 AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA GAGCCCCAGG AGCTTCCAGA 2880 AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT GTGGGACTAT GGCATGAGCA 2940 GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC TGTGCCCCAG TTCAAGAAGG 3000 TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC CCTGTACAGA GGGGAGCTGA 3060 ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA GGTGGAGGAC AACATCATGG 3120 TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA CAGCAGCCTG ATCAGCTATG 3180 AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT TGTGAAGCCC AATGAAACCA 3240 AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC CAAGGATGAG TTTGACTGCA 3300 AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA TGTGCACTCT GGCCTGATTG 3360 GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC CCATGGCAGG CAGGTGACTG 3420 TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC CAAGAGCTGG TACTTCACTG 3480 AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA GATGGAGGAC CCCACCTTCA 3540 AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT GGACACCCTG CCTGGCCTGG 3600 TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG CATGGGCAGC AATGAGAACA 3660 TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG GAAGAAGGAG GAGTACAAGA 3720 TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT GGAGATGCTG CCCAGCAAGG 3780 CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT GCATGCTGGC ATGAGCACCC 3840 TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG CATGGCCTCT GGCCACATCA 3900 GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG GGCCCCCAAG CTGGCCAGGC 3960 TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA GCCCTTCAGC TGGATCAAGG 4020 TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC CCAGGGGGCC AGGCAGAAGT 4080 TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG CCTGGATGGC AAGAAGTGGC 4140 AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT CTTTGGCAAT GTGGACAGCT 4200 CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC CAGATACATC AGGCTGCACC 4260 CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT GATGGGCTGT GACCTGAACA 4320 GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC TGATGCCCAG ATCACTGCCA 4380 GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG CAAGGCCAGG CTGCACCTGC 4440 AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC CAAGGAGTGG CTGCAGGTGG 4500 ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA GGGGGTGAAG AGCCTGCTGA 4560 CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA GGATGGCCAC CAGTGGACCC 4620 TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA CCAGGACAGC TTCACCCCTG 4680 TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT GAGGATTCAC CCCCAGAGCT 4740 GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG TGAGGCCCAG GACCTGTACT 4800 AATAAAAGAT CTTTATTTTC ATTAGATCTG TGTGTTGGTT TTTTGTGTGA GTGATGGAGT 4860 TGGCCACTCC CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC 4920 GACGCCCGGG CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG 4980 CCAA 4984 SEQ ID NO: 6 <211> 4805 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 6 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG 180 GACACAGGAC GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA 240 GCCCCTGTTT GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC 300 CCCGTTGCCC CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA 360 GCTTCAGGCA CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC 420 ACCTGCTTCT TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG 480 GGGGCTGTGG AGCTGAGCTG GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT 540 GCCAGGTTCC CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG 600 AAGACCCTGT TTGTGGAGTT CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC 660 TGGATGGGCC TGCTGGGCCC CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC 720 CTGAAGAACA TGGCCAGCCA CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG 780 GCCTCTGAGG GGGCTGAGTA TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG 840 GTGTTCCCTG GGGGCAGCCA CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG 900 GCCTCTGACC CCCTGTGCCT GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC 960 CTGAACTCTG GCCTGATTGG GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG 1020 AAGACCCAGA CCCTGCACAA GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC 1080 TGGCACTCTG AAACCAAGAA CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC 1140 TGGCCCAAGA TGCACACTGT GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC 1200 TGCCACAGGA AGTCTGTGTA CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC 1260 AGCATCTTCC TGGAGGGCCA CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG 1320 ATCAGCCCCA TCACCTTCCT GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG 1380 CTGTTCTGCC ACATCAGCAG CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC 1440 AGCTGCCCTG AGGAGCCCCA GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT 1500 GATGACCTGA CTGACTCTGA GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC 1560 TTCATCCAGA TCAGGTCTGT GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT 1620 GCTGAGGAGG AGGACTGGGA CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC 1680 AAGAGCCAGT ACCTGAACAA TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG 1740 TTCATGGCCT ACACTGATGA AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC 1800 ATCCTGGGCC CCCTGCTGTA TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC 1860 CAGGCCAGCA GGCCCTACAA CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC 1920 AGCAGGAGGC TGCCCAAGGG GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG 1980 ATCTTCAAGT ACAAGTGGAC TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG 2040 TGCCTGACCA GATACTACAG CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG 2100 ATTGGCCCCC TGCTGATCTG CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG 2160 TCTGACAAGA GGAATGTGAT CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG 2220 ACTGAGAACA TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG 2280 TTCCAGGCCA GCAACATCAT GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG 2340 TCTGTGTGCC TGCATGAGGT GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC 2400 TTCCTGTCTG TGTTCTTCTC TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC 2460 CTGACCCTGT TCCCCTTCTC TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG 2520 TGGATTCTGG GCTGCCACAA CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA 2580 GTCTCCAGCT GTGACAAGAA CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT 2640 GCCTACCTGC TGAGCAAGAA CAATGCCATT GAGCCCAGGA GCTTCCAGAA GAAGACCAGG 2700 CACTACTTCA TTGCTGCTGT GGAGAGGCTG TGGGACTATG GCATGAGCAG CAGCCCCCAT 2760 GTGCTGAGGA ACAGGGCCCA GTCTGGCTCT GTGCCCCAGT TCAAGAAGGT GGTGTTCCAG 2820 GAGTTCACTG ATGGCAGCTT CACCCAGCCC CTGTACAGAG GGGAGCTGAA TGAGCACCTG 2880 GGCCTGCTGG GCCCCTACAT CAGGGCTGAG GTGGAGGACA ACATCATGGT GACCTTCAGG 2940 AACCAGGCCA GCAGGCCCTA CAGCTTCTAC AGCAGCCTGA TCAGCTATGA GGAGGACCAG 3000 AGGCAGGGGG CTGAGCCCAG GAAGAACTTT GTGAAGCCCA ATGAAACCAA GACCTACTTC 3060 TGGAAGGTGC AGCACCACAT GGCCCCCACC AAGGATGAGT TTGACTGCAA GGCCTGGGCC 3120 TACTTCTCTG ATGTGGACCT GGAGAAGGAT GTGCACTCTG GCCTGATTGG CCCCCTGCTG 3180 GTGTGCCACA CCAACACCCT GAACCCTGCC CATGGCAGGC AGGTGACTGT GCAGGAGTTT 3240 GCCCTGTTCT TCACCATCTT TGATGAAACC AAGAGCTGGT ACTTCACTGA GAACATGGAG 3300 AGGAACTGCA GGGCCCCCTG CAACATCCAG ATGGAGGACC CCACCTTCAA GGAGAACTAC 3360 AGGTTCCATG CCATCAATGG CTACATCATG GACACCCTGC CTGGCCTGGT GATGGCCCAG 3420 GACCAGAGGA TCAGGTGGTA CCTGCTGAGC ATGGGCAGCA ATGAGAACAT CCACAGCATC 3480 CACTTCTCTG GCCATGTGTT CACTGTGAGG AAGAAGGAGG AGTACAAGAT GGCCCTGTAC 3540 AACCTGTACC CTGGGGTGTT TGAGACTGTG GAGATGCTGC CCAGCAAGGC TGGCATCTGG 3600 AGGGTGGAGT GCCTGATTGG GGAGCACCTG CATGCTGGCA TGAGCACCCT GTTCCTGGTG 3660 TACAGCAACA AGTGCCAGAC CCCCCTGGGC ATGGCCTCTG GCCACATCAG GGACTTCCAG 3720 ATCACTGCCT CTGGCCAGTA TGGCCAGTGG GCCCCCAAGC TGGCCAGGCT GCACTACTCT 3780 GGCAGCATCA ATGCCTGGAG CACCAAGGAG CCCTTCAGCT GGATCAAGGT GGACCTGCTG 3840 GCCCCCATGA TCATCCATGG CATCAAGACC CAGGGGGCCA GGCAGAAGTT CAGCAGCCTG 3900 TACATCAGCC AGTTCATCAT CATGTACAGC CTGGATGGCA AGAAGTGGCA GACCTACAGG 3960 GGCAACAGCA CTGGCACCCT GATGGTGTTC TTTGGCAATG TGGACAGCTC TGGCATCAAG 4020 CACAACATCT TCAACCCCCC CATCATTGCC AGATACATCA GGCTGCACCC CACCCACTAC 4080 AGCATCAGGA GCACCCTGAG GATGGAGCTG ATGGGCTGTG ACCTGAACAG CTGCAGCATG 4140 CCCCTGGGCA TGGAGAGCAA GGCCATCTCT GATGCCCAGA TCACTGCCAG CAGCTACTTC 4200 ACCAACATGT TTGCCACCTG GAGCCCCAGC AAGGCCAGGC TGCACCTGCA GGGCAGGAGC 4260 AATGCCTGGA GGCCCCAGGT CAACAACCCC AAGGAGTGGC TGCAGGTGGA CTTCCAGAAG 4320 ACCATGAAGG TGACTGGGGT GACCACCCAG GGGGTGAAGA GCCTGCTGAC CAGCATGTAT 4380 GTGAAGGAGT TCCTGATCAG CAGCAGCCAG GATGGCCACC AGTGGACCCT GTTCTTCCAG 4440 AATGGCAAGG TGAAGGTGTT CCAGGGCAAC CAGGACAGCT TCACCCCTGT GGTGAACAGC 4500 CTGGACCCCC CCCTGCTGAC CAGATACCTG AGGATTCACC CCCAGAGCTG GGTGCACCAG 4560 ATTGCCCTGA GGATGGAGGT GCTGGGCTGT GAGGCCCAGG ACCTGTACTG AAATAAAAGA 4620 TCTTTATTTT CATTAGATCT GTGTGTTGGT TTTTTGTGTG AGGAACCCCT AGTGATGGAG 4680 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGGGCGACC AAAGGTCGCC 4740 CGACGCCCGG GCTTTGCCCG GGCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 4800 GCCAA 4805 SEQ ID NO: 7 <211> 4934 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 7 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG 180 GACACAGGAC GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA 240 GCCCCTGTTT GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC 300 CCCGTTGCCC CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA 360 GCTTCAGGCA CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC 420 ACCTGCTTCT TCCTGTGCCT GCTGAGATTC TGCTTTAGTG CCACCAGAAG ATACTACCTG 480 GGTGCAGTGG AACTGTCATG GGACTATATG CAAAGTGATC TCGGTGAGCT GCCTGTGGAC 540 GCAAGGTAAA GGCATGTCCT GTAGGGTCTG ATCGGGGCCA GGATTGTGGG GATGTAAGTC 600 TGCTTGGAGG AAGGTGCAGA CATCGGGTTA GGATGGTTGT GATGCTATTC TGACTTTTTC 660 CTTTCTTCAC GCAGATTTCC TCCTAGAGTG CCAAAATCTT TTCCATTCAA CACCTCAGTC 720 GTGTACAAAA AGACTCTGTT TGTAGAATTC ACGGATCACC TTTTCAACAT CGCTAAGCCC 780 AGGCCCCCCT GGATGGGCCT GCTGGGCCCC ACCATCCAGG CTGAGGTGTA TGACACTGTG 840 GTGATCACCC TGAAGAACAT GGCCAGCCAC CCTGTGAGCC TGCATGCTGT GGGGGTGAGC 900 TACTGGAAGG CCTCTGAGGG GGCTGAGTAT GATGACCAGA CCAGCCAGAG GGAGAAGGAG 960 GATGACAAGG TGTTCCCTGG GGGCAGCCAC ACCTATGTGT GGCAGGTGCT GAAGGAGAAT 1020 GGCCCCATGG CCTCTGACCC CCTGTGCCTG ACCTACAGCT ACCTGAGCCA TGTGGACCTG 1080 GTGAAGGACC TGAACTCTGG CCTGATTGGG GCCCTGCTGG TGTGCAGGGA GGGCAGCCTG 1140 GCCAAGGAGA AGACCCAGAC CCTGCACAAG TTCATCCTGC TGTTTGCTGT GTTTGATGAG 1200 GGCAAGAGCT GGCACTCTGA AACCAAGAAC AGCCTGATGC AGGACAGGGA TGCTGCCTCT 1260 GCCAGGGCCT GGCCCAAGAT GCACACTGTG AATGGCTATG TGAACAGGAG CCTGCCTGGC 1320 CTGATTGGCT GCCACAGGAA GTCTGTGTAC TGGCATGTGA TTGGCATGGG CACCACCCCT 1380 GAGGTGCACA GCATCTTCCT GGAGGGCCAC ACCTTCCTGG TCAGGAACCA CAGGCAGGCC 1440 AGCCTGGAGA TCAGCCCCAT CACCTTCCTG ACTGCCCAGA CCCTGCTGAT GGACCTGGGC 1500 CAGTTCCTGC TGTTCTGCCA CATCAGCAGC CACCAGCATG ATGGCATGGA GGCCTATGTG 1560 AAGGTGGACA GCTGCCCTGA GGAGCCCCAG CTGAGGATGA AGAACAATGA GGAGGCTGAG 1620 GACTATGATG ATGACCTGAC TGACTCTGAG ATGGATGTGG TGAGGTTTGA TGATGACAAC 1680 AGCCCCAGCT TCATCCAGAT CAGGTCTGTG GCCAAGAAGC ACCCCAAGAC CTGGGTGCAC 1740 TACATTGCTG CTGAGGAGGA GGACTGGGAC TATGCCCCCC TGGTGCTGGC CCCTGATGAC 1800 AGGAGCTACA AGAGCCAGTA CCTGAACAAT GGCCCCCAGA GGATTGGCAG GAAGTACAAG 1860 AAGGTCAGGT TCATGGCCTA CACTGATGAA ACCTTCAAGA CCAGGGAGGC CATCCAGCAT 1920 GAGTCTGGCA TCCTGGGCCC CCTGCTGTAT GGGGAGGTGG GGGACACCCT GCTGATCATC 1980 TTCAAGAACC AGGCCAGCAG GCCCTACAAC ATCTACCCCC ATGGCATCAC TGATGTGAGG 2040 CCCCTGTACA GCAGGAGGCT GCCCAAGGGG GTGAAGCACC TGAAGGACTT CCCCATCCTG 2100 CCTGGGGAGA TCTTCAAGTA CAAGTGGACT GTGACTGTGG AGGATGGCCC CACCAAGTCT 2160 GACCCCAGGT GCCTGACCAG ATACTACAGC AGCTTTGTGA ACATGGAGAG GGACCTGGCC 2220 TCTGGCCTGA TTGGCCCCCT GCTGATCTGC TACAAGGAGT CTGTGGACCA GAGGGGCAAC 2280 CAGATCATGT CTGACAAGAG GAATGTGATC CTGTTCTCTG TGTTTGATGA GAACAGGAGC 2340 TGGTACCTGA CTGAGAACAT CCAGAGGTTC CTGCCCAACC CTGCTGGGGT GCAGCTGGAG 2400 GACCCTGAGT TCCAGGCCAG CAACATCATG CACAGCATCA ATGGCTATGT GTTTGACAGC 2460 CTGCAGCTGT CTGTGTGCCT GCATGAGGTG GCCTACTGGT ACATCCTGAG CATTGGGGCC 2520 CAGACTGACT TCCTGTCTGT GTTCTTCTCT GGCTACACCT TCAAGCACAA GATGGTGTAT 2580 GAGGACACCC TGACCCTGTT CCCCTTCTCT GGGGAGACTG TGTTCATGAG CATGGAGAAC 2640 CCTGGCCTGT GGATTCTGGG CTGCCACAAC TCTGACTTCA GGAACAGGGG CATGACTGCC 2700 CTGCTGAAAG TCTCCAGCTG TGACAAGAAC ACTGGGGACT ACTATGAGGA CAGCTATGAG 2760 GACATCTCTG CCTACCTGCT GAGCAAGAAC AATGCCATTG AGCCCAGGAG CTTCCAGAAG 2820 AAGACCAGGC ACTACTTCAT TGCTGCTGTG GAGAGGCTGT GGGACTATGG CATGAGCAGC 2880 AGCCCCCATG TGCTGAGGAA CAGGGCCCAG TCTGGCTCTG TGCCCCAGTT CAAGAAGGTG 2940 GTGTTCCAGG AGTTCACTGA TGGCAGCTTC ACCCAGCCCC TGTACAGAGG GGAGCTGAAT 3000 GAGCACCTGG GCCTGCTGGG CCCCTACATC AGGGCTGAGG TGGAGGACAA CATCATGGTG 3060 ACCTTCAGGA ACCAGGCCAG CAGGCCCTAC AGCTTCTACA GCAGCCTGAT CAGCTATGAG 3120 GAGGACCAGA GGCAGGGGGC TGAGCCCAGG AAGAACTTTG TGAAGCCCAA TGAAACCAAG 3180 ACCTACTTCT GGAAGGTGCA GCACCACATG GCCCCCACCA AGGATGAGTT TGACTGCAAG 3240 GCCTGGGCCT ACTTCTCTGA TGTGGACCTG GAGAAGGATG TGCACTCTGG CCTGATTGGC 3300 CCCCTGCTGG TGTGCCACAC CAACACCCTG AACCCTGCCC ATGGCAGGCA GGTGACTGTG 3360 CAGGAGTTTG CCCTGTTCTT CACCATCTTT GATGAAACCA AGAGCTGGTA CTTCACTGAG 3420 AACATGGAGA GGAACTGCAG GGCCCCCTGC AACATCCAGA TGGAGGACCC CACCTTCAAG 3480 GAGAACTACA GGTTCCATGC CATCAATGGC TACATCATGG ACACCCTGCC TGGCCTGGTG 3540 ATGGCCCAGG ACCAGAGGAT CAGGTGGTAC CTGCTGAGCA TGGGCAGCAA TGAGAACATC 3600 CACAGCATCC ACTTCTCTGG CCATGTGTTC ACTGTGAGGA AGAAGGAGGA GTACAAGATG 3660 GCCCTGTACA ACCTGTACCC TGGGGTGTTT GAGACTGTGG AGATGCTGCC CAGCAAGGCT 3720 GGCATCTGGA GGGTGGAGTG CCTGATTGGG GAGCACCTGC ATGCTGGCAT GAGCACCCTG 3780 TTCCTGGTGT ACAGCAACAA GTGCCAGACC CCCCTGGGCA TGGCCTCTGG CCACATCAGG 3840 GACTTCCAGA TCACTGCCTC TGGCCAGTAT GGCCAGTGGG CCCCCAAGCT GGCCAGGCTG 3900 CACTACTCTG GCAGCATCAA TGCCTGGAGC ACCAAGGAGC CCTTCAGCTG GATCAAGGTG 3960 GACCTGCTGG CCCCCATGAT CATCCATGGC ATCAAGACCC AGGGGGCCAG GCAGAAGTTC 4020 AGCAGCCTGT ACATCAGCCA GTTCATCATC ATGTACAGCC TGGATGGCAA GAAGTGGCAG 4080 ACCTACAGGG GCAACAGCAC TGGCACCCTG ATGGTGTTCT TTGGCAATGT GGACAGCTCT 4140 GGCATCAAGC ACAACATCTT CAACCCCCCC ATCATTGCCA GATACATCAG GCTGCACCCC 4200 ACCCACTACA GCATCAGGAG CACCCTGAGG ATGGAGCTGA TGGGCTGTGA CCTGAACAGC 4260 TGCAGCATGC CCCTGGGCAT GGAGAGCAAG GCCATCTCTG ATGCCCAGAT CACTGCCAGC 4320 AGCTACTTCA CCAACATGTT TGCCACCTGG AGCCCCAGCA AGGCCAGGCT GCACCTGCAG 4380 GGCAGGAGCA ATGCCTGGAG GCCCCAGGTC AACAACCCCA AGGAGTGGCT GCAGGTGGAC 4440 TTCCAGAAGA CCATGAAGGT GACTGGGGTG ACCACCCAGG GGGTGAAGAG CCTGCTGACC 4500 AGCATGTATG TGAAGGAGTT CCTGATCAGC AGCAGCCAGG ATGGCCACCA GTGGACCCTG 4560 TTCTTCCAGA ATGGCAAGGT GAAGGTGTTC CAGGGCAACC AGGACAGCTT CACCCCTGTG 4620 GTGAACAGCC TGGACCCCCC CCTGCTGACC AGATACCTGA GGATTCACCC CCAGAGCTGG 4680 GTGCACCAGA TTGCCCTGAG GATGGAGGTG CTGGGCTGTG AGGCCCAGGA CCTGTACTGA 4740 AATAAAAGAT CTTTATTTTC ATTAGATCTG TGTGTTGGTT TTTTGTGTGA GGAACCCCTA 4800 GTGATGGAGT TGGCCACTCC CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA 4860 AAGGTCGCCC GACGCCCGGG CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA 4920 GAGGGAGTGG CCAA 4934 SEQ ID NO: 8 <211> 4934 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 8 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG 180 GACACAGGAC GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA 240 GCCCCTGTTT GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC 300 CCCGTTGCCC CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA 360 GCTTCAGGCA CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC 420 ACCTGCTTCT TCCTGTGCCT GCTGAGATTC TGCTTTAGTG CCACCAGAAG ATACTACCTG 480 GGTGCAGTGG AACTGTCATG GGACTATATG CAAAGTGATC TCGGTGAGCT GCCTGTGGAC 540 GCAAGGTAAA GGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGGGG GATGTAAGTC 600 TGCTTGGAGG AAGGTGCAGA CATCGGGTTA GGATGGTTGT GATGCTATTC TGACTTTTTC 660 CTTTCTTCAC GCAGATTTCC TCCTAGAGTG CCAAAATCTT TTCCATTCAA CACCTCAGTC 720 GTGTACAAAA AGACTCTGTT TGTAGAATTC ACGGATCACC TTTTCAACAT CGCTAAGCCC 780 AGGCCCCCCT GGATGGGCCT GCTGGGCCCC ACCATCCAGG CTGAGGTGTA TGACACTGTG 840 GTGATCACCC TGAAGAACAT GGCCAGCCAC CCTGTGAGCC TGCATGCTGT GGGGGTGAGC 900 TACTGGAAGG CCTCTGAGGG GGCTGAGTAT GATGACCAGA CCAGCCAGAG GGAGAAGGAG 960 GATGACAAGG TGTTCCCTGG GGGCAGCCAC ACCTATGTGT GGCAGGTGCT GAAGGAGAAT 1020 GGCCCCATGG CCTCTGACCC CCTGTGCCTG ACCTACAGCT ACCTGAGCCA TGTGGACCTG 1080 GTGAAGGACC TGAACTCTGG CCTGATTGGG GCCCTGCTGG TGTGCAGGGA GGGCAGCCTG 1140 GCCAAGGAGA AGACCCAGAC CCTGCACAAG TTCATCCTGC TGTTTGCTGT GTTTGATGAG 1200 GGCAAGAGCT GGCACTCTGA AACCAAGAAC AGCCTGATGC AGGACAGGGA TGCTGCCTCT 1260 GCCAGGGCCT GGCCCAAGAT GCACACTGTG AATGGCTATG TGAACAGGAG CCTGCCTGGC 1320 CTGATTGGCT GCCACAGGAA GTCTGTGTAC TGGCATGTGA TTGGCATGGG CACCACCCCT 1380 GAGGTGCACA GCATCTTCCT GGAGGGCCAC ACCTTCCTGG TCAGGAACCA CAGGCAGGCC 1440 AGCCTGGAGA TCAGCCCCAT CACCTTCCTG ACTGCCCAGA CCCTGCTGAT GGACCTGGGC 1500 CAGTTCCTGC TGTTCTGCCA CATCAGCAGC CACCAGCATG ATGGCATGGA GGCCTATGTG 1560 AAGGTGGACA GCTGCCCTGA GGAGCCCCAG CTGAGGATGA AGAACAATGA GGAGGCTGAG 1620 GACTATGATG ATGACCTGAC TGACTCTGAG ATGGATGTGG TGAGGTTTGA TGATGACAAC 1680 AGCCCCAGCT TCATCCAGAT CAGGTCTGTG GCCAAGAAGC ACCCCAAGAC CTGGGTGCAC 1740 TACATTGCTG CTGAGGAGGA GGACTGGGAC TATGCCCCCC TGGTGCTGGC CCCTGATGAC 1800 AGGAGCTACA AGAGCCAGTA CCTGAACAAT GGCCCCCAGA GGATTGGCAG GAAGTACAAG 1860 AAGGTCAGGT TCATGGCCTA CACTGATGAA ACCTTCAAGA CCAGGGAGGC CATCCAGCAT 1920 GAGTCTGGCA TCCTGGGCCC CCTGCTGTAT GGGGAGGTGG GGGACACCCT GCTGATCATC 1980 TTCAAGAACC AGGCCAGCAG GCCCTACAAC ATCTACCCCC ATGGCATCAC TGATGTGAGG 2040 CCCCTGTACA GCAGGAGGCT GCCCAAGGGG GTGAAGCACC TGAAGGACTT CCCCATCCTG 2100 CCTGGGGAGA TCTTCAAGTA CAAGTGGACT GTGACTGTGG AGGATGGCCC CACCAAGTCT 2160 GACCCCAGGT GCCTGACCAG ATACTACAGC AGCTTTGTGA ACATGGAGAG GGACCTGGCC 2220 TCTGGCCTGA TTGGCCCCCT GCTGATCTGC TACAAGGAGT CTGTGGACCA GAGGGGCAAC 2280 CAGATCATGT CTGACAAGAG GAATGTGATC CTGTTCTCTG TGTTTGATGA GAACAGGAGC 2340 TGGTACCTGA CTGAGAACAT CCAGAGGTTC CTGCCCAACC CTGCTGGGGT GCAGCTGGAG 2400 GACCCTGAGT TCCAGGCCAG CAACATCATG CACAGCATCA ATGGCTATGT GTTTGACAGC 2460 CTGCAGCTGT CTGTGTGCCT GCATGAGGTG GCCTACTGGT ACATCCTGAG CATTGGGGCC 2520 CAGACTGACT TCCTGTCTGT GTTCTTCTCT GGCTACACCT TCAAGCACAA GATGGTGTAT 2580 GAGGACACCC TGACCCTGTT CCCCTTCTCT GGGGAGACTG TGTTCATGAG CATGGAGAAC 2640 CCTGGCCTGT GGATTCTGGG CTGCCACAAC TCTGACTTCA GGAACAGGGG CATGACTGCC 2700 CTGCTGAAAG TCTCCAGCTG TGACAAGAAC ACTGGGGACT ACTATGAGGA CAGCTATGAG 2760 GACATCTCTG CCTACCTGCT GAGCAAGAAC AATGCCATTG AGCCCAGGAG CTTCCAGAAG 2820 AAGACCAGGC ACTACTTCAT TGCTGCTGTG GAGAGGCTGT GGGACTATGG CATGAGCAGC 2880 AGCCCCCATG TGCTGAGGAA CAGGGCCCAG TCTGGCTCTG TGCCCCAGTT CAAGAAGGTG 2940 GTGTTCCAGG AGTTCACTGA TGGCAGCTTC ACCCAGCCCC TGTACAGAGG GGAGCTGAAT 3000 GAGCACCTGG GCCTGCTGGG CCCCTACATC AGGGCTGAGG TGGAGGACAA CATCATGGTG 3060 ACCTTCAGGA ACCAGGCCAG CAGGCCCTAC AGCTTCTACA GCAGCCTGAT CAGCTATGAG 3120 GAGGACCAGA GGCAGGGGGC TGAGCCCAGG AAGAACTTTG TGAAGCCCAA TGAAACCAAG 3180 ACCTACTTCT GGAAGGTGCA GCACCACATG GCCCCCACCA AGGATGAGTT TGACTGCAAG 3240 GCCTGGGCCT ACTTCTCTGA TGTGGACCTG GAGAAGGATG TGCACTCTGG CCTGATTGGC 3300 CCCCTGCTGG TGTGCCACAC CAACACCCTG AACCCTGCCC ATGGCAGGCA GGTGACTGTG 3360 CAGGAGTTTG CCCTGTTCTT CACCATCTTT GATGAAACCA AGAGCTGGTA CTTCACTGAG 3420 AACATGGAGA GGAACTGCAG GGCCCCCTGC AACATCCAGA TGGAGGACCC CACCTTCAAG 3480 GAGAACTACA GGTTCCATGC CATCAATGGC TACATCATGG ACACCCTGCC TGGCCTGGTG 3540 ATGGCCCAGG ACCAGAGGAT CAGGTGGTAC CTGCTGAGCA TGGGCAGCAA TGAGAACATC 3600 CACAGCATCC ACTTCTCTGG CCATGTGTTC ACTGTGAGGA AGAAGGAGGA GTACAAGATG 3660 GCCCTGTACA ACCTGTACCC TGGGGTGTTT GAGACTGTGG AGATGCTGCC CAGCAAGGCT 3720 GGCATCTGGA GGGTGGAGTG CCTGATTGGG GAGCACCTGC ATGCTGGCAT GAGCACCCTG 3780 TTCCTGGTGT ACAGCAACAA GTGCCAGACC CCCCTGGGCA TGGCCTCTGG CCACATCAGG 3840 GACTTCCAGA TCACTGCCTC TGGCCAGTAT GGCCAGTGGG CCCCCAAGCT GGCCAGGCTG 3900 CACTACTCTG GCAGCATCAA TGCCTGGAGC ACCAAGGAGC CCTTCAGCTG GATCAAGGTG 3960 GACCTGCTGG CCCCCATGAT CATCCATGGC ATCAAGACCC AGGGGGCCAG GCAGAAGTTC 4020 AGCAGCCTGT ACATCAGCCA GTTCATCATC ATGTACAGCC TGGATGGCAA GAAGTGGCAG 4080 ACCTACAGGG GCAACAGCAC TGGCACCCTG ATGGTGTTCT TTGGCAATGT GGACAGCTCT 4140 GGCATCAAGC ACAACATCTT CAACCCCCCC ATCATTGCCA GATACATCAG GCTGCACCCC 4200 ACCCACTACA GCATCAGGAG CACCCTGAGG ATGGAGCTGA TGGGCTGTGA CCTGAACAGC 4260 TGCAGCATGC CCCTGGGCAT GGAGAGCAAG GCCATCTCTG ATGCCCAGAT CACTGCCAGC 4320 AGCTACTTCA CCAACATGTT TGCCACCTGG AGCCCCAGCA AGGCCAGGCT GCACCTGCAG 4380 GGCAGGAGCA ATGCCTGGAG GCCCCAGGTC AACAACCCCA AGGAGTGGCT GCAGGTGGAC 4440 TTCCAGAAGA CCATGAAGGT GACTGGGGTG ACCACCCAGG GGGTGAAGAG CCTGCTGACC 4500 AGCATGTATG TGAAGGAGTT CCTGATCAGC AGCAGCCAGG ATGGCCACCA GTGGACCCTG 4560 TTCTTCCAGA ATGGCAAGGT GAAGGTGTTC CAGGGCAACC AGGACAGCTT CACCCCTGTG 4620 GTGAACAGCC TGGACCCCCC CCTGCTGACC AGATACCTGA GGATTCACCC CCAGAGCTGG 4680 GTGCACCAGA TTGCCCTGAG GATGGAGGTG CTGGGCTGTG AGGCCCAGGA CCTGTACTGA 4740 AATAAAAGAT CTTTATTTTC ATTAGATCTG TGTGTTGGTT TTTTGTGTGA GGAACCCCTA 4800 GTGATGGAGT TGGCCACTCC CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA 4860 AAGGTCGCCC GACGCCCGGG CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA 4920 GAGGGAGTGG CCAA 4934 SEQ ID NO: 9 <211> 4934 <212> DNA <213> ADENO-ASSOCIATED VIRUS <400> 9 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGTTTG CTGCTTGCAA TGTTTGCCCA TTTTAGGGTG 180 GACACAGGAC GCTGTGGTTT CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA 240 GCCCCTGTTT GCTCCTCCGA TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC 300 CCCGTTGCCC CTCTGGATCC ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA 360 GCTTCAGGCA CCACCACTGA CCTGGGACAG TGAATCGCCA CCATGCAGAT TGAGCTGAGC 420 ACCTGCTTCT TCCTGTGCCT GCTGAGATTC TGCTTTAGTG CCACCAGAAG ATACTACCTG 480 GGTGCAGTGG AACTGTCATG GGACTATATG CAAAGTGATC TCGGTGAGCT GCCTGTGGAC 540 GCAAGGTAAA GGCATGTCCT GTAGGGTCTG ATCGGGGCCA GGATTGTGGG GATGTAAGTC 600 TGCTTGGAGG AAGCCCTAAA ATGGGCAAAC ATTGCAAGCA GCAAACATTC TGACTTTTTC 660 CTTTCTTCAC GCAGATTTCC TCCTAGAGTG CCAAAATCTT TTCCATTCAA CACCTCAGTC 720 GTGTACAAAA AGACTCTGTT TGTAGAATTC ACGGATCACC TTTTCAACAT CGCTAAGCCC 780 AGGCCCCCCT GGATGGGCCT GCTGGGCCCC ACCATCCAGG CTGAGGTGTA TGACACTGTG 840 GTGATCACCC TGAAGAACAT GGCCAGCCAC CCTGTGAGCC TGCATGCTGT GGGGGTGAGC 900 TACTGGAAGG CCTCTGAGGG GGCTGAGTAT GATGACCAGA CCAGCCAGAG GGAGAAGGAG 960 GATGACAAGG TGTTCCCTGG GGGCAGCCAC ACCTATGTGT GGCAGGTGCT GAAGGAGAAT 1020 GGCCCCATGG CCTCTGACCC CCTGTGCCTG ACCTACAGCT ACCTGAGCCA TGTGGACCTG 1080 GTGAAGGACC TGAACTCTGG CCTGATTGGG GCCCTGCTGG TGTGCAGGGA GGGCAGCCTG 1140 GCCAAGGAGA AGACCCAGAC CCTGCACAAG TTCATCCTGC TGTTTGCTGT GTTTGATGAG 1200 GGCAAGAGCT GGCACTCTGA AACCAAGAAC AGCCTGATGC AGGACAGGGA TGCTGCCTCT 1260 GCCAGGGCCT GGCCCAAGAT GCACACTGTG AATGGCTATG TGAACAGGAG CCTGCCTGGC 1320 CTGATTGGCT GCCACAGGAA GTCTGTGTAC TGGCATGTGA TTGGCATGGG CACCACCCCT 1380 GAGGTGCACA GCATCTTCCT GGAGGGCCAC ACCTTCCTGG TCAGGAACCA CAGGCAGGCC 1440 AGCCTGGAGA TCAGCCCCAT CACCTTCCTG ACTGCCCAGA CCCTGCTGAT GGACCTGGGC 1500 CAGTTCCTGC TGTTCTGCCA CATCAGCAGC CACCAGCATG ATGGCATGGA GGCCTATGTG 1560 AAGGTGGACA GCTGCCCTGA GGAGCCCCAG CTGAGGATGA AGAACAATGA GGAGGCTGAG 1620 GACTATGATG ATGACCTGAC TGACTCTGAG ATGGATGTGG TGAGGTTTGA TGATGACAAC 1680 AGCCCCAGCT TCATCCAGAT CAGGTCTGTG GCCAAGAAGC ACCCCAAGAC CTGGGTGCAC 1740 TACATTGCTG CTGAGGAGGA GGACTGGGAC TATGCCCCCC TGGTGCTGGC CCCTGATGAC 1800 AGGAGCTACA AGAGCCAGTA CCTGAACAAT GGCCCCCAGA GGATTGGCAG GAAGTACAAG 1860 AAGGTCAGGT TCATGGCCTA CACTGATGAA ACCTTCAAGA CCAGGGAGGC CATCCAGCAT 1920 GAGTCTGGCA TCCTGGGCCC CCTGCTGTAT GGGGAGGTGG GGGACACCCT GCTGATCATC 1980 TTCAAGAACC AGGCCAGCAG GCCCTACAAC ATCTACCCCC ATGGCATCAC TGATGTGAGG 2040 CCCCTGTACA GCAGGAGGCT GCCCAAGGGG GTGAAGCACC TGAAGGACTT CCCCATCCTG 2100 CCTGGGGAGA TCTTCAAGTA CAAGTGGACT GTGACTGTGG AGGATGGCCC CACCAAGTCT 2160 GACCCCAGGT GCCTGACCAG ATACTACAGC AGCTTTGTGA ACATGGAGAG GGACCTGGCC 2220 TCTGGCCTGA TTGGCCCCCT GCTGATCTGC TACAAGGAGT CTGTGGACCA GAGGGGCAAC 2280 CAGATCATGT CTGACAAGAG GAATGTGATC CTGTTCTCTG TGTTTGATGA GAACAGGAGC 2340 TGGTACCTGA CTGAGAACAT CCAGAGGTTC CTGCCCAACC CTGCTGGGGT GCAGCTGGAG 2400 GACCCTGAGT TCCAGGCCAG CAACATCATG CACAGCATCA ATGGCTATGT GTTTGACAGC 2460 CTGCAGCTGT CTGTGTGCCT GCATGAGGTG GCCTACTGGT ACATCCTGAG CATTGGGGCC 2520 CAGACTGACT TCCTGTCTGT GTTCTTCTCT GGCTACACCT TCAAGCACAA GATGGTGTAT 2580 GAGGACACCC TGACCCTGTT CCCCTTCTCT GGGGAGACTG TGTTCATGAG CATGGAGAAC 2640 CCTGGCCTGT GGATTCTGGG CTGCCACAAC TCTGACTTCA GGAACAGGGG CATGACTGCC 2700 CTGCTGAAAG TCTCCAGCTG TGACAAGAAC ACTGGGGACT ACTATGAGGA CAGCTATGAG 2760 GACATCTCTG CCTACCTGCT GAGCAAGAAC AATGCCATTG AGCCCAGGAG CTTCCAGAAG 2820 AAGACCAGGC ACTACTTCAT TGCTGCTGTG GAGAGGCTGT GGGACTATGG CATGAGCAGC 2880 AGCCCCCATG TGCTGAGGAA CAGGGCCCAG TCTGGCTCTG TGCCCCAGTT CAAGAAGGTG 2940 GTGTTCCAGG AGTTCACTGA TGGCAGCTTC ACCCAGCCCC TGTACAGAGG GGAGCTGAAT 3000 GAGCACCTGG GCCTGCTGGG CCCCTACATC AGGGCTGAGG TGGAGGACAA CATCATGGTG 3060 ACCTTCAGGA ACCAGGCCAG CAGGCCCTAC AGCTTCTACA GCAGCCTGAT CAGCTATGAG 3120 GAGGACCAGA GGCAGGGGGC TGAGCCCAGG AAGAACTTTG TGAAGCCCAA TGAAACCAAG 3180 ACCTACTTCT GGAAGGTGCA GCACCACATG GCCCCCACCA AGGATGAGTT TGACTGCAAG 3240 GCCTGGGCCT ACTTCTCTGA TGTGGACCTG GAGAAGGATG TGCACTCTGG CCTGATTGGC 3300 CCCCTGCTGG TGTGCCACAC CAACACCCTG AACCCTGCCC ATGGCAGGCA GGTGACTGTG 3360 CAGGAGTTTG CCCTGTTCTT CACCATCTTT GATGAAACCA AGAGCTGGTA CTTCACTGAG 3420 AACATGGAGA GGAACTGCAG GGCCCCCTGC AACATCCAGA TGGAGGACCC CACCTTCAAG 3480 GAGAACTACA GGTTCCATGC CATCAATGGC TACATCATGG ACACCCTGCC TGGCCTGGTG 3540 ATGGCCCAGG ACCAGAGGAT CAGGTGGTAC CTGCTGAGCA TGGGCAGCAA TGAGAACATC 3600 CACAGCATCC ACTTCTCTGG CCATGTGTTC ACTGTGAGGA AGAAGGAGGA GTACAAGATG 3660 GCCCTGTACA ACCTGTACCC TGGGGTGTTT GAGACTGTGG AGATGCTGCC CAGCAAGGCT 3720 GGCATCTGGA GGGTGGAGTG CCTGATTGGG GAGCACCTGC ATGCTGGCAT GAGCACCCTG 3780 TTCCTGGTGT ACAGCAACAA GTGCCAGACC CCCCTGGGCA TGGCCTCTGG CCACATCAGG 3840 GACTTCCAGA TCACTGCCTC TGGCCAGTAT GGCCAGTGGG CCCCCAAGCT GGCCAGGCTG 3900 CACTACTCTG GCAGCATCAA TGCCTGGAGC ACCAAGGAGC CCTTCAGCTG GATCAAGGTG 3960 GACCTGCTGG CCCCCATGAT CATCCATGGC ATCAAGACCC AGGGGGCCAG GCAGAAGTTC 4020 AGCAGCCTGT ACATCAGCCA GTTCATCATC ATGTACAGCC TGGATGGCAA GAAGTGGCAG 4080 ACCTACAGGG GCAACAGCAC TGGCACCCTG ATGGTGTTCT TTGGCAATGT GGACAGCTCT 4140 GGCATCAAGC ACAACATCTT CAACCCCCCC ATCATTGCCA GATACATCAG GCTGCACCCC 4200 ACCCACTACA GCATCAGGAG CACCCTGAGG ATGGAGCTGA TGGGCTGTGA CCTGAACAGC 4260 TGCAGCATGC CCCTGGGCAT GGAGAGCAAG GCCATCTCTG ATGCCCAGAT CACTGCCAGC 4320 AGCTACTTCA CCAACATGTT TGCCACCTGG AGCCCCAGCA AGGCCAGGCT GCACCTGCAG 4380 GGCAGGAGCA ATGCCTGGAG GCCCCAGGTC AACAACCCCA AGGAGTGGCT GCAGGTGGAC 4440 TTCCAGAAGA CCATGAAGGT GACTGGGGTG ACCACCCAGG GGGTGAAGAG CCTGCTGACC 4500 AGCATGTATG TGAAGGAGTT CCTGATCAGC AGCAGCCAGG ATGGCCACCA GTGGACCCTG 4560 TTCTTCCAGA ATGGCAAGGT GAAGGTGTTC CAGGGCAACC AGGACAGCTT CACCCCTGTG 4620 GTGAACAGCC TGGACCCCCC CCTGCTGACC AGATACCTGA GGATTCACCC CCAGAGCTGG 4680 GTGCACCAGA TTGCCCTGAG GATGGAGGTG CTGGGCTGTG AGGCCCAGGA CCTGTACTGA 4740 AATAAAAGAT CTTTATTTTC ATTAGATCTG TGTGTTGGTT TTTTGTGTGA GGAACCCCTA 4800 GTGATGGAGT TGGCCACTCC CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA 4860 AAGGTCGCCC GACGCCCGGG CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA 4920 GAGGGAGTGG CCAA 4934 SEQ ID NO: 10 <211> 5511 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 10 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGTAA GTACTAGCAG CTACAATCCA GCTACCATTC TGCTTTTATT TTATGGTTGG 780 GATAAGGCTG GATTATTCTG AGTCCAAGCT AGGCCCTTTT GCTAATCATG TTCATACCTC 840 TTATCTTCCT CCCACAGCTC CTGGGCAACG TGCTGGTCTG TGTGCTGGCC CATCACTTTG 900 GCAAAGAATT GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT TCCTGTGCCT 960 GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG AGCTGAGCTG 1020 GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC CCCCCAGAGT 1080 GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT TTGTGGAGTT 1140 CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC TGCTGGGCCC 1200 CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA TGGCCAGCCA 1260 CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG GGGCTGAGTA 1320 TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG GGGGCAGCCA 1380 CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC CCCTGTGCCT 1440 GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG GCCTGATTGG 1500 GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA CCCTGCACAA 1560 GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG AAACCAAGAA 1620 CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA TGCACACTGT 1680 GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA AGTCTGTGTA 1740 CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC TGGAGGGCCA 1800 CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA TCACCTTCCT 1860 GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC ACATCAGCAG 1920 CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG AGGAGCCCCA 1980 GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA CTGACTCTGA 2040 GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA TCAGGTCTGT 2100 GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG AGGACTGGGA 2160 CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT ACCTGAACAA 2220 TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT ACACTGATGA 2280 AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC CCCTGCTGTA 2340 TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA GGCCCTACAA 2400 CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC TGCCCAAGGG 2460 GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT ACAAGTGGAC 2520 TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA GATACTACAG 2580 CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC TGCTGATCTG 2640 CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA GGAATGTGAT 2700 CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA TCCAGAGGTT 2760 CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA GCAACATCAT 2820 GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC TGCATGAGGT 2880 GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG TGTTCTTCTC 2940 TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT TCCCCTTCTC 3000 TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG GCTGCCACAA 3060 CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT GTGACAAGAA 3120 CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC TGAGCAAGAA 3180 CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA GGCACCAGAG 3240 GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG ATGACACCAT 3300 CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA ACCAGAGCCC 3360 CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA GGCTGTGGGA 3420 CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG GCTCTGTGCC 3480 CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC AGCCCCTGTA 3540 CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG CTGAGGTGGA 3600 GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT TCTACAGCAG 3660 CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA ACTTTGTGAA 3720 GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC CCACCAAGGA 3780 TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA AGGATGTGCA 3840 CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC CTGCCCATGG 3900 CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG AAACCAAGAG 3960 CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA TCCAGATGGA 4020 GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA TCATGGACAC 4080 CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC TGAGCATGGG 4140 CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG TGAGGAAGAA 4200 GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA CTGTGGAGAT 4260 GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC ACCTGCATGC 4320 TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC TGGGCATGGC 4380 CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC AGTGGGCCCC 4440 CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA AGGAGCCCTT 4500 CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA AGACCCAGGG 4560 GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT ACAGCCTGGA 4620 TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG TGTTCTTTGG 4680 CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA TTGCCAGATA 4740 CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG AGCTGATGGG 4800 CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA TCTCTGATGC 4860 CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC CCAGCAAGGC 4920 CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA ACCCCAAGGA 4980 GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA CCCAGGGGGT 5040 GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA GCCAGGATGG 5100 CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG GCAACCAGGA 5160 CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT ACCTGAGGAT 5220 TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG GCTGTGAGGC 5280 CCAGGACCTG TACTGACCTC GAGGAATAAA GGAAATTTAT TTTCATTGCA ATAGTGTGTT 5340 GGTTTTTTGT GTCACGTGGC GGCCGCAGGA ACCCCTAGTG ATGGAGTTGG CCACTCCCTC 5400 TCTGCGCGCT CGCTCGCTCA CTGAGGCCGG GCGACCAAAG GTCGCCCGAC GCCCGGGCTT 5460 TGCCCGGGCG GCCTCAGTGA GCGAGCGAGC GCGCAGAGAG GGAGTGGCCA A 5511 SEQ ID NO: 11 <211> 5688 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 11 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGTAA GTACTAGCAG CTACAATCCA GCTACCATTC TGCTTTTATT TTATGGTTGG 780 GATAAGGCTG GATTATTCTG AGTCCAAGCT AGGCCCTTTT GCTAATCATG TTCATACCTC 840 TTATCTTCCT CCCACAGCTC CTGGGCAACG TGCTGGTCTG TGTGCTGGCC CATCACTTTG 900 GCAAAGAATT GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT TCCTGTGCCT 960 GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG AGCTGAGCTG 1020 GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC CCCCCAGAGT 1080 GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT TTGTGGAGTT 1140 CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC TGCTGGGCCC 1200 CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA TGGCCAGCCA 1260 CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG GGGCTGAGTA 1320 TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG GGGGCAGCCA 1380 CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC CCCTGTGCCT 1440 GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG GCCTGATTGG 1500 GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA CCCTGCACAA 1560 GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG AAACCAAGAA 1620 CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA TGCACACTGT 1680 GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA AGTCTGTGTA 1740 CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC TGGAGGGCCA 1800 CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA TCACCTTCCT 1860 GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC ACATCAGCAG 1920 CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG AGGAGCCCCA 1980 GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA CTGACTCTGA 2040 GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA TCAGGTCTGT 2100 GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG AGGACTGGGA 2160 CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT ACCTGAACAA 2220 TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT ACACTGATGA 2280 AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC CCCTGCTGTA 2340 TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA GGCCCTACAA 2400 CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC TGCCCAAGGG 2460 GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT ACAAGTGGAC 2520 TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA GATACTACAG 2580 CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC TGCTGATCTG 2640 CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA GGAATGTGAT 2700 CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA TCCAGAGGTT 2760 CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA GCAACATCAT 2820 GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC TGCATGAGGT 2880 GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG TGTTCTTCTC 2940 TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT TCCCCTTCTC 3000 TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG GCTGCCACAA 3060 CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT GTGACAAGAA 3120 CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC TGAGCAAGAA 3180 CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA GGCACCAGAG 3240 GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG ATGACACCAT 3300 CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA ACCAGAGCCC 3360 CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA GGCTGTGGGA 3420 CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG GCTCTGTGCC 3480 CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC AGCCCCTGTA 3540 CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG CTGAGGTGGA 3600 GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT TCTACAGCAG 3660 CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA ACTTTGTGAA 3720 GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC CCACCAAGGA 3780 TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA AGGATGTGCA 3840 CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC CTGCCCATGG 3900 CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG AAACCAAGAG 3960 CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA TCCAGATGGA 4020 GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA TCATGGACAC 4080 CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC TGAGCATGGG 4140 CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG TGAGGAAGAA 4200 GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA CTGTGGAGAT 4260 GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC ACCTGCATGC 4320 TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC TGGGCATGGC 4380 CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC AGTGGGCCCC 4440 CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA AGGAGCCCTT 4500 CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA AGACCCAGGG 4560 GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT ACAGCCTGGA 4620 TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG TGTTCTTTGG 4680 CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA TTGCCAGATA 4740 CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG AGCTGATGGG 4800 CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA TCTCTGATGC 4860 CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC CCAGCAAGGC 4920 CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA ACCCCAAGGA 4980 GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA CCCAGGGGGT 5040 GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA GCCAGGATGG 5100 CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG GCAACCAGGA 5160 CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT ACCTGAGGAT 5220 TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG GCTGTGAGGC 5280 CCAGGACCTG TACTGACCTC GAGGTGTGCC TTCTAGTTGC CAGCCATCTG TTGTTTGCCC 5340 CTCCCCCGTG CCTTCCTTGA CCCTGGAAGG TGCCACTCCC ACTGTCCTTT CCTAATAAAA 5400 TGAGGAAATT GCATCGCATT GTCTGAGTAG GTGTCATTCT ATTCTGGGGG GTGGGGTGGG 5460 GCAGGACAGC AAGGGGGAGG ATTGGGAAGA CAATAGCAGG CATGCTGGGG ATGCGGTGGG 5520 CTCTATGGGC ACGTGGCGGC CGCAGGAACC CCTAGTGATG GAGTTGGCCA CTCCCTCTCT 5580 GCGCGCTCGC TCGCTCACTG AGGCCGGGCG ACCAAAGGTC GCCCGACGCC CGGGCTTTGC 5640 CCGGGCGGCC TCAGTGAGCG AGCGAGCGCG CAGAGAGGGA GTGGCCAA 5688 SEQ ID NO: 12 <211> 5613 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 12 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGTAA GTACTAGCAG CTACAATCCA GCTACCATTC TGCTTTTATT TTATGGTTGG 780 GATAAGGCTG GATTATTCTG AGTCCAAGCT AGGCCCTTTT GCTAATCATG TTCATACCTC 840 TTATCTTCCT CCCACAGCTC CTGGGCAACG TGCTGGTCTG TGTGCTGGCC CATCACTTTG 900 GCAAAGAATT GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT TCCTGTGCCT 960 GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG AGCTGAGCTG 1020 GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC CCCCCAGAGT 1080 GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT TTGTGGAGTT 1140 CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC TGCTGGGCCC 1200 CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA TGGCCAGCCA 1260 CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG GGGCTGAGTA 1320 TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG GGGGCAGCCA 1380 CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC CCCTGTGCCT 1440 GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG GCCTGATTGG 1500 GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA CCCTGCACAA 1560 GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG AAACCAAGAA 1620 CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA TGCACACTGT 1680 GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA AGTCTGTGTA 1740 CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC TGGAGGGCCA 1800 CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA TCACCTTCCT 1860 GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC ACATCAGCAG 1920 CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG AGGAGCCCCA 1980 GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA CTGACTCTGA 2040 GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA TCAGGTCTGT 2100 GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG AGGACTGGGA 2160 CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT ACCTGAACAA 2220 TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT ACACTGATGA 2280 AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC CCCTGCTGTA 2340 TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA GGCCCTACAA 2400 CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC TGCCCAAGGG 2460 GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT ACAAGTGGAC 2520 TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA GATACTACAG 2580 CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC TGCTGATCTG 2640 CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA GGAATGTGAT 2700 CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA TCCAGAGGTT 2760 CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA GCAACATCAT 2820 GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC TGCATGAGGT 2880 GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG TGTTCTTCTC 2940 TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT TCCCCTTCTC 3000 TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG GCTGCCACAA 3060 CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT GTGACAAGAA 3120 CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC TGAGCAAGAA 3180 CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA GGCACCAGAG 3240 GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG ATGACACCAT 3300 CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA ACCAGAGCCC 3360 CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA GGCTGTGGGA 3420 CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG GCTCTGTGCC 3480 CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC AGCCCCTGTA 3540 CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG CTGAGGTGGA 3600 GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT TCTACAGCAG 3660 CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA ACTTTGTGAA 3720 GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC CCACCAAGGA 3780 TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA AGGATGTGCA 3840 CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC CTGCCCATGG 3900 CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG AAACCAAGAG 3960 CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA TCCAGATGGA 4020 GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA TCATGGACAC 4080 CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC TGAGCATGGG 4140 CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG TGAGGAAGAA 4200 GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA CTGTGGAGAT 4260 GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC ACCTGCATGC 4320 TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC TGGGCATGGC 4380 CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC AGTGGGCCCC 4440 CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA AGGAGCCCTT 4500 CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA AGACCCAGGG 4560 GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT ACAGCCTGGA 4620 TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG TGTTCTTTGG 4680 CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA TTGCCAGATA 4740 CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG AGCTGATGGG 4800 CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA TCTCTGATGC 4860 CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC CCAGCAAGGC 4920 CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA ACCCCAAGGA 4980 GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA CCCAGGGGGT 5040 GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA GCCAGGATGG 5100 CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG GCAACCAGGA 5160 CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT ACCTGAGGAT 5220 TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG GCTGTGAGGC 5280 CCAGGACCTG TACTGACCTC GAGGCACTGT CCTTTCCTAA TAAAATGAGG AAATTGCATC 5340 GCATTGTCTG AGTAGGTGTC ATTCTATTCT GGGGGGTGGG GTGGGGCAGG ACAGCAAGGG 5400 GGAGGATTGG GAAGACAATA GCAGGCATGC TGGGGATGCG GTGGGCTCTA TGGGCACGTG 5460 GCGGCCGCAG GAACCCCTAG TGATGGAGTT GGCCACTCCC TCTCTGCGCG CTCGCTCGCT 5520 CACTGAGGCC GGGCGACCAA AGGTCGCCCG ACGCCCGGGC TTTGCCCGGG CGGCCTCAGT 5580 GAGCGAGCGA GCGCGCAGAG AGGGAGTGGC CAA 5613 SEQ ID NO: 13 <211> 5362 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 13 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACT 360 GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC AGATCCCAGC CAGTGGACTT 420 AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC 480 CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC 540 AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGTA AGTACTAGCA GCTACAATCC 600 AGCTACCATT CTGCTTTTAT TTTATGGTTG GGATAAGGCT GGATTATTCT GAGTCCAAGC 660 TAGGCCCTTT TGCTAATCAT GTTCATACCT CTTATCTTCC TCCCACAGCT CCTGGGCAAC 720 GTGCTGGTCT GTGTGCTGGC CCATCACTTT GGCAAAGAAT TGCGATCGCC ACCATGCAGA 780 TTGAGCTGAG CACCTGCTTC TTCCTGTGCC TGCTGAGGTT CTGCTTCTCT GCCACCAGGA 840 GATACTACCT GGGGGCTGTG GAGCTGAGCT GGGACTACAT GCAGTCTGAC CTGGGGGAGC 900 TGCCTGTGGA TGCCAGGTTC CCCCCCAGAG TGCCCAAGAG CTTCCCCTTC AACACCTCTG 960 TGGTGTACAA GAAGACCCTG TTTGTGGAGT TCACTGACCA CCTGTTCAAC ATTGCCAAGC 1020 CCAGGCCCCC CTGGATGGGC CTGCTGGGCC CCACCATCCA GGCTGAGGTG TATGACACTG 1080 TGGTGATCAC CCTGAAGAAC ATGGCCAGCC ACCCTGTGAG CCTGCATGCT GTGGGGGTGA 1140 GCTACTGGAA GGCCTCTGAG GGGGCTGAGT ATGATGACCA GACCAGCCAG AGGGAGAAGG 1200 AGGATGACAA GGTGTTCCCT GGGGGCAGCC ACACCTATGT GTGGCAGGTG CTGAAGGAGA 1260 ATGGCCCCAT GGCCTCTGAC CCCCTGTGCC TGACCTACAG CTACCTGAGC CATGTGGACC 1320 TGGTGAAGGA CCTGAACTCT GGCCTGATTG GGGCCCTGCT GGTGTGCAGG GAGGGCAGCC 1380 TGGCCAAGGA GAAGACCCAG ACCCTGCACA AGTTCATCCT GCTGTTTGCT GTGTTTGATG 1440 AGGGCAAGAG CTGGCACTCT GAAACCAAGA ACAGCCTGAT GCAGGACAGG GATGCTGCCT 1500 CTGCCAGGGC CTGGCCCAAG ATGCACACTG TGAATGGCTA TGTGAACAGG AGCCTGCCTG 1560 GCCTGATTGG CTGCCACAGG AAGTCTGTGT ACTGGCATGT GATTGGCATG GGCACCACCC 1620 CTGAGGTGCA CAGCATCTTC CTGGAGGGCC ACACCTTCCT GGTCAGGAAC CACAGGCAGG 1680 CCAGCCTGGA GATCAGCCCC ATCACCTTCC TGACTGCCCA GACCCTGCTG ATGGACCTGG 1740 GCCAGTTCCT GCTGTTCTGC CACATCAGCA GCCACCAGCA TGATGGCATG GAGGCCTATG 1800 TGAAGGTGGA CAGCTGCCCT GAGGAGCCCC AGCTGAGGAT GAAGAACAAT GAGGAGGCTG 1860 AGGACTATGA TGATGACCTG ACTGACTCTG AGATGGATGT GGTGAGGTTT GATGATGACA 1920 ACAGCCCCAG CTTCATCCAG ATCAGGTCTG TGGCCAAGAA GCACCCCAAG ACCTGGGTGC 1980 ACTACATTGC TGCTGAGGAG GAGGACTGGG ACTATGCCCC CCTGGTGCTG GCCCCTGATG 2040 ACAGGAGCTA CAAGAGCCAG TACCTGAACA ATGGCCCCCA GAGGATTGGC AGGAAGTACA 2100 AGAAGGTCAG GTTCATGGCC TACACTGATG AAACCTTCAA GACCAGGGAG GCCATCCAGC 2160 ATGAGTCTGG CATCCTGGGC CCCCTGCTGT ATGGGGAGGT GGGGGACACC CTGCTGATCA 2220 TCTTCAAGAA CCAGGCCAGC AGGCCCTACA ACATCTACCC CCATGGCATC ACTGATGTGA 2280 GGCCCCTGTA CAGCAGGAGG CTGCCCAAGG GGGTGAAGCA CCTGAAGGAC TTCCCCATCC 2340 TGCCTGGGGA GATCTTCAAG TACAAGTGGA CTGTGACTGT GGAGGATGGC CCCACCAAGT 2400 CTGACCCCAG GTGCCTGACC AGATACTACA GCAGCTTTGT GAACATGGAG AGGGACCTGG 2460 CCTCTGGCCT GATTGGCCCC CTGCTGATCT GCTACAAGGA GTCTGTGGAC CAGAGGGGCA 2520 ACCAGATCAT GTCTGACAAG AGGAATGTGA TCCTGTTCTC TGTGTTTGAT GAGAACAGGA 2580 GCTGGTACCT GACTGAGAAC ATCCAGAGGT TCCTGCCCAA CCCTGCTGGG GTGCAGCTGG 2640 AGGACCCTGA GTTCCAGGCC AGCAACATCA TGCACAGCAT CAATGGCTAT GTGTTTGACA 2700 GCCTGCAGCT GTCTGTGTGC CTGCATGAGG TGGCCTACTG GTACATCCTG AGCATTGGGG 2760 CCCAGACTGA CTTCCTGTCT GTGTTCTTCT CTGGCTACAC CTTCAAGCAC AAGATGGTGT 2820 ATGAGGACAC CCTGACCCTG TTCCCCTTCT CTGGGGAGAC TGTGTTCATG AGCATGGAGA 2880 ACCCTGGCCT GTGGATTCTG GGCTGCCACA ACTCTGACTT CAGGAACAGG GGCATGACTG 2940 CCCTGCTGAA AGTCTCCAGC TGTGACAAGA ACACTGGGGA CTACTATGAG GACAGCTATG 3000 AGGACATCTC TGCCTACCTG CTGAGCAAGA ACAATGCCAT TGAGCCCAGG AGCTTCAGCC 3060 AGAACCCCCC AGTGCTGAAG AGGCACCAGA GGGAGATCAC CAGGACCACC CTGCAGTCTG 3120 ACCAGGAGGA GATTGACTAT GATGACACCA TCTCTGTGGA GATGAAGAAG GAGGACTTTG 3180 ACATCTACGA CGAGGACGAG AACCAGAGCC CCAGGAGCTT CCAGAAGAAG ACCAGGCACT 3240 ACTTCATTGC TGCTGTGGAG AGGCTGTGGG ACTATGGCAT GAGCAGCAGC CCCCATGTGC 3300 TGAGGAACAG GGCCCAGTCT GGCTCTGTGC CCCAGTTCAA GAAGGTGGTG TTCCAGGAGT 3360 TCACTGATGG CAGCTTCACC CAGCCCCTGT ACAGAGGGGA GCTGAATGAG CACCTGGGCC 3420 TGCTGGGCCC CTACATCAGG GCTGAGGTGG AGGACAACAT CATGGTGACC TTCAGGAACC 3480 AGGCCAGCAG GCCCTACAGC TTCTACAGCA GCCTGATCAG CTATGAGGAG GACCAGAGGC 3540 AGGGGGCTGA GCCCAGGAAG AACTTTGTGA AGCCCAATGA AACCAAGACC TACTTCTGGA 3600 AGGTGCAGCA CCACATGGCC CCCACCAAGG ATGAGTTTGA CTGCAAGGCC TGGGCCTACT 3660 TCTCTGATGT GGACCTGGAG AAGGATGTGC ACTCTGGCCT GATTGGCCCC CTGCTGGTGT 3720 GCCACACCAA CACCCTGAAC CCTGCCCATG GCAGGCAGGT GACTGTGCAG GAGTTTGCCC 3780 TGTTCTTCAC CATCTTTGAT GAAACCAAGA GCTGGTACTT CACTGAGAAC ATGGAGAGGA 3840 ACTGCAGGGC CCCCTGCAAC ATCCAGATGG AGGACCCCAC CTTCAAGGAG AACTACAGGT 3900 TCCATGCCAT CAATGGCTAC ATCATGGACA CCCTGCCTGG CCTGGTGATG GCCCAGGACC 3960 AGAGGATCAG GTGGTACCTG CTGAGCATGG GCAGCAATGA GAACATCCAC AGCATCCACT 4020 TCTCTGGCCA TGTGTTCACT GTGAGGAAGA AGGAGGAGTA CAAGATGGCC CTGTACAACC 4080 TGTACCCTGG GGTGTTTGAG ACTGTGGAGA TGCTGCCCAG CAAGGCTGGC ATCTGGAGGG 4140 TGGAGTGCCT GATTGGGGAG CACCTGCATG CTGGCATGAG CACCCTGTTC CTGGTGTACA 4200 GCAACAAGTG CCAGACCCCC CTGGGCATGG CCTCTGGCCA CATCAGGGAC TTCCAGATCA 4260 CTGCCTCTGG CCAGTATGGC CAGTGGGCCC CCAAGCTGGC CAGGCTGCAC TACTCTGGCA 4320 GCATCAATGC CTGGAGCACC AAGGAGCCCT TCAGCTGGAT CAAGGTGGAC CTGCTGGCCC 4380 CCATGATCAT CCATGGCATC AAGACCCAGG GGGCCAGGCA GAAGTTCAGC AGCCTGTACA 4440 TCAGCCAGTT CATCATCATG TACAGCCTGG ATGGCAAGAA GTGGCAGACC TACAGGGGCA 4500 ACAGCACTGG CACCCTGATG GTGTTCTTTG GCAATGTGGA CAGCTCTGGC ATCAAGCACA 4560 ACATCTTCAA CCCCCCCATC ATTGCCAGAT ACATCAGGCT GCACCCCACC CACTACAGCA 4620 TCAGGAGCAC CCTGAGGATG GAGCTGATGG GCTGTGACCT GAACAGCTGC AGCATGCCCC 4680 TGGGCATGGA GAGCAAGGCC ATCTCTGATG CCCAGATCAC TGCCAGCAGC TACTTCACCA 4740 ACATGTTTGC CACCTGGAGC CCCAGCAAGG CCAGGCTGCA CCTGCAGGGC AGGAGCAATG 4800 CCTGGAGGCC CCAGGTCAAC AACCCCAAGG AGTGGCTGCA GGTGGACTTC CAGAAGACCA 4860 TGAAGGTGAC TGGGGTGACC ACCCAGGGGG TGAAGAGCCT GCTGACCAGC ATGTATGTGA 4920 AGGAGTTCCT GATCAGCAGC AGCCAGGATG GCCACCAGTG GACCCTGTTC TTCCAGAATG 4980 GCAAGGTGAA GGTGTTCCAG GGCAACCAGG ACAGCTTCAC CCCTGTGGTG AACAGCCTGG 5040 ACCCCCCCCT GCTGACCAGA TACCTGAGGA TTCACCCCCA GAGCTGGGTG CACCAGATTG 5100 CCCTGAGGAT GGAGGTGCTG GGCTGTGAGG CCCAGGACCT GTACTGACCT CGAGGAATAA 5160 AGGAAATTTA TTTTCATTGC AATAGTGTGT TGGTTTTTTG TGTCACGTGG CGGCCGCAGG 5220 AACCCCTAGT GATGGAGTTG GCCACTCCCT CTCTGCGCGC TCGCTCGCTC ACTGAGGCCG 5280 GGCGACCAAA GGTCGCCCGA CGCCCGGGCT TTGCCCGGGC GGCCTCAGTG AGCGAGCGAG 5340 CGCGCAGAGA GGGAGTGGCC AA 5362 SEQ ID NO: 14 <211> 5464 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 14 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACT 360 GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC AGATCCCAGC CAGTGGACTT 420 AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC 480 CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC 540 AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGTA AGTACTAGCA GCTACAATCC 600 AGCTACCATT CTGCTTTTAT TTTATGGTTG GGATAAGGCT GGATTATTCT GAGTCCAAGC 660 TAGGCCCTTT TGCTAATCAT GTTCATACCT CTTATCTTCC TCCCACAGCT CCTGGGCAAC 720 GTGCTGGTCT GTGTGCTGGC CCATCACTTT GGCAAAGAAT TGCGATCGCC ACCATGCAGA 780 TTGAGCTGAG CACCTGCTTC TTCCTGTGCC TGCTGAGGTT CTGCTTCTCT GCCACCAGGA 840 GATACTACCT GGGGGCTGTG GAGCTGAGCT GGGACTACAT GCAGTCTGAC CTGGGGGAGC 900 TGCCTGTGGA TGCCAGGTTC CCCCCCAGAG TGCCCAAGAG CTTCCCCTTC AACACCTCTG 960 TGGTGTACAA GAAGACCCTG TTTGTGGAGT TCACTGACCA CCTGTTCAAC ATTGCCAAGC 1020 CCAGGCCCCC CTGGATGGGC CTGCTGGGCC CCACCATCCA GGCTGAGGTG TATGACACTG 1080 TGGTGATCAC CCTGAAGAAC ATGGCCAGCC ACCCTGTGAG CCTGCATGCT GTGGGGGTGA 1140 GCTACTGGAA GGCCTCTGAG GGGGCTGAGT ATGATGACCA GACCAGCCAG AGGGAGAAGG 1200 AGGATGACAA GGTGTTCCCT GGGGGCAGCC ACACCTATGT GTGGCAGGTG CTGAAGGAGA 1260 ATGGCCCCAT GGCCTCTGAC CCCCTGTGCC TGACCTACAG CTACCTGAGC CATGTGGACC 1320 TGGTGAAGGA CCTGAACTCT GGCCTGATTG GGGCCCTGCT GGTGTGCAGG GAGGGCAGCC 1380 TGGCCAAGGA GAAGACCCAG ACCCTGCACA AGTTCATCCT GCTGTTTGCT GTGTTTGATG 1440 AGGGCAAGAG CTGGCACTCT GAAACCAAGA ACAGCCTGAT GCAGGACAGG GATGCTGCCT 1500 CTGCCAGGGC CTGGCCCAAG ATGCACACTG TGAATGGCTA TGTGAACAGG AGCCTGCCTG 1560 GCCTGATTGG CTGCCACAGG AAGTCTGTGT ACTGGCATGT GATTGGCATG GGCACCACCC 1620 CTGAGGTGCA CAGCATCTTC CTGGAGGGCC ACACCTTCCT GGTCAGGAAC CACAGGCAGG 1680 CCAGCCTGGA GATCAGCCCC ATCACCTTCC TGACTGCCCA GACCCTGCTG ATGGACCTGG 1740 GCCAGTTCCT GCTGTTCTGC CACATCAGCA GCCACCAGCA TGATGGCATG GAGGCCTATG 1800 TGAAGGTGGA CAGCTGCCCT GAGGAGCCCC AGCTGAGGAT GAAGAACAAT GAGGAGGCTG 1860 AGGACTATGA TGATGACCTG ACTGACTCTG AGATGGATGT GGTGAGGTTT GATGATGACA 1920 ACAGCCCCAG CTTCATCCAG ATCAGGTCTG TGGCCAAGAA GCACCCCAAG ACCTGGGTGC 1980 ACTACATTGC TGCTGAGGAG GAGGACTGGG ACTATGCCCC CCTGGTGCTG GCCCCTGATG 2040 ACAGGAGCTA CAAGAGCCAG TACCTGAACA ATGGCCCCCA GAGGATTGGC AGGAAGTACA 2100 AGAAGGTCAG GTTCATGGCC TACACTGATG AAACCTTCAA GACCAGGGAG GCCATCCAGC 2160 ATGAGTCTGG CATCCTGGGC CCCCTGCTGT ATGGGGAGGT GGGGGACACC CTGCTGATCA 2220 TCTTCAAGAA CCAGGCCAGC AGGCCCTACA ACATCTACCC CCATGGCATC ACTGATGTGA 2280 GGCCCCTGTA CAGCAGGAGG CTGCCCAAGG GGGTGAAGCA CCTGAAGGAC TTCCCCATCC 2340 TGCCTGGGGA GATCTTCAAG TACAAGTGGA CTGTGACTGT GGAGGATGGC CCCACCAAGT 2400 CTGACCCCAG GTGCCTGACC AGATACTACA GCAGCTTTGT GAACATGGAG AGGGACCTGG 2460 CCTCTGGCCT GATTGGCCCC CTGCTGATCT GCTACAAGGA GTCTGTGGAC CAGAGGGGCA 2520 ACCAGATCAT GTCTGACAAG AGGAATGTGA TCCTGTTCTC TGTGTTTGAT GAGAACAGGA 2580 GCTGGTACCT GACTGAGAAC ATCCAGAGGT TCCTGCCCAA CCCTGCTGGG GTGCAGCTGG 2640 AGGACCCTGA GTTCCAGGCC AGCAACATCA TGCACAGCAT CAATGGCTAT GTGTTTGACA 2700 GCCTGCAGCT GTCTGTGTGC CTGCATGAGG TGGCCTACTG GTACATCCTG AGCATTGGGG 2760 CCCAGACTGA CTTCCTGTCT GTGTTCTTCT CTGGCTACAC CTTCAAGCAC AAGATGGTGT 2820 ATGAGGACAC CCTGACCCTG TTCCCCTTCT CTGGGGAGAC TGTGTTCATG AGCATGGAGA 2880 ACCCTGGCCT GTGGATTCTG GGCTGCCACA ACTCTGACTT CAGGAACAGG GGCATGACTG 2940 CCCTGCTGAA AGTCTCCAGC TGTGACAAGA ACACTGGGGA CTACTATGAG GACAGCTATG 3000 AGGACATCTC TGCCTACCTG CTGAGCAAGA ACAATGCCAT TGAGCCCAGG AGCTTCAGCC 3060 AGAACCCCCC AGTGCTGAAG AGGCACCAGA GGGAGATCAC CAGGACCACC CTGCAGTCTG 3120 ACCAGGAGGA GATTGACTAT GATGACACCA TCTCTGTGGA GATGAAGAAG GAGGACTTTG 3180 ACATCTACGA CGAGGACGAG AACCAGAGCC CCAGGAGCTT CCAGAAGAAG ACCAGGCACT 3240 ACTTCATTGC TGCTGTGGAG AGGCTGTGGG ACTATGGCAT GAGCAGCAGC CCCCATGTGC 3300 TGAGGAACAG GGCCCAGTCT GGCTCTGTGC CCCAGTTCAA GAAGGTGGTG TTCCAGGAGT 3360 TCACTGATGG CAGCTTCACC CAGCCCCTGT ACAGAGGGGA GCTGAATGAG CACCTGGGCC 3420 TGCTGGGCCC CTACATCAGG GCTGAGGTGG AGGACAACAT CATGGTGACC TTCAGGAACC 3480 AGGCCAGCAG GCCCTACAGC TTCTACAGCA GCCTGATCAG CTATGAGGAG GACCAGAGGC 3540 AGGGGGCTGA GCCCAGGAAG AACTTTGTGA AGCCCAATGA AACCAAGACC TACTTCTGGA 3600 AGGTGCAGCA CCACATGGCC CCCACCAAGG ATGAGTTTGA CTGCAAGGCC TGGGCCTACT 3660 TCTCTGATGT GGACCTGGAG AAGGATGTGC ACTCTGGCCT GATTGGCCCC CTGCTGGTGT 3720 GCCACACCAA CACCCTGAAC CCTGCCCATG GCAGGCAGGT GACTGTGCAG GAGTTTGCCC 3780 TGTTCTTCAC CATCTTTGAT GAAACCAAGA GCTGGTACTT CACTGAGAAC ATGGAGAGGA 3840 ACTGCAGGGC CCCCTGCAAC ATCCAGATGG AGGACCCCAC CTTCAAGGAG AACTACAGGT 3900 TCCATGCCAT CAATGGCTAC ATCATGGACA CCCTGCCTGG CCTGGTGATG GCCCAGGACC 3960 AGAGGATCAG GTGGTACCTG CTGAGCATGG GCAGCAATGA GAACATCCAC AGCATCCACT 4020 TCTCTGGCCA TGTGTTCACT GTGAGGAAGA AGGAGGAGTA CAAGATGGCC CTGTACAACC 4080 TGTACCCTGG GGTGTTTGAG ACTGTGGAGA TGCTGCCCAG CAAGGCTGGC ATCTGGAGGG 4140 TGGAGTGCCT GATTGGGGAG CACCTGCATG CTGGCATGAG CACCCTGTTC CTGGTGTACA 4200 GCAACAAGTG CCAGACCCCC CTGGGCATGG CCTCTGGCCA CATCAGGGAC TTCCAGATCA 4260 CTGCCTCTGG CCAGTATGGC CAGTGGGCCC CCAAGCTGGC CAGGCTGCAC TACTCTGGCA 4320 GCATCAATGC CTGGAGCACC AAGGAGCCCT TCAGCTGGAT CAAGGTGGAC CTGCTGGCCC 4380 CCATGATCAT CCATGGCATC AAGACCCAGG GGGCCAGGCA GAAGTTCAGC AGCCTGTACA 4440 TCAGCCAGTT CATCATCATG TACAGCCTGG ATGGCAAGAA GTGGCAGACC TACAGGGGCA 4500 ACAGCACTGG CACCCTGATG GTGTTCTTTG GCAATGTGGA CAGCTCTGGC ATCAAGCACA 4560 ACATCTTCAA CCCCCCCATC ATTGCCAGAT ACATCAGGCT GCACCCCACC CACTACAGCA 4620 TCAGGAGCAC CCTGAGGATG GAGCTGATGG GCTGTGACCT GAACAGCTGC AGCATGCCCC 4680 TGGGCATGGA GAGCAAGGCC ATCTCTGATG CCCAGATCAC TGCCAGCAGC TACTTCACCA 4740 ACATGTTTGC CACCTGGAGC CCCAGCAAGG CCAGGCTGCA CCTGCAGGGC AGGAGCAATG 4800 CCTGGAGGCC CCAGGTCAAC AACCCCAAGG AGTGGCTGCA GGTGGACTTC CAGAAGACCA 4860 TGAAGGTGAC TGGGGTGACC ACCCAGGGGG TGAAGAGCCT GCTGACCAGC ATGTATGTGA 4920 AGGAGTTCCT GATCAGCAGC AGCCAGGATG GCCACCAGTG GACCCTGTTC TTCCAGAATG 4980 GCAAGGTGAA GGTGTTCCAG GGCAACCAGG ACAGCTTCAC CCCTGTGGTG AACAGCCTGG 5040 ACCCCCCCCT GCTGACCAGA TACCTGAGGA TTCACCCCCA GAGCTGGGTG CACCAGATTG 5100 CCCTGAGGAT GGAGGTGCTG GGCTGTGAGG CCCAGGACCT GTACTGACCT CGAGGCACTG 5160 TCCTTTCCTA ATAAAATGAG GAAATTGCAT CGCATTGTCT GAGTAGGTGT CATTCTATTC 5220 TGGGGGGTGG GGTGGGGCAG GACAGCAAGG GGGAGGATTG GGAAGACAAT AGCAGGCATG 5280 CTGGGGATGC GGTGGGCTCT ATGGGCACGT GGCGGCCGCA GGAACCCCTA GTGATGGAGT 5340 TGGCCACTCC CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC 5400 GACGCCCGGG CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG 5460 CCAA 5464 SEQ ID NO: 15 <211> 6354 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 15 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTAAACGTC GACAGGTTAA 180 TTTTTAAAAA GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC 240 TCTGGTTAAT AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC 300 TGGACTTATC CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTCAGGTTAA TTTTTAAAAA 360 GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC TCTGGTTAAT 420 AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC TGGACTTATC 480 CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTGTCGACTG GACACAGGAC GCTGTGGTTT 540 CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA 600 TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC 660 ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA 720 CCTGGGACAG TGAATCGTAA GTACTAGCAG CTACAATCCA GCTACCATTC TGCTTTTATT 780 TTATGGTTGG GATAAGGCTG GATTATTCTG AGTCCAAGCT AGGCCCTTTT GCTAATCATG 840 TTCATACCTC TTATCTTCCT CCCACAGCTC CTGGGCAACG TGCTGGTCTG TGTGCTGGCC 900 CATCACTTTG GCAAAGAATT GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT 960 TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG 1020 AGCTGAGCTG GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC 1080 CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT 1140 TTGTGGAGTT CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC 1200 TGCTGGGCCC CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA 1260 TGGCCAGCCA CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG 1320 GGGCTGAGTA TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG 1380 GGGGCAGCCA CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC 1440 CCCTGTGCCT GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG 1500 GCCTGATTGG GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA 1560 CCCTGCACAA GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG 1620 AAACCAAGAA CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA 1680 TGCACACTGT GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA 1740 AGTCTGTGTA CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC 1800 TGGAGGGCCA CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA 1860 TCACCTTCCT GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC 1920 ACATCAGCAG CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG 1980 AGGAGCCCCA GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA 2040 CTGACTCTGA GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA 2100 TCAGGTCTGT GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG 2160 AGGACTGGGA CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT 2220 ACCTGAACAA TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT 2280 ACACTGATGA AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC 2340 CCCTGCTGTA TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA 2400 GGCCCTACAA CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC 2460 TGCCCAAGGG GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT 2520 ACAAGTGGAC TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA 2580 GATACTACAG CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC 2640 TGCTGATCTG CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA 2700 GGAATGTGAT CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA 2760 TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA 2820 GCAACATCAT GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC 2880 TGCATGAGGT GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG 2940 TGTTCTTCTC TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT 3000 TCCCCTTCTC TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG 3060 GCTGCCACAA CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT 3120 GTGACAAGAA CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC 3180 TGAGCAAGAA CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA 3240 GGCACCAGAG GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG 3300 ATGACACCAT CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA 3360 ACCAGAGCCC CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA 3420 GGCTGTGGGA CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG 3480 GCTCTGTGCC CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC 3540 AGCCCCTGTA CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG 3600 CTGAGGTGGA GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT 3660 TCTACAGCAG CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA 3720 ACTTTGTGAA GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC 3780 CCACCAAGGA TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA 3840 AGGATGTGCA CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC 3900 CTGCCCATGG CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG 3960 AAACCAAGAG CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA 4020 TCCAGATGGA GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA 4080 TCATGGACAC CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC 4140 TGAGCATGGG CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG 4200 TGAGGAAGAA GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA 4260 CTGTGGAGAT GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC 4320 ACCTGCATGC TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC 4380 TGGGCATGGC CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC 4440 AGTGGGCCCC CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA 4500 AGGAGCCCTT CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA 4560 AGACCCAGGG GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT 4620 ACAGCCTGGA TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG 4680 TGTTCTTTGG CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA 4740 TTGCCAGATA CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG 4800 AGCTGATGGG CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA 4860 TCTCTGATGC CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC 4920 CCAGCAAGGC CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA 4980 ACCCCAAGGA GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA 5040 CCCAGGGGGT GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA 5100 GCCAGGATGG CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG 5160 GCAACCAGGA CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT 5220 ACCTGAGGAT TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG 5280 GCTGTGAGGC CCAGGACCTG TACTGACCTC GAGGTGTGCC TTCTAGTTGC CAGCCATCTG 5340 TTGTTTGCCC CTCCCCCGTG CCTTCCTTGA CCCTGGAAGG TGCCACTCCC ACTGTCCTTT 5400 CCTAATAAAA TGAGGAAATT GCATCGCATT GTCTGAGTAG GTGTCATTCT ATTCTGGGGG 5460 GTGGGGTGGG GCAGGACAGC AAGGGGGAGG ATTGGGAAGA CAATAGCAGG CATGCTGGGG 5520 ATGCGGTGGG CTCTATGGGC ACGTGCCCTC TCACACTACC TAAACCACGC CAGGACAACC 5580 TCTGCTCCTC TCCACCGAAA TTCCAAGGGG TCGAGTGGAT GTTGGAGGTG GCATGGGCCC 5640 AGAGAGGTCT CTGACCTCTG CCCCAGCTCC AAGGTCAGCA GGCAGGGAGG GCTGTGTGTT 5700 TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA TGAGTAGGCT GAAGTTTGTT 5760 CAGTGTGGAC TTCAGAGGCA GCACACAAAC AGCTGCTGGA GGATGGGAAC TGAGGGGTTG 5820 GAAGGGGGCA GGGTGAGCCC AGAAACTCCT GTGTGCCTCT GAGCCTGCAG CCCTCTCACA 5880 CTACCTAAAC CACGCCAGGA CAACCTCTGC TCCTCTCCAC CGAAATTCCA AGGGGTCGAG 5940 TGGATGTTGG AGGTGGCATG GGCCCAGAGA GGTCTCTGAC CTCTGCCCCA GCTCCAAGGT 6000 CAGCAGGCAG GGAGGGCTGT GTGTTTGCTG TTTGCTGCTT GCAATGTTTG CCCATTTTAG 6060 GGACATGAGT AGGCTGAAGT TTGTTCAGTG TGGACTTCAG AGGCAGCACA CAAACAGCTG 6120 CTGGAGGATG GGAACTGAGG GGTTGGAAGG GGGCAGGGTG AGCCCAGAAA CTCCTGTGTG 6180 CCTCTGAGCC TGCAGCACGT GGCGGCCGCA GGAACCCCTA GTGATGGAGT TGGCCACTCC 6240 CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC GACGCCCGGG 6300 CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG CCAA 6354 SEQ ID NO: 16 <211> 6308 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 16 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTAATTTTTA AAAAGCAGTC 180 AAAAGTCCAA GTGGCCCTTG GCAGCATTTA CTCTCTCTGT TTGCTCTGGT TAATAATCTC 240 AGGAGCACAA ACATTCCTGG AGGCAGGAGA AGAAATCAAC ATCCTGGACT TATCCTCTGG 300 GCCTGTTAAT TTTTAAAAAG CAGTCAAAAG TCCAAGTGGC CCTTGGCAGC ATTTACTCTC 360 TCTGTTTGCT CTGGTTAATA ATCTCAGGAG CACAAACATT CCTGGAGGCA GGAGAAGAAA 420 TCAACATCCT GGACTTATCC TCTGGGCCTA GGCCTGAGGC TGGTCAAAAT TGAACCTCCT 480 CCTGCTCTGA GCAGCCTGGG GGGCAGACTA AGCAGAGGGC TGTGCAGACC CACATAAAGA 540 GCCTACTGTG TGCCAGGCAC TTCACCCGAG GCACTTCACA AGCATGCTTG GGAATGAAAC 600 TTCCAACTCT TTGGGATGCA GGTGAAACAG TTCCTGGTTC AGAGAGGTGA AGCGGCCTGC 660 CTGAGGCAGC ACAGCTCTTC TTTACAGATG TGCTTCCCCA CCTCTACCCT GTCTCACGGC 720 CCCCCATGCC AGCCTGACGG TTGTGTCTGC CTCAGTCATG CTCCATTTTT CCATCGGGAC 780 CATCAAGAGG GTGTTTGTGT CTAAGGCTGA CTGGGTAACT TTGGATGAGC GGTCTCTCCG 840 CTCTGAGCCT GTTTCCTCAT CTGTCAAATG GGCTCTAACC CACTCTGATC TCCCAGGGCG 900 GCAGTAAGTC TTCAGCATCA GGCATTTTGG GGTGACTCAG TAAATGGTAG ATCTTGCTAC 960 CAGTGGAACA GCCACTAAGG ATTCTGCAGT GAGAGCAGAG GGCCAGCTAA GTGGTACTCT 1020 CCCAGAGACT GTCTGACTCA CGCCACCCCC TCCACCTTGG ACACAGGACG CTGTGGTTTC 1080 TGAGCCAGGT ACAATGACTC CTTTCGGTAA GTGCAGTGGA AGCTGTACAC TGCCCAGGCA 1140 AAGCGTCCGG GCAGCGTAGG CGGGCGACTC AGATCCCAGC CAGTGGACTT AGCCCCTGTT 1200 TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC CCCCGTTGCC 1260 CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC AGCTTCAGGC 1320 ACCACCACTG ACCTGGGACA GTGAATCGTA AGTACTAGCA GCTACAATCC AGCTACCATT 1380 CTGCTTTTAT TTTATGGTTG GGATAAGGCT GGATTATTCT GAGTCCAAGC TAGGCCCTTT 1440 TGCTAATCAT GTTCATACCT CTTATCTTCC TCCCACAGCT CCTGGGCAAC GTGCTGGTCT 1500 GTGTGCTGGC CCATCACTTT GGCAAAGAAT TGCGATCGCC ACCATGCAGA TTGAGCTGAG 1560 CACCTGCTTC TTCCTGTGCC TGCTGAGGTT CTGCTTCTCT GCCACCAGGA GATACTACCT 1620 GGGGGCTGTG GAGCTGAGCT GGGACTACAT GCAGTCTGAC CTGGGGGAGC TGCCTGTGGA 1680 TGCCAGGTTC CCCCCCAGAG TGCCCAAGAG CTTCCCCTTC AACACCTCTG TGGTGTACAA 1740 GAAGACCCTG TTTGTGGAGT TCACTGACCA CCTGTTCAAC ATTGCCAAGC CCAGGCCCCC 1800 CTGGATGGGC CTGCTGGGCC CCACCATCCA GGCTGAGGTG TATGACACTG TGGTGATCAC 1860 CCTGAAGAAC ATGGCCAGCC ACCCTGTGAG CCTGCATGCT GTGGGGGTGA GCTACTGGAA 1920 GGCCTCTGAG GGGGCTGAGT ATGATGACCA GACCAGCCAG AGGGAGAAGG AGGATGACAA 1980 GGTGTTCCCT GGGGGCAGCC ACACCTATGT GTGGCAGGTG CTGAAGGAGA ATGGCCCCAT 2040 GGCCTCTGAC CCCCTGTGCC TGACCTACAG CTACCTGAGC CATGTGGACC TGGTGAAGGA 2100 CCTGAACTCT GGCCTGATTG GGGCCCTGCT GGTGTGCAGG GAGGGCAGCC TGGCCAAGGA 2160 GAAGACCCAG ACCCTGCACA AGTTCATCCT GCTGTTTGCT GTGTTTGATG AGGGCAAGAG 2220 CTGGCACTCT GAAACCAAGA ACAGCCTGAT GCAGGACAGG GATGCTGCCT CTGCCAGGGC 2280 CTGGCCCAAG ATGCACACTG TGAATGGCTA TGTGAACAGG AGCCTGCCTG GCCTGATTGG 2340 CTGCCACAGG AAGTCTGTGT ACTGGCATGT GATTGGCATG GGCACCACCC CTGAGGTGCA 2400 CAGCATCTTC CTGGAGGGCC ACACCTTCCT GGTCAGGAAC CACAGGCAGG CCAGCCTGGA 2460 GATCAGCCCC ATCACCTTCC TGACTGCCCA GACCCTGCTG ATGGACCTGG GCCAGTTCCT 2520 GCTGTTCTGC CACATCAGCA GCCACCAGCA TGATGGCATG GAGGCCTATG TGAAGGTGGA 2580 CAGCTGCCCT GAGGAGCCCC AGCTGAGGAT GAAGAACAAT GAGGAGGCTG AGGACTATGA 2640 TGATGACCTG ACTGACTCTG AGATGGATGT GGTGAGGTTT GATGATGACA ACAGCCCCAG 2700 CTTCATCCAG ATCAGGTCTG TGGCCAAGAA GCACCCCAAG ACCTGGGTGC ACTACATTGC 2760 TGCTGAGGAG GAGGACTGGG ACTATGCCCC CCTGGTGCTG GCCCCTGATG ACAGGAGCTA 2820 CAAGAGCCAG TACCTGAACA ATGGCCCCCA GAGGATTGGC AGGAAGTACA AGAAGGTCAG 2880 GTTCATGGCC TACACTGATG AAACCTTCAA GACCAGGGAG GCCATCCAGC ATGAGTCTGG 2940 CATCCTGGGC CCCCTGCTGT ATGGGGAGGT GGGGGACACC CTGCTGATCA TCTTCAAGAA 3000 CCAGGCCAGC AGGCCCTACA ACATCTACCC CCATGGCATC ACTGATGTGA GGCCCCTGTA 3060 CAGCAGGAGG CTGCCCAAGG GGGTGAAGCA CCTGAAGGAC TTCCCCATCC TGCCTGGGGA 3120 GATCTTCAAG TACAAGTGGA CTGTGACTGT GGAGGATGGC CCCACCAAGT CTGACCCCAG 3180 GTGCCTGACC AGATACTACA GCAGCTTTGT GAACATGGAG AGGGACCTGG CCTCTGGCCT 3240 GATTGGCCCC CTGCTGATCT GCTACAAGGA GTCTGTGGAC CAGAGGGGCA ACCAGATCAT 3300 GTCTGACAAG AGGAATGTGA TCCTGTTCTC TGTGTTTGAT GAGAACAGGA GCTGGTACCT 3360 GACTGAGAAC ATCCAGAGGT TCCTGCCCAA CCCTGCTGGG GTGCAGCTGG AGGACCCTGA 3420 GTTCCAGGCC AGCAACATCA TGCACAGCAT CAATGGCTAT GTGTTTGACA GCCTGCAGCT 3480 GTCTGTGTGC CTGCATGAGG TGGCCTACTG GTACATCCTG AGCATTGGGG CCCAGACTGA 3540 CTTCCTGTCT GTGTTCTTCT CTGGCTACAC CTTCAAGCAC AAGATGGTGT ATGAGGACAC 3600 CCTGACCCTG TTCCCCTTCT CTGGGGAGAC TGTGTTCATG AGCATGGAGA ACCCTGGCCT 3660 GTGGATTCTG GGCTGCCACA ACTCTGACTT CAGGAACAGG GGCATGACTG CCCTGCTGAA 3720 AGTCTCCAGC TGTGACAAGA ACACTGGGGA CTACTATGAG GACAGCTATG AGGACATCTC 3780 TGCCTACCTG CTGAGCAAGA ACAATGCCAT TGAGCCCAGG AGCTTCAGCC AGAACCCCCC 3840 AGTGCTGAAG AGGCACCAGA GGGAGATCAC CAGGACCACC CTGCAGTCTG ACCAGGAGGA 3900 GATTGACTAT GATGACACCA TCTCTGTGGA GATGAAGAAG GAGGACTTTG ACATCTACGA 3960 CGAGGACGAG AACCAGAGCC CCAGGAGCTT CCAGAAGAAG ACCAGGCACT ACTTCATTGC 4020 TGCTGTGGAG AGGCTGTGGG ACTATGGCAT GAGCAGCAGC CCCCATGTGC TGAGGAACAG 4080 GGCCCAGTCT GGCTCTGTGC CCCAGTTCAA GAAGGTGGTG TTCCAGGAGT TCACTGATGG 4140 CAGCTTCACC CAGCCCCTGT ACAGAGGGGA GCTGAATGAG CACCTGGGCC TGCTGGGCCC 4200 CTACATCAGG GCTGAGGTGG AGGACAACAT CATGGTGACC TTCAGGAACC AGGCCAGCAG 4260 GCCCTACAGC TTCTACAGCA GCCTGATCAG CTATGAGGAG GACCAGAGGC AGGGGGCTGA 4320 GCCCAGGAAG AACTTTGTGA AGCCCAATGA AACCAAGACC TACTTCTGGA AGGTGCAGCA 4380 CCACATGGCC CCCACCAAGG ATGAGTTTGA CTGCAAGGCC TGGGCCTACT TCTCTGATGT 4440 GGACCTGGAG AAGGATGTGC ACTCTGGCCT GATTGGCCCC CTGCTGGTGT GCCACACCAA 4500 CACCCTGAAC CCTGCCCATG GCAGGCAGGT GACTGTGCAG GAGTTTGCCC TGTTCTTCAC 4560 CATCTTTGAT GAAACCAAGA GCTGGTACTT CACTGAGAAC ATGGAGAGGA ACTGCAGGGC 4620 CCCCTGCAAC ATCCAGATGG AGGACCCCAC CTTCAAGGAG AACTACAGGT TCCATGCCAT 4680 CAATGGCTAC ATCATGGACA CCCTGCCTGG CCTGGTGATG GCCCAGGACC AGAGGATCAG 4740 GTGGTACCTG CTGAGCATGG GCAGCAATGA GAACATCCAC AGCATCCACT TCTCTGGCCA 4800 TGTGTTCACT GTGAGGAAGA AGGAGGAGTA CAAGATGGCC CTGTACAACC TGTACCCTGG 4860 GGTGTTTGAG ACTGTGGAGA TGCTGCCCAG CAAGGCTGGC ATCTGGAGGG TGGAGTGCCT 4920 GATTGGGGAG CACCTGCATG CTGGCATGAG CACCCTGTTC CTGGTGTACA GCAACAAGTG 4980 CCAGACCCCC CTGGGCATGG CCTCTGGCCA CATCAGGGAC TTCCAGATCA CTGCCTCTGG 5040 CCAGTATGGC CAGTGGGCCC CCAAGCTGGC CAGGCTGCAC TACTCTGGCA GCATCAATGC 5100 CTGGAGCACC AAGGAGCCCT TCAGCTGGAT CAAGGTGGAC CTGCTGGCCC CCATGATCAT 5160 CCATGGCATC AAGACCCAGG GGGCCAGGCA GAAGTTCAGC AGCCTGTACA TCAGCCAGTT 5220 CATCATCATG TACAGCCTGG ATGGCAAGAA GTGGCAGACC TACAGGGGCA ACAGCACTGG 5280 CACCCTGATG GTGTTCTTTG GCAATGTGGA CAGCTCTGGC ATCAAGCACA ACATCTTCAA 5340 CCCCCCCATC ATTGCCAGAT ACATCAGGCT GCACCCCACC CACTACAGCA TCAGGAGCAC 5400 CCTGAGGATG GAGCTGATGG GCTGTGACCT GAACAGCTGC AGCATGCCCC TGGGCATGGA 5460 GAGCAAGGCC ATCTCTGATG CCCAGATCAC TGCCAGCAGC TACTTCACCA ACATGTTTGC 5520 CACCTGGAGC CCCAGCAAGG CCAGGCTGCA CCTGCAGGGC AGGAGCAATG CCTGGAGGCC 5580 CCAGGTCAAC AACCCCAAGG AGTGGCTGCA GGTGGACTTC CAGAAGACCA TGAAGGTGAC 5640 TGGGGTGACC ACCCAGGGGG TGAAGAGCCT GCTGACCAGC ATGTATGTGA AGGAGTTCCT 5700 GATCAGCAGC AGCCAGGATG GCCACCAGTG GACCCTGTTC TTCCAGAATG GCAAGGTGAA 5760 GGTGTTCCAG GGCAACCAGG ACAGCTTCAC CCCTGTGGTG AACAGCCTGG ACCCCCCCCT 5820 GCTGACCAGA TACCTGAGGA TTCACCCCCA GAGCTGGGTG CACCAGATTG CCCTGAGGAT 5880 GGAGGTGCTG GGCTGTGAGG CCCAGGACCT GTACTGACCT CGAGCTGTGC CTTCTAGTTG 5940 CCAGCCATCT GTTGTTTGCC CCTCCCCCGT GCCTTCCTTG ACCCTGGAAG GTGCCACTCC 6000 CACTGTCCTT TCCTAATAAA ATGAGGAAAT TGCATCGCAT TGTCTGAGTA GGTGTCATTC 6060 TATTCTGGGG GGTGGGGTGG GGCAGGACAG CAAGGGGGAG GATTGGGAAG ACAATAGCAG 6120 GCATGCTGGG GATGCGGTGG GCTCTATGGA CCGGTGCGGC CGCAGGAACC CCTAGTGATG 6180 GAGTTGGCCA CTCCCTCTCT GCGCGCTCGC TCGCTCACTG AGGCCGGGCG ACCAAAGGTC 6240 GCCCGACGCC CGGGCTTTGC CCGGGCGGCC TCAGTGAGCG AGCGAGCGCG CAGAGAGGGA 6300 GTGGCCAA 6308 SEQ ID NO: 17 <211> 5635 <212> DNA <213> ADENO-ASSOCIATE VIRUS 2 <400> 17 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTAATTTTTA AAAAGCAGTC 180 AAAAGTCCAA GTGGCCCTTG GCAGCATTTA CTCTCTCTGT TTGCTCTGGT TAATAATCTC 240 AGGAGCACAA ACATTCCTGG AGGCAGGAGA AGAAATCAAC ATCCTGGACT TATCCTCTGG 300 GCCTGTTAAT TTTTAAAAAG CAGTCAAAAG TCCAAGTGGC CCTTGGCAGC ATTTACTCTC 360 TCTGTTTGCT CTGGTTAATA ATCTCAGGAG CACAAACATT CCTGGAGGCA GGAGAAGAAA 420 TCAACATCCT GGACTTATCC TCTGGGCCTA GTCGACTGGA CACAGGACGC TGTGGTTTCT 480 GAGCCAGGGG GCGACTCAGA TCCCAGCCAG TGGACTTAGC CCCTGTTTGC TCCTCCGATA 540 ACTGGGGTGA CCTTGGTTAA TATTCACCAG CAGCCTCCCC CGTTGCCCCT CTGGATCCAC 600 TGCTTAAATA CGGACGAGGA CAGGGCCCTG TCTCCTCAGC TTCAGGCACC ACCACTGACC 660 TGGGACAGTG AATCGTAAGT ACTAGCAGCT ACAATCCAGC TACCATTCTG CTTTTATTTT 720 ATGGTTGGGA TAAGGCTGGA TTATTCTGAG TCCAAGCTAG GCCCTTTTGC TAATCATGTT 780 CATACCTCTT ATCTTCCTCC CACAGCTCCT GGGCAACGTG CTGGTCTGTG TGCTGGCCCA 840 TCACTTTGGC AAAGAATTGC GATCGCCACC ATGCAGATTG AGCTGAGCAC CTGCTTCTTC 900 CTGTGCCTGC TGAGGTTCTG CTTCTCTGCC ACCAGGAGAT ACTACCTGGG GGCTGTGGAG 960 CTGAGCTGGG ACTACATGCA GTCTGACCTG GGGGAGCTGC CTGTGGATGC CAGGTTCCCC 1020 CCCAGAGTGC CCAAGAGCTT CCCCTTCAAC ACCTCTGTGG TGTACAAGAA GACCCTGTTT 1080 GTGGAGTTCA CTGACCACCT GTTCAACATT GCCAAGCCCA GGCCCCCCTG GATGGGCCTG 1140 CTGGGCCCCA CCATCCAGGC TGAGGTGTAT GACACTGTGG TGATCACCCT GAAGAACATG 1200 GCCAGCCACC CTGTGAGCCT GCATGCTGTG GGGGTGAGCT ACTGGAAGGC CTCTGAGGGG 1260 GCTGAGTATG ATGACCAGAC CAGCCAGAGG GAGAAGGAGG ATGACAAGGT GTTCCCTGGG 1320 GGCAGCCACA CCTATGTGTG GCAGGTGCTG AAGGAGAATG GCCCCATGGC CTCTGACCCC 1380 CTGTGCCTGA CCTACAGCTA CCTGAGCCAT GTGGACCTGG TGAAGGACCT GAACTCTGGC 1440 CTGATTGGGG CCCTGCTGGT GTGCAGGGAG GGCAGCCTGG CCAAGGAGAA GACCCAGACC 1500 CTGCACAAGT TCATCCTGCT GTTTGCTGTG TTTGATGAGG GCAAGAGCTG GCACTCTGAA 1560 ACCAAGAACA GCCTGATGCA GGACAGGGAT GCTGCCTCTG CCAGGGCCTG GCCCAAGATG 1620 CACACTGTGA ATGGCTATGT GAACAGGAGC CTGCCTGGCC TGATTGGCTG CCACAGGAAG 1680 TCTGTGTACT GGCATGTGAT TGGCATGGGC ACCACCCCTG AGGTGCACAG CATCTTCCTG 1740 GAGGGCCACA CCTTCCTGGT CAGGAACCAC AGGCAGGCCA GCCTGGAGAT CAGCCCCATC 1800 ACCTTCCTGA CTGCCCAGAC CCTGCTGATG GACCTGGGCC AGTTCCTGCT GTTCTGCCAC 1860 ATCAGCAGCC ACCAGCATGA TGGCATGGAG GCCTATGTGA AGGTGGACAG CTGCCCTGAG 1920 GAGCCCCAGC TGAGGATGAA GAACAATGAG GAGGCTGAGG ACTATGATGA TGACCTGACT 1980 GACTCTGAGA TGGATGTGGT GAGGTTTGAT GATGACAACA GCCCCAGCTT CATCCAGATC 2040 AGGTCTGTGG CCAAGAAGCA CCCCAAGACC TGGGTGCACT ACATTGCTGC TGAGGAGGAG 2100 GACTGGGACT ATGCCCCCCT GGTGCTGGCC CCTGATGACA GGAGCTACAA GAGCCAGTAC 2160 CTGAACAATG GCCCCCAGAG GATTGGCAGG AAGTACAAGA AGGTCAGGTT CATGGCCTAC 2220 ACTGATGAAA CCTTCAAGAC CAGGGAGGCC ATCCAGCATG AGTCTGGCAT CCTGGGCCCC 2280 CTGCTGTATG GGGAGGTGGG GGACACCCTG CTGATCATCT TCAAGAACCA GGCCAGCAGG 2340 CCCTACAACA TCTACCCCCA TGGCATCACT GATGTGAGGC CCCTGTACAG CAGGAGGCTG 2400 CCCAAGGGGG TGAAGCACCT GAAGGACTTC CCCATCCTGC CTGGGGAGAT CTTCAAGTAC 2460 AAGTGGACTG TGACTGTGGA GGATGGCCCC ACCAAGTCTG ACCCCAGGTG CCTGACCAGA 2520 TACTACAGCA GCTTTGTGAA CATGGAGAGG GACCTGGCCT CTGGCCTGAT TGGCCCCCTG 2580 CTGATCTGCT ACAAGGAGTC TGTGGACCAG AGGGGCAACC AGATCATGTC TGACAAGAGG 2640 AATGTGATCC TGTTCTCTGT GTTTGATGAG AACAGGAGCT GGTACCTGAC TGAGAACATC 2700 CAGAGGTTCC TGCCCAACCC TGCTGGGGTG CAGCTGGAGG ACCCTGAGTT CCAGGCCAGC 2760 AACATCATGC ACAGCATCAA TGGCTATGTG TTTGACAGCC TGCAGCTGTC TGTGTGCCTG 2820 CATGAGGTGG CCTACTGGTA CATCCTGAGC ATTGGGGCCC AGACTGACTT CCTGTCTGTG 2880 TTCTTCTCTG GCTACACCTT CAAGCACAAG ATGGTGTATG AGGACACCCT GACCCTGTTC 2940 CCCTTCTCTG GGGAGACTGT GTTCATGAGC ATGGAGAACC CTGGCCTGTG GATTCTGGGC 3000 TGCCACAACT CTGACTTCAG GAACAGGGGC ATGACTGCCC TGCTGAAAGT CTCCAGCTGT 3060 GACAAGAACA CTGGGGACTA CTATGAGGAC AGCTATGAGG ACATCTCTGC CTACCTGCTG 3120 AGCAAGAACA ATGCCATTGA GCCCAGGAGC TTCAGCCAGA ACCCCCCAGT GCTGAAGAGG 3180 CACCAGAGGG AGATCACCAG GACCACCCTG CAGTCTGACC AGGAGGAGAT TGACTATGAT 3240 GACACCATCT CTGTGGAGAT GAAGAAGGAG GACTTTGACA TCTACGACGA GGACGAGAAC 3300 CAGAGCCCCA GGAGCTTCCA GAAGAAGACC AGGCACTACT TCATTGCTGC TGTGGAGAGG 3360 CTGTGGGACT ATGGCATGAG CAGCAGCCCC CATGTGCTGA GGAACAGGGC CCAGTCTGGC 3420 TCTGTGCCCC AGTTCAAGAA GGTGGTGTTC CAGGAGTTCA CTGATGGCAG CTTCACCCAG 3480 CCCCTGTACA GAGGGGAGCT GAATGAGCAC CTGGGCCTGC TGGGCCCCTA CATCAGGGCT 3540 GAGGTGGAGG ACAACATCAT GGTGACCTTC AGGAACCAGG CCAGCAGGCC CTACAGCTTC 3600 TACAGCAGCC TGATCAGCTA TGAGGAGGAC CAGAGGCAGG GGGCTGAGCC CAGGAAGAAC 3660 TTTGTGAAGC CCAATGAAAC CAAGACCTAC TTCTGGAAGG TGCAGCACCA CATGGCCCCC 3720 ACCAAGGATG AGTTTGACTG CAAGGCCTGG GCCTACTTCT CTGATGTGGA CCTGGAGAAG 3780 GATGTGCACT CTGGCCTGAT TGGCCCCCTG CTGGTGTGCC ACACCAACAC CCTGAACCCT 3840 GCCCATGGCA GGCAGGTGAC TGTGCAGGAG TTTGCCCTGT TCTTCACCAT CTTTGATGAA 3900 ACCAAGAGCT GGTACTTCAC TGAGAACATG GAGAGGAACT GCAGGGCCCC CTGCAACATC 3960 CAGATGGAGG ACCCCACCTT CAAGGAGAAC TACAGGTTCC ATGCCATCAA TGGCTACATC 4020 ATGGACACCC TGCCTGGCCT GGTGATGGCC CAGGACCAGA GGATCAGGTG GTACCTGCTG 4080 AGCATGGGCA GCAATGAGAA CATCCACAGC ATCCACTTCT CTGGCCATGT GTTCACTGTG 4140 AGGAAGAAGG AGGAGTACAA GATGGCCCTG TACAACCTGT ACCCTGGGGT GTTTGAGACT 4200 GTGGAGATGC TGCCCAGCAA GGCTGGCATC TGGAGGGTGG AGTGCCTGAT TGGGGAGCAC 4260 CTGCATGCTG GCATGAGCAC CCTGTTCCTG GTGTACAGCA ACAAGTGCCA GACCCCCCTG 4320 GGCATGGCCT CTGGCCACAT CAGGGACTTC CAGATCACTG CCTCTGGCCA GTATGGCCAG 4380 TGGGCCCCCA AGCTGGCCAG GCTGCACTAC TCTGGCAGCA TCAATGCCTG GAGCACCAAG 4440 GAGCCCTTCA GCTGGATCAA GGTGGACCTG CTGGCCCCCA TGATCATCCA TGGCATCAAG 4500 ACCCAGGGGG CCAGGCAGAA GTTCAGCAGC CTGTACATCA GCCAGTTCAT CATCATGTAC 4560 AGCCTGGATG GCAAGAAGTG GCAGACCTAC AGGGGCAACA GCACTGGCAC CCTGATGGTG 4620 TTCTTTGGCA ATGTGGACAG CTCTGGCATC AAGCACAACA TCTTCAACCC CCCCATCATT 4680 GCCAGATACA TCAGGCTGCA CCCCACCCAC TACAGCATCA GGAGCACCCT GAGGATGGAG 4740 CTGATGGGCT GTGACCTGAA CAGCTGCAGC ATGCCCCTGG GCATGGAGAG CAAGGCCATC 4800 TCTGATGCCC AGATCACTGC CAGCAGCTAC TTCACCAACA TGTTTGCCAC CTGGAGCCCC 4860 AGCAAGGCCA GGCTGCACCT GCAGGGCAGG AGCAATGCCT GGAGGCCCCA GGTCAACAAC 4920 CCCAAGGAGT GGCTGCAGGT GGACTTCCAG AAGACCATGA AGGTGACTGG GGTGACCACC 4980 CAGGGGGTGA AGAGCCTGCT GACCAGCATG TATGTGAAGG AGTTCCTGAT CAGCAGCAGC 5040 CAGGATGGCC ACCAGTGGAC CCTGTTCTTC CAGAATGGCA AGGTGAAGGT GTTCCAGGGC 5100 AACCAGGACA GCTTCACCCC TGTGGTGAAC AGCCTGGACC CCCCCCTGCT GACCAGATAC 5160 CTGAGGATTC ACCCCCAGAG CTGGGTGCAC CAGATTGCCC TGAGGATGGA GGTGCTGGGC 5220 TGTGAGGCCC AGGACCTGTA CTGACCTCGA GCTGTGCCTT CTAGTTGCCA GCCATCTGTT 5280 GTTTGCCCCT CCCCCGTGCC TTCCTTGACC CTGGAAGGTG CCACTCCCAC TGTCCTTTCC 5340 TAATAAAATG AGGAAATTGC ATCGCATTGT CTGAGTAGGT GTCATTCTAT TCTGGGGGGT 5400 GGGGTGGGGC AGGACAGCAA GGGGGAGGAT TGGGAAGACA ATAGCAGGCA TGCTGGGGAT 5460 GCGGTGGGCT CTATGGACCG GTGCGGCCGC AGGAACCCCT AGTGATGGAG TTGGCCACTC 5520 CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGGGCGACC AAAGGTCGCC CGACGCCCGG 5580 GCTTTGCCCG GGCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG GCCAA 5635 SEQ ID NO: 18 <211> 6962 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 18 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTA GGCTCAGAGG CACACAGGAG 180 TTTCTGGGCT CACCCTGCCC CCTTCCAACC CCTCAGTTCC CATCCTCCAG CAGCTGTTTG 240 TGTGCTGCCT CTGAAGTCCA CACTGAACAA ACTTCAGCCT ACTCATGTCC CTAAAATGGG 300 CAAACATTGC AAGCAGCAAA CAGCAAACAC ACAGCCCTCC CTGCCTGCTG ACCTTGGAGC 360 TGGGGCAGAG GTCAGAGACC TCTCTGGGCC CATGCCACCT CCAACATCCA CTCGACCCCT 420 TGGAATTTCG GTGGAGAGGA GCAGAGGTTG TCCTGGCGTG GTTTAGGTAG TGTGAGAGGG 480 GTCGACAGGC TCAGAGGCAC ACAGGAGTTT CTGGGCTCAC CCTGCCCCCT TCCAACCCCT 540 CAGTTCCCAT CCTCCAGCAG CTGTTTGTGT GCTGCCTCTG AAGTCCACAC TGAACAAACT 600 TCAGCCTACT CATGTCCCTA AAATGGGCAA ACATTGCAAG CAGCAAACAG CAAACACACA 660 GCCCTCCCTG CCTGCTGACC TTGGAGCTGG GGCAGAGGTC AGAGACCTCT CTGGGCCCAT 720 GCCACCTCCA ACATCCACTC GACCCCTTGG AATTTCGGTG GAGAGGAGCA GAGGTTGTCC 780 TGGCGTGGTT TAGGTAGTGT GAGAGGGGTC GACGTTAATT TTTAAAAAGC AGTCAAAAGT 840 CCAAGTGGCC CTTGGCAGCA TTTACTCTCT CTGTTTGCTC TGGTTAATAA TCTCAGGAGC 900 ACAAACATTC CTGGAGGCAG GAGAAGAAAT CAACATCCTG GACTTATCCT CTGGGCCTGT 960 TAATTTTTAA AAAGCAGTCA AAAGTCCAAG TGGCCCTTGG CAGCATTTAC TCTCTCTGTT 1020 TGCTCTGGTT AATAATCTCA GGAGCACAAA CATTCCTGGA GGCAGGAGAA GAAATCAACA 1080 TCCTGGACTT ATCCTCTGGG CCTAGGCCTG AGGCTGGTCA AAATTGAACC TCCTCCTGCT 1140 CTGAGCAGCC TGGGGGGCAG ACTAAGCAGA GGGCTGTGCA GACCCACATA AAGAGCCTAC 1200 TGTGTGCCAG GCACTTCACC CGAGGCACTT CACAAGCATG CTTGGGAATG AAACTTCCAA 1260 CTCTTTGGGA TGCAGGTGAA ACAGTTCCTG GTTCAGAGAG GTGAAGCGGC CTGCCTGAGG 1320 CAGCACAGCT CTTCTTTACA GATGTGCTTC CCCACCTCTA CCCTGTCTCA CGGCCCCCCA 1380 TGCCAGCCTG ACGGTTGTGT CTGCCTCAGT CATGCTCCAT TTTTCCATCG GGACCATCAA 1440 GAGGGTGTTT GTGTCTAAGG CTGACTGGGT AACTTTGGAT GAGCGGTCTC TCCGCTCTGA 1500 GCCTGTTTCC TCATCTGTCA AATGGGCTCT AACCCACTCT GATCTCCCAG GGCGGCAGTA 1560 AGTCTTCAGC ATCAGGCATT TTGGGGTGAC TCAGTAAATG GTAGATCTTG CTACCAGTGG 1620 AACAGCCACT AAGGATTCTG CAGTGAGAGC AGAGGGCCAG CTAAGTGGTA CTCTCCCAGA 1680 GACTGTCTGA CTCACGCCAC CCCCTCCACC TTGGACACAG GACGCTGTGG TTTCTGAGCC 1740 AGGTACAATG ACTCCTTTCG GTAAGTGCAG TGGAAGCTGT ACACTGCCCA GGCAAAGCGT 1800 CCGGGCAGCG TAGGCGGGCG ACTCAGATCC CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC 1860 TCCGATAACT GGGGTGACCT TGGTTAATAT TCACCAGCAG CCTCCCCCGT TGCCCCTCTG 1920 GATCCACTGC TTAAATACGG ACGAGGACAG GGCCCTGTCT CCTCAGCTTC AGGCACCACC 1980 ACTGACCTGG GACAGTGAAT CGTAAGTACT AGCAGCTACA ATCCAGCTAC CATTCTGCTT 2040 TTATTTTATG GTTGGGATAA GGCTGGATTA TTCTGAGTCC AAGCTAGGCC CTTTTGCTAA 2100 TCATGTTCAT ACCTCTTATC TTCCTCCCAC AGCTCCTGGG CAACGTGCTG GTCTGTGTGC 2160 TGGCCCATCA CTTTGGCAAA GAATTGCGAT CGCCACCATG CAGATTGAGC TGAGCACCTG 2220 CTTCTTCCTG TGCCTGCTGA GGTTCTGCTT CTCTGCCACC AGGAGATACT ACCTGGGGGC 2280 TGTGGAGCTG AGCTGGGACT ACATGCAGTC TGACCTGGGG GAGCTGCCTG TGGATGCCAG 2340 GTTCCCCCCC AGAGTGCCCA AGAGCTTCCC CTTCAACACC TCTGTGGTGT ACAAGAAGAC 2400 CCTGTTTGTG GAGTTCACTG ACCACCTGTT CAACATTGCC AAGCCCAGGC CCCCCTGGAT 2460 GGGCCTGCTG GGCCCCACCA TCCAGGCTGA GGTGTATGAC ACTGTGGTGA TCACCCTGAA 2520 GAACATGGCC AGCCACCCTG TGAGCCTGCA TGCTGTGGGG GTGAGCTACT GGAAGGCCTC 2580 TGAGGGGGCT GAGTATGATG ACCAGACCAG CCAGAGGGAG AAGGAGGATG ACAAGGTGTT 2640 CCCTGGGGGC AGCCACACCT ATGTGTGGCA GGTGCTGAAG GAGAATGGCC CCATGGCCTC 2700 TGACCCCCTG TGCCTGACCT ACAGCTACCT GAGCCATGTG GACCTGGTGA AGGACCTGAA 2760 CTCTGGCCTG ATTGGGGCCC TGCTGGTGTG CAGGGAGGGC AGCCTGGCCA AGGAGAAGAC 2820 CCAGACCCTG CACAAGTTCA TCCTGCTGTT TGCTGTGTTT GATGAGGGCA AGAGCTGGCA 2880 CTCTGAAACC AAGAACAGCC TGATGCAGGA CAGGGATGCT GCCTCTGCCA GGGCCTGGCC 2940 CAAGATGCAC ACTGTGAATG GCTATGTGAA CAGGAGCCTG CCTGGCCTGA TTGGCTGCCA 3000 CAGGAAGTCT GTGTACTGGC ATGTGATTGG CATGGGCACC ACCCCTGAGG TGCACAGCAT 3060 CTTCCTGGAG GGCCACACCT TCCTGGTCAG GAACCACAGG CAGGCCAGCC TGGAGATCAG 3120 CCCCATCACC TTCCTGACTG CCCAGACCCT GCTGATGGAC CTGGGCCAGT TCCTGCTGTT 3180 CTGCCACATC AGCAGCCACC AGCATGATGG CATGGAGGCC TATGTGAAGG TGGACAGCTG 3240 CCCTGAGGAG CCCCAGCTGA GGATGAAGAA CAATGAGGAG GCTGAGGACT ATGATGATGA 3300 CCTGACTGAC TCTGAGATGG ATGTGGTGAG GTTTGATGAT GACAACAGCC CCAGCTTCAT 3360 CCAGATCAGG TCTGTGGCCA AGAAGCACCC CAAGACCTGG GTGCACTACA TTGCTGCTGA 3420 GGAGGAGGAC TGGGACTATG CCCCCCTGGT GCTGGCCCCT GATGACAGGA GCTACAAGAG 3480 CCAGTACCTG AACAATGGCC CCCAGAGGAT TGGCAGGAAG TACAAGAAGG TCAGGTTCAT 3540 GGCCTACACT GATGAAACCT TCAAGACCAG GGAGGCCATC CAGCATGAGT CTGGCATCCT 3600 GGGCCCCCTG CTGTATGGGG AGGTGGGGGA CACCCTGCTG ATCATCTTCA AGAACCAGGC 3660 CAGCAGGCCC TACAACATCT ACCCCCATGG CATCACTGAT GTGAGGCCCC TGTACAGCAG 3720 GAGGCTGCCC AAGGGGGTGA AGCACCTGAA GGACTTCCCC ATCCTGCCTG GGGAGATCTT 3780 CAAGTACAAG TGGACTGTGA CTGTGGAGGA TGGCCCCACC AAGTCTGACC CCAGGTGCCT 3840 GACCAGATAC TACAGCAGCT TTGTGAACAT GGAGAGGGAC CTGGCCTCTG GCCTGATTGG 3900 CCCCCTGCTG ATCTGCTACA AGGAGTCTGT GGACCAGAGG GGCAACCAGA TCATGTCTGA 3960 CAAGAGGAAT GTGATCCTGT TCTCTGTGTT TGATGAGAAC AGGAGCTGGT ACCTGACTGA 4020 GAACATCCAG AGGTTCCTGC CCAACCCTGC TGGGGTGCAG CTGGAGGACC CTGAGTTCCA 4080 GGCCAGCAAC ATCATGCACA GCATCAATGG CTATGTGTTT GACAGCCTGC AGCTGTCTGT 4140 GTGCCTGCAT GAGGTGGCCT ACTGGTACAT CCTGAGCATT GGGGCCCAGA CTGACTTCCT 4200 GTCTGTGTTC TTCTCTGGCT ACACCTTCAA GCACAAGATG GTGTATGAGG ACACCCTGAC 4260 CCTGTTCCCC TTCTCTGGGG AGACTGTGTT CATGAGCATG GAGAACCCTG GCCTGTGGAT 4320 TCTGGGCTGC CACAACTCTG ACTTCAGGAA CAGGGGCATG ACTGCCCTGC TGAAAGTCTC 4380 CAGCTGTGAC AAGAACACTG GGGACTACTA TGAGGACAGC TATGAGGACA TCTCTGCCTA 4440 CCTGCTGAGC AAGAACAATG CCATTGAGCC CAGGAGCTTC AGCCAGAACC CCCCAGTGCT 4500 GAAGAGGCAC CAGAGGGAGA TCACCAGGAC CACCCTGCAG TCTGACCAGG AGGAGATTGA 4560 CTATGATGAC ACCATCTCTG TGGAGATGAA GAAGGAGGAC TTTGACATCT ACGACGAGGA 4620 CGAGAACCAG AGCCCCAGGA GCTTCCAGAA GAAGACCAGG CACTACTTCA TTGCTGCTGT 4680 GGAGAGGCTG TGGGACTATG GCATGAGCAG CAGCCCCCAT GTGCTGAGGA ACAGGGCCCA 4740 GTCTGGCTCT GTGCCCCAGT TCAAGAAGGT GGTGTTCCAG GAGTTCACTG ATGGCAGCTT 4800 CACCCAGCCC CTGTACAGAG GGGAGCTGAA TGAGCACCTG GGCCTGCTGG GCCCCTACAT 4860 CAGGGCTGAG GTGGAGGACA ACATCATGGT GACCTTCAGG AACCAGGCCA GCAGGCCCTA 4920 CAGCTTCTAC AGCAGCCTGA TCAGCTATGA GGAGGACCAG AGGCAGGGGG CTGAGCCCAG 4980 GAAGAACTTT GTGAAGCCCA ATGAAACCAA GACCTACTTC TGGAAGGTGC AGCACCACAT 5040 GGCCCCCACC AAGGATGAGT TTGACTGCAA GGCCTGGGCC TACTTCTCTG ATGTGGACCT 5100 GGAGAAGGAT GTGCACTCTG GCCTGATTGG CCCCCTGCTG GTGTGCCACA CCAACACCCT 5160 GAACCCTGCC CATGGCAGGC AGGTGACTGT GCAGGAGTTT GCCCTGTTCT TCACCATCTT 5220 TGATGAAACC AAGAGCTGGT ACTTCACTGA GAACATGGAG AGGAACTGCA GGGCCCCCTG 5280 CAACATCCAG ATGGAGGACC CCACCTTCAA GGAGAACTAC AGGTTCCATG CCATCAATGG 5340 CTACATCATG GACACCCTGC CTGGCCTGGT GATGGCCCAG GACCAGAGGA TCAGGTGGTA 5400 CCTGCTGAGC ATGGGCAGCA ATGAGAACAT CCACAGCATC CACTTCTCTG GCCATGTGTT 5460 CACTGTGAGG AAGAAGGAGG AGTACAAGAT GGCCCTGTAC AACCTGTACC CTGGGGTGTT 5520 TGAGACTGTG GAGATGCTGC CCAGCAAGGC TGGCATCTGG AGGGTGGAGT GCCTGATTGG 5580 GGAGCACCTG CATGCTGGCA TGAGCACCCT GTTCCTGGTG TACAGCAACA AGTGCCAGAC 5640 CCCCCTGGGC ATGGCCTCTG GCCACATCAG GGACTTCCAG ATCACTGCCT CTGGCCAGTA 5700 TGGCCAGTGG GCCCCCAAGC TGGCCAGGCT GCACTACTCT GGCAGCATCA ATGCCTGGAG 5760 CACCAAGGAG CCCTTCAGCT GGATCAAGGT GGACCTGCTG GCCCCCATGA TCATCCATGG 5820 CATCAAGACC CAGGGGGCCA GGCAGAAGTT CAGCAGCCTG TACATCAGCC AGTTCATCAT 5880 CATGTACAGC CTGGATGGCA AGAAGTGGCA GACCTACAGG GGCAACAGCA CTGGCACCCT 5940 GATGGTGTTC TTTGGCAATG TGGACAGCTC TGGCATCAAG CACAACATCT TCAACCCCCC 6000 CATCATTGCC AGATACATCA GGCTGCACCC CACCCACTAC AGCATCAGGA GCACCCTGAG 6060 GATGGAGCTG ATGGGCTGTG ACCTGAACAG CTGCAGCATG CCCCTGGGCA TGGAGAGCAA 6120 GGCCATCTCT GATGCCCAGA TCACTGCCAG CAGCTACTTC ACCAACATGT TTGCCACCTG 6180 GAGCCCCAGC AAGGCCAGGC TGCACCTGCA GGGCAGGAGC AATGCCTGGA GGCCCCAGGT 6240 CAACAACCCC AAGGAGTGGC TGCAGGTGGA CTTCCAGAAG ACCATGAAGG TGACTGGGGT 6300 GACCACCCAG GGGGTGAAGA GCCTGCTGAC CAGCATGTAT GTGAAGGAGT TCCTGATCAG 6360 CAGCAGCCAG GATGGCCACC AGTGGACCCT GTTCTTCCAG AATGGCAAGG TGAAGGTGTT 6420 CCAGGGCAAC CAGGACAGCT TCACCCCTGT GGTGAACAGC CTGGACCCCC CCCTGCTGAC 6480 CAGATACCTG AGGATTCACC CCCAGAGCTG GGTGCACCAG ATTGCCCTGA GGATGGAGGT 6540 GCTGGGCTGT GAGGCCCAGG ACCTGTACTG ACCTCGAGCT GTGCCTTCTA GTTGCCAGCC 6600 ATCTGTTGTT TGCCCCTCCC CCGTGCCTTC CTTGACCCTG GAAGGTGCCA CTCCCACTGT 6660 CCTTTCCTAA TAAAATGAGG AAATTGCATC GCATTGTCTG AGTAGGTGTC ATTCTATTCT 6720 GGGGGGTGGG GTGGGGCAGG ACAGCAAGGG GGAGGATTGG GAAGACAATA GCAGGCATGC 6780 TGGGGATGCG GTGGGCTCTA TGGACCGGTG CGGCCGCAGG AACCCCTAGT GATGGAGTTG 6840 GCCACTCCCT CTCTGCGCGC TCGCTCGCTC ACTGAGGCCG GGCGACCAAA GGTCGCCCGA 6900 CGCCCGGGCT TTGCCCGGGC GGCCTCAGTG AGCGAGCGAG CGCGCAGAGA GGGAGTGGCC 6960 AA 6962 SEQ ID NO: 19 <211> 6289 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 19 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTA GGCTCAGAGG CACACAGGAG 180 TTTCTGGGCT CACCCTGCCC CCTTCCAACC CCTCAGTTCC CATCCTCCAG CAGCTGTTTG 240 TGTGCTGCCT CTGAAGTCCA CACTGAACAA ACTTCAGCCT ACTCATGTCC CTAAAATGGG 300 CAAACATTGC AAGCAGCAAA CAGCAAACAC ACAGCCCTCC CTGCCTGCTG ACCTTGGAGC 360 TGGGGCAGAG GTCAGAGACC TCTCTGGGCC CATGCCACCT CCAACATCCA CTCGACCCCT 420 TGGAATTTCG GTGGAGAGGA GCAGAGGTTG TCCTGGCGTG GTTTAGGTAG TGTGAGAGGG 480 GTCGACAGGC TCAGAGGCAC ACAGGAGTTT CTGGGCTCAC CCTGCCCCCT TCCAACCCCT 540 CAGTTCCCAT CCTCCAGCAG CTGTTTGTGT GCTGCCTCTG AAGTCCACAC TGAACAAACT 600 TCAGCCTACT CATGTCCCTA AAATGGGCAA ACATTGCAAG CAGCAAACAG CAAACACACA 660 GCCCTCCCTG CCTGCTGACC TTGGAGCTGG GGCAGAGGTC AGAGACCTCT CTGGGCCCAT 720 GCCACCTCCA ACATCCACTC GACCCCTTGG AATTTCGGTG GAGAGGAGCA GAGGTTGTCC 780 TGGCGTGGTT TAGGTAGTGT GAGAGGGGTC GACGTTAATT TTTAAAAAGC AGTCAAAAGT 840 CCAAGTGGCC CTTGGCAGCA TTTACTCTCT CTGTTTGCTC TGGTTAATAA TCTCAGGAGC 900 ACAAACATTC CTGGAGGCAG GAGAAGAAAT CAACATCCTG GACTTATCCT CTGGGCCTGT 960 TAATTTTTAA AAAGCAGTCA AAAGTCCAAG TGGCCCTTGG CAGCATTTAC TCTCTCTGTT 1020 TGCTCTGGTT AATAATCTCA GGAGCACAAA CATTCCTGGA GGCAGGAGAA GAAATCAACA 1080 TCCTGGACTT ATCCTCTGGG CCTAGTCGAC TGGACACAGG ACGCTGTGGT TTCTGAGCCA 1140 GGGGGCGACT CAGATCCCAG CCAGTGGACT TAGCCCCTGT TTGCTCCTCC GATAACTGGG 1200 GTGACCTTGG TTAATATTCA CCAGCAGCCT CCCCCGTTGC CCCTCTGGAT CCACTGCTTA 1260 AATACGGACG AGGACAGGGC CCTGTCTCCT CAGCTTCAGG CACCACCACT GACCTGGGAC 1320 AGTGAATCGT AAGTACTAGC AGCTACAATC CAGCTACCAT TCTGCTTTTA TTTTATGGTT 1380 GGGATAAGGC TGGATTATTC TGAGTCCAAG CTAGGCCCTT TTGCTAATCA TGTTCATACC 1440 TCTTATCTTC CTCCCACAGC TCCTGGGCAA CGTGCTGGTC TGTGTGCTGG CCCATCACTT 1500 TGGCAAAGAA TTGCGATCGC CACCATGCAG ATTGAGCTGA GCACCTGCTT CTTCCTGTGC 1560 CTGCTGAGGT TCTGCTTCTC TGCCACCAGG AGATACTACC TGGGGGCTGT GGAGCTGAGC 1620 TGGGACTACA TGCAGTCTGA CCTGGGGGAG CTGCCTGTGG ATGCCAGGTT CCCCCCCAGA 1680 GTGCCCAAGA GCTTCCCCTT CAACACCTCT GTGGTGTACA AGAAGACCCT GTTTGTGGAG 1740 TTCACTGACC ACCTGTTCAA CATTGCCAAG CCCAGGCCCC CCTGGATGGG CCTGCTGGGC 1800 CCCACCATCC AGGCTGAGGT GTATGACACT GTGGTGATCA CCCTGAAGAA CATGGCCAGC 1860 CACCCTGTGA GCCTGCATGC TGTGGGGGTG AGCTACTGGA AGGCCTCTGA GGGGGCTGAG 1920 TATGATGACC AGACCAGCCA GAGGGAGAAG GAGGATGACA AGGTGTTCCC TGGGGGCAGC 1980 CACACCTATG TGTGGCAGGT GCTGAAGGAG AATGGCCCCA TGGCCTCTGA CCCCCTGTGC 2040 CTGACCTACA GCTACCTGAG CCATGTGGAC CTGGTGAAGG ACCTGAACTC TGGCCTGATT 2100 GGGGCCCTGC TGGTGTGCAG GGAGGGCAGC CTGGCCAAGG AGAAGACCCA GACCCTGCAC 2160 AAGTTCATCC TGCTGTTTGC TGTGTTTGAT GAGGGCAAGA GCTGGCACTC TGAAACCAAG 2220 AACAGCCTGA TGCAGGACAG GGATGCTGCC TCTGCCAGGG CCTGGCCCAA GATGCACACT 2280 GTGAATGGCT ATGTGAACAG GAGCCTGCCT GGCCTGATTG GCTGCCACAG GAAGTCTGTG 2340 TACTGGCATG TGATTGGCAT GGGCACCACC CCTGAGGTGC ACAGCATCTT CCTGGAGGGC 2400 CACACCTTCC TGGTCAGGAA CCACAGGCAG GCCAGCCTGG AGATCAGCCC CATCACCTTC 2460 CTGACTGCCC AGACCCTGCT GATGGACCTG GGCCAGTTCC TGCTGTTCTG CCACATCAGC 2520 AGCCACCAGC ATGATGGCAT GGAGGCCTAT GTGAAGGTGG ACAGCTGCCC TGAGGAGCCC 2580 CAGCTGAGGA TGAAGAACAA TGAGGAGGCT GAGGACTATG ATGATGACCT GACTGACTCT 2640 GAGATGGATG TGGTGAGGTT TGATGATGAC AACAGCCCCA GCTTCATCCA GATCAGGTCT 2700 GTGGCCAAGA AGCACCCCAA GACCTGGGTG CACTACATTG CTGCTGAGGA GGAGGACTGG 2760 GACTATGCCC CCCTGGTGCT GGCCCCTGAT GACAGGAGCT ACAAGAGCCA GTACCTGAAC 2820 AATGGCCCCC AGAGGATTGG CAGGAAGTAC AAGAAGGTCA GGTTCATGGC CTACACTGAT 2880 GAAACCTTCA AGACCAGGGA GGCCATCCAG CATGAGTCTG GCATCCTGGG CCCCCTGCTG 2940 TATGGGGAGG TGGGGGACAC CCTGCTGATC ATCTTCAAGA ACCAGGCCAG CAGGCCCTAC 3000 AACATCTACC CCCATGGCAT CACTGATGTG AGGCCCCTGT ACAGCAGGAG GCTGCCCAAG 3060 GGGGTGAAGC ACCTGAAGGA CTTCCCCATC CTGCCTGGGG AGATCTTCAA GTACAAGTGG 3120 ACTGTGACTG TGGAGGATGG CCCCACCAAG TCTGACCCCA GGTGCCTGAC CAGATACTAC 3180 AGCAGCTTTG TGAACATGGA GAGGGACCTG GCCTCTGGCC TGATTGGCCC CCTGCTGATC 3240 TGCTACAAGG AGTCTGTGGA CCAGAGGGGC AACCAGATCA TGTCTGACAA GAGGAATGTG 3300 ATCCTGTTCT CTGTGTTTGA TGAGAACAGG AGCTGGTACC TGACTGAGAA CATCCAGAGG 3360 TTCCTGCCCA ACCCTGCTGG GGTGCAGCTG GAGGACCCTG AGTTCCAGGC CAGCAACATC 3420 ATGCACAGCA TCAATGGCTA TGTGTTTGAC AGCCTGCAGC TGTCTGTGTG CCTGCATGAG 3480 GTGGCCTACT GGTACATCCT GAGCATTGGG GCCCAGACTG ACTTCCTGTC TGTGTTCTTC 3540 TCTGGCTACA CCTTCAAGCA CAAGATGGTG TATGAGGACA CCCTGACCCT GTTCCCCTTC 3600 TCTGGGGAGA CTGTGTTCAT GAGCATGGAG AACCCTGGCC TGTGGATTCT GGGCTGCCAC 3660 AACTCTGACT TCAGGAACAG GGGCATGACT GCCCTGCTGA AAGTCTCCAG CTGTGACAAG 3720 AACACTGGGG ACTACTATGA GGACAGCTAT GAGGACATCT CTGCCTACCT GCTGAGCAAG 3780 AACAATGCCA TTGAGCCCAG GAGCTTCAGC CAGAACCCCC CAGTGCTGAA GAGGCACCAG 3840 AGGGAGATCA CCAGGACCAC CCTGCAGTCT GACCAGGAGG AGATTGACTA TGATGACACC 3900 ATCTCTGTGG AGATGAAGAA GGAGGACTTT GACATCTACG ACGAGGACGA GAACCAGAGC 3960 CCCAGGAGCT TCCAGAAGAA GACCAGGCAC TACTTCATTG CTGCTGTGGA GAGGCTGTGG 4020 GACTATGGCA TGAGCAGCAG CCCCCATGTG CTGAGGAACA GGGCCCAGTC TGGCTCTGTG 4080 CCCCAGTTCA AGAAGGTGGT GTTCCAGGAG TTCACTGATG GCAGCTTCAC CCAGCCCCTG 4140 TACAGAGGGG AGCTGAATGA GCACCTGGGC CTGCTGGGCC CCTACATCAG GGCTGAGGTG 4200 GAGGACAACA TCATGGTGAC CTTCAGGAAC CAGGCCAGCA GGCCCTACAG CTTCTACAGC 4260 AGCCTGATCA GCTATGAGGA GGACCAGAGG CAGGGGGCTG AGCCCAGGAA GAACTTTGTG 4320 AAGCCCAATG AAACCAAGAC CTACTTCTGG AAGGTGCAGC ACCACATGGC CCCCACCAAG 4380 GATGAGTTTG ACTGCAAGGC CTGGGCCTAC TTCTCTGATG TGGACCTGGA GAAGGATGTG 4440 CACTCTGGCC TGATTGGCCC CCTGCTGGTG TGCCACACCA ACACCCTGAA CCCTGCCCAT 4500 GGCAGGCAGG TGACTGTGCA GGAGTTTGCC CTGTTCTTCA CCATCTTTGA TGAAACCAAG 4560 AGCTGGTACT TCACTGAGAA CATGGAGAGG AACTGCAGGG CCCCCTGCAA CATCCAGATG 4620 GAGGACCCCA CCTTCAAGGA GAACTACAGG TTCCATGCCA TCAATGGCTA CATCATGGAC 4680 ACCCTGCCTG GCCTGGTGAT GGCCCAGGAC CAGAGGATCA GGTGGTACCT GCTGAGCATG 4740 GGCAGCAATG AGAACATCCA CAGCATCCAC TTCTCTGGCC ATGTGTTCAC TGTGAGGAAG 4800 AAGGAGGAGT ACAAGATGGC CCTGTACAAC CTGTACCCTG GGGTGTTTGA GACTGTGGAG 4860 ATGCTGCCCA GCAAGGCTGG CATCTGGAGG GTGGAGTGCC TGATTGGGGA GCACCTGCAT 4920 GCTGGCATGA GCACCCTGTT CCTGGTGTAC AGCAACAAGT GCCAGACCCC CCTGGGCATG 4980 GCCTCTGGCC ACATCAGGGA CTTCCAGATC ACTGCCTCTG GCCAGTATGG CCAGTGGGCC 5040 CCCAAGCTGG CCAGGCTGCA CTACTCTGGC AGCATCAATG CCTGGAGCAC CAAGGAGCCC 5100 TTCAGCTGGA TCAAGGTGGA CCTGCTGGCC CCCATGATCA TCCATGGCAT CAAGACCCAG 5160 GGGGCCAGGC AGAAGTTCAG CAGCCTGTAC ATCAGCCAGT TCATCATCAT GTACAGCCTG 5220 GATGGCAAGA AGTGGCAGAC CTACAGGGGC AACAGCACTG GCACCCTGAT GGTGTTCTTT 5280 GGCAATGTGG ACAGCTCTGG CATCAAGCAC AACATCTTCA ACCCCCCCAT CATTGCCAGA 5340 TACATCAGGC TGCACCCCAC CCACTACAGC ATCAGGAGCA CCCTGAGGAT GGAGCTGATG 5400 GGCTGTGACC TGAACAGCTG CAGCATGCCC CTGGGCATGG AGAGCAAGGC CATCTCTGAT 5460 GCCCAGATCA CTGCCAGCAG CTACTTCACC AACATGTTTG CCACCTGGAG CCCCAGCAAG 5520 GCCAGGCTGC ACCTGCAGGG CAGGAGCAAT GCCTGGAGGC CCCAGGTCAA CAACCCCAAG 5580 GAGTGGCTGC AGGTGGACTT CCAGAAGACC ATGAAGGTGA CTGGGGTGAC CACCCAGGGG 5640 GTGAAGAGCC TGCTGACCAG CATGTATGTG AAGGAGTTCC TGATCAGCAG CAGCCAGGAT 5700 GGCCACCAGT GGACCCTGTT CTTCCAGAAT GGCAAGGTGA AGGTGTTCCA GGGCAACCAG 5760 GACAGCTTCA CCCCTGTGGT GAACAGCCTG GACCCCCCCC TGCTGACCAG ATACCTGAGG 5820 ATTCACCCCC AGAGCTGGGT GCACCAGATT GCCCTGAGGA TGGAGGTGCT GGGCTGTGAG 5880 GCCCAGGACC TGTACTGACC TCGAGCTGTG CCTTCTAGTT GCCAGCCATC TGTTGTTTGC 5940 CCCTCCCCCG TGCCTTCCTT GACCCTGGAA GGTGCCACTC CCACTGTCCT TTCCTAATAA 6000 AATGAGGAAA TTGCATCGCA TTGTCTGAGT AGGTGTCATT CTATTCTGGG GGGTGGGGTG 6060 GGGCAGGACA GCAAGGGGGA GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG 6120 GGCTCTATGG ACCGGTGCGG CCGCAGGAAC CCCTAGTGAT GGAGTTGGCC ACTCCCTCTC 6180 TGCGCGCTCG CTCGCTCACT GAGGCCGGGC GACCAAAGGT CGCCCGACGC CCGGGCTTTG 6240 CCCGGGCGGC CTCAGTGAGC GAGCGAGCGC GCAGAGAGGG AGTGGCCAA 6289 SEQ ID NO: 20 <211> 5430 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 20 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACGT GGACTTAGCC 180 CCTGTTTGCT CCTCCGATAA CTGGGGTGAC CTTGGTTAAT ATTCACCAGC AGCCTCCCCG 240 TGGACTTAGC CCCTGTTTGC TCCTCCGATA ACTGGGGTGA CCTTGGTTAA TATTCACCAG 300 CAGCCTCCCC ACGCGAAACG TCGACTGGAC ACAGGACGCT GTGGTTTCTG AGCCAGGGGG 360 CGACTCAGAT CCCAGCCAGT GGACTTAGCC CCTGTTTGCT CCTCCGATAA CTGGGGTGAC 420 CTTGGTTAAT ATTCACCAGC AGCCTCCCCC GTTGCCCCTC TGGATCCACT GCTTAAATAC 480
Figure imgf000174_0001
GGACGAGGAC AGGGCCCTGT CTCCTCAGCT TCAGGCACCA CCACTGACCT GGGACAGTGA 540
Figure imgf000174_0002
ATCGTAAGTA CTAGCAGCTA CAATCCAGCT ACCATTCTGC TTTTATTTTA TGGTTGGGAT 600
Figure imgf000174_0003
AAGGCTGGAT TATTCTGAGT CCAAGCTAGG CCCTTTTGCT AATCATGTTC ATACCTCTTA 660
Figure imgf000174_0004
TCTTCCTCCC ACAGCTCCTG GGCAACGTGC TGGTCTGTGT GCTGGCCCAT CACTTTGGCA 720
Figure imgf000174_0005
AAGAATTGCG ATCGCCACCA TGCAGATTGA GCTGAGCACC TGCTTCTTCC TGTGCCTGCT
Figure imgf000174_0006
GAGGTTCTGC TTCTCTGCCA CCAGGAGATA CTACCTGGGG GCTGTGGAGC TGAGCTGGGA
Figure imgf000174_0007
CTACATGCAG TCTGACCTGG GGGAGCTGCC TGTGGATGCC AGGTTCCCCC CCAGAGTGCC
Figure imgf000174_0008
CAAGAGCTTC CCCTTCAACA CCTCTGTGGT GTACAAGAAG ACCCTGTTTG TGGAGTTCAC
Figure imgf000174_0009
TGACCACCTG TTCAACATTG CCAAGCCCAG GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC
Figure imgf000174_0010
CATCCAGGCT GAGGTGTATG ACACTGTGGT GATCACCCTG AAGAACATGG CCAGCCACCC
Figure imgf000174_0011
TGTGAGCCTG CATGCTGTGG GGGTGAGCTA CTGGAAGGCC TCTGAGGGGG CTGAGTATGA
Figure imgf000174_0012
TGACCAGACC AGCCAGAGGG AGAAGGAGGA TGACAAGGTG TTCCCTGGGG GCAGCCACAC
Figure imgf000174_0013
CTATGTGTGG CAGGTGCTGA AGGAGAATGG CCCCATGGCC TCTGACCCCC TGTGCCTGAC
Figure imgf000174_0014
CTACAGCTAC CTGAGCCATG TGGACCTGGT GAAGGACCTG AACTCTGGCC TGATTGGGGC
Figure imgf000174_0015
CCTGCTGGTG TGCAGGGAGG GCAGCCTGGC CAAGGAGAAG ACCCAGACCC TGCACAAGTT
Figure imgf000174_0016
CATCCTGCTG TTTGCTGTGT TTGATGAGGG CAAGAGCTGG CACTCTGAAA CCAAGAACAG
Figure imgf000174_0017
CCTGATGCAG GACAGGGATG CTGCCTCTGC CAGGGCCTGG CCCAAGATGC ACACTGTGAA
Figure imgf000174_0018
TGGCTATGTG AACAGGAGCC TGCCTGGCCT GATTGGCTGC CACAGGAAGT CTGTGTACTG
Figure imgf000174_0019
GCATGTGATT GGCATGGGCA CCACCCCTGA GGTGCACAGC ATCTTCCTGG AGGGCCACAC
Figure imgf000174_0020
CTTCCTGGTC AGGAACCACA GGCAGGCCAG CCTGGAGATC AGCCCCATCA CCTTCCTGAC
Figure imgf000174_0021
TGCCCAGACC CTGCTGATGG ACCTGGGCCA GTTCCTGCTG TTCTGCCACA TCAGCAGCCA
Figure imgf000174_0022
CCAGCATGAT GGCATGGAGG CCTATGTGAA GGTGGACAGC TGCCCTGAGG AGCCCCAGCT
Figure imgf000174_0023
GAGGATGAAG AACAATGAGG AGGCTGAGGA CTATGATGAT GACCTGACTG ACTCTGAGAT
Figure imgf000174_0024
GGATGTGGTG AGGTTTGATG ATGACAACAG CCCCAGCTTC ATCCAGATCA GGTCTGTGGC
Figure imgf000174_0025
CAAGAAGCAC CCCAAGACCT GGGTGCACTA CATTGCTGCT GAGGAGGAGG ACTGGGACTA
Figure imgf000174_0026
Figure imgf000174_0027
TGCCCCCCTG GTGCTGGCCC CTGATGACAG GAGCTACAAG AGCCAGTACC TGAACAATGG
Figure imgf000174_0028
CCCCCAGAGG ATTGGCAGGA AGTACAAGAA GGTCAGGTTC ATGGCCTACA CTGATGAAAC
Figure imgf000174_0029
CTTCAAGACC AGGGAGGCCA TCCAGCATGA GTCTGGCATC CTGGGCCCCC TGCTGTATGG
Figure imgf000174_0030
GGAGGTGGGG GACACCCTGC TGATCATCTT CAAGAACCAG GCCAGCAGGC CCTACAACAT 2220 CTACCCCCAT GGCATCACTG ATGTGAGGCC CCTGTACAGC AGGAGGCTGC CCAAGGGGGT 2280 GAAGCACCTG AAGGACTTCC CCATCCTGCC TGGGGAGATC TTCAAGTACA AGTGGACTGT 2340 GACTGTGGAG GATGGCCCCA CCAAGTCTGA CCCCAGGTGC CTGACCAGAT ACTACAGCAG 2400 CTTTGTGAAC ATGGAGAGGG ACCTGGCCTC TGGCCTGATT GGCCCCCTGC TGATCTGCTA 2460 CAAGGAGTCT GTGGACCAGA GGGGCAACCA GATCATGTCT GACAAGAGGA ATGTGATCCT 2520 GTTCTCTGTG TTTGATGAGA ACAGGAGCTG GTACCTGACT GAGAACATCC AGAGGTTCCT 2580 GCCCAACCCT GCTGGGGTGC AGCTGGAGGA CCCTGAGTTC CAGGCCAGCA ACATCATGCA 2640 CAGCATCAAT GGCTATGTGT TTGACAGCCT GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC 2700 CTACTGGTAC ATCCTGAGCA TTGGGGCCCA GACTGACTTC CTGTCTGTGT TCTTCTCTGG 2760 CTACACCTTC AAGCACAAGA TGGTGTATGA GGACACCCTG ACCCTGTTCC CCTTCTCTGG 2820 GGAGACTGTG TTCATGAGCA TGGAGAACCC TGGCCTGTGG ATTCTGGGCT GCCACAACTC 2880 TGACTTCAGG AACAGGGGCA TGACTGCCCT GCTGAAAGTC TCCAGCTGTG ACAAGAACAC 2940 TGGGGACTAC TATGAGGACA GCTATGAGGA CATCTCTGCC TACCTGCTGA GCAAGAACAA 3000 TGCCATTGAG CCCAGGAGCT TCAGCCAGAA CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA 3060 GATCACCAGG ACCACCCTGC AGTCTGACCA GGAGGAGATT GACTATGATG ACACCATCTC 3120 TGTGGAGATG AAGAAGGAGG ACTTTGACAT CTACGACGAG GACGAGAACC AGAGCCCCAG 3180 GAGCTTCCAG AAGAAGACCA GGCACTACTT CATTGCTGCT GTGGAGAGGC TGTGGGACTA 3240 TGGCATGAGC AGCAGCCCCC ATGTGCTGAG GAACAGGGCC CAGTCTGGCT CTGTGCCCCA 3300 GTTCAAGAAG GTGGTGTTCC AGGAGTTCAC TGATGGCAGC TTCACCCAGC CCCTGTACAG 3360 AGGGGAGCTG AATGAGCACC TGGGCCTGCT GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA 3420 CAACATCATG GTGACCTTCA GGAACCAGGC CAGCAGGCCC TACAGCTTCT ACAGCAGCCT 3480 GATCAGCTAT GAGGAGGACC AGAGGCAGGG GGCTGAGCCC AGGAAGAACT TTGTGAAGCC 3540 CAATGAAACC AAGACCTACT TCTGGAAGGT GCAGCACCAC ATGGCCCCCA CCAAGGATGA 3600 GTTTGACTGC AAGGCCTGGG CCTACTTCTC TGATGTGGAC CTGGAGAAGG ATGTGCACTC 3660 TGGCCTGATT GGCCCCCTGC TGGTGTGCCA CACCAACACC CTGAACCCTG CCCATGGCAG 3720 GCAGGTGACT GTGCAGGAGT TTGCCCTGTT CTTCACCATC TTTGATGAAA CCAAGAGCTG 3780 GTACTTCACT GAGAACATGG AGAGGAACTG CAGGGCCCCC TGCAACATCC AGATGGAGGA 3840 CCCCACCTTC AAGGAGAACT ACAGGTTCCA TGCCATCAAT GGCTACATCA TGGACACCCT 3900 GCCTGGCCTG GTGATGGCCC AGGACCAGAG GATCAGGTGG TACCTGCTGA GCATGGGCAG 3960 CAATGAGAAC ATCCACAGCA TCCACTTCTC TGGCCATGTG TTCACTGTGA GGAAGAAGGA 4020 GGAGTACAAG ATGGCCCTGT ACAACCTGTA CCCTGGGGTG TTTGAGACTG TGGAGATGCT 4080 GCCCAGCAAG GCTGGCATCT GGAGGGTGGA GTGCCTGATT GGGGAGCACC TGCATGCTGG 4140 CATGAGCACC CTGTTCCTGG TGTACAGCAA CAAGTGCCAG ACCCCCCTGG GCATGGCCTC 4200 TGGCCACATC AGGGACTTCC AGATCACTGC CTCTGGCCAG TATGGCCAGT GGGCCCCCAA 4260 GCTGGCCAGG CTGCACTACT CTGGCAGCAT CAATGCCTGG AGCACCAAGG AGCCCTTCAG 4320 CTGGATCAAG GTGGACCTGC TGGCCCCCAT GATCATCCAT GGCATCAAGA CCCAGGGGGC 4380 CAGGCAGAAG TTCAGCAGCC TGTACATCAG CCAGTTCATC ATCATGTACA GCCTGGATGG 4440 CAAGAAGTGG CAGACCTACA GGGGCAACAG CACTGGCACC CTGATGGTGT TCTTTGGCAA 4500 TGTGGACAGC TCTGGCATCA AGCACAACAT CTTCAACCCC CCCATCATTG CCAGATACAT 4560 CAGGCTGCAC CCCACCCACT ACAGCATCAG GAGCACCCTG AGGATGGAGC TGATGGGCTG 4620 TGACCTGAAC AGCTGCAGCA TGCCCCTGGG CATGGAGAGC AAGGCCATCT CTGATGCCCA 4680 GATCACTGCC AGCAGCTACT TCACCAACAT GTTTGCCACC TGGAGCCCCA GCAAGGCCAG 4740 GCTGCACCTG CAGGGCAGGA GCAATGCCTG GAGGCCCCAG GTCAACAACC CCAAGGAGTG 4800 GCTGCAGGTG GACTTCCAGA AGACCATGAA GGTGACTGGG GTGACCACCC AGGGGGTGAA 4860 GAGCCTGCTG ACCAGCATGT ATGTGAAGGA GTTCCTGATC AGCAGCAGCC AGGATGGCCA 4920 CCAGTGGACC CTGTTCTTCC AGAATGGCAA GGTGAAGGTG TTCCAGGGCA ACCAGGACAG 4980 CTTCACCCCT GTGGTGAACA GCCTGGACCC CCCCCTGCTG ACCAGATACC TGAGGATTCA 5040 CCCCCAGAGC TGGGTGCACC AGATTGCCCT GAGGATGGAG GTGCTGGGCT GTGAGGCCCA 5100 GGACCTGTAC TGACCTCGAG GCACTGTCCT TTCCTAATAA AATGAGGAAA TTGCATCGCA 5160 TTGTCTGAGT AGGTGTCATT CTATTCTGGG GGGTGGGGTG GGGCAGGACA GCAAGGGGGA 5220 GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG GGCTCTATGG GCACGTGGCG 5280 GCCGCAGGAA CCCCTAGTGA TGGAGTTGGC CACTCCCTCT CTGCGCGCTC GCTCGCTCAC 5340 TGAGGCCGGG CGACCAAAGG TCGCCCGACG CCCGGGCTTT GCCCGGGCGG CCTCAGTGAG 5400 CGAGCGAGCG CGCAGAGAGG GAGTGGCCAA 5430 SEQ ID NO: 21 <211> 5779 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 21 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACGT GGACTTAGCC 180 CCTGTTTGCT CCTCCGATAA CTGGGGTGAC CTTGGTTAAT ATTCACCAGC AGCCTCCCCG 240 TGGACTTAGC CCCTGTTTGC TCCTCCGATA ACTGGGGTGA CCTTGGTTAA TATTCACCAG 300 CAGCCTCCCC ACGCGAAACG TCGACTGGAC ACAGGACGCT GTGGTTTCTG AGCCAGGGGG 360 CGACTCAGAT CCCAGCCAGT GGACTTAGCC CCTGTTTGCT CCTCCGATAA CTGGGGTGAC 420 CTTGGTTAAT ATTCACCAGC AGCCTCCCCC GTTGCCCCTC TGGATCCACT GCTTAAATAC 480 GGACGAGGAC AGGGCCCTGT CTCCTCAGCT TCAGGCACCA CCACTGACCT GGGACAGTGA 540 ATCGTAAGTA CTAGCAGCTA CAATCCAGCT ACCATTCTGC TTTTATTTTA TGGTTGGGAT 600 AAGGCTGGAT TATTCTGAGT CCAAGCTAGG CCCTTTTGCT AATCATGTTC ATACCTCTTA 660 TCTTCCTCCC ACAGCTCCTG GGCAACGTGC TGGTCTGTGT GCTGGCCCAT CACTTTGGCA 720 AAGAATTGCG ATCGCCACCA TGCAGATTGA GCTGAGCACC TGCTTCTTCC TGTGCCTGCT 780 GAGGTTCTGC TTCTCTGCCA CCAGGAGATA CTACCTGGGG GCTGTGGAGC TGAGCTGGGA 840 CTACATGCAG TCTGACCTGG GGGAGCTGCC TGTGGATGCC AGGTTCCCCC CCAGAGTGCC 900 CAAGAGCTTC CCCTTCAACA CCTCTGTGGT GTACAAGAAG ACCCTGTTTG TGGAGTTCAC 960 TGACCACCTG TTCAACATTG CCAAGCCCAG GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC 1020 CATCCAGGCT GAGGTGTATG ACACTGTGGT GATCACCCTG AAGAACATGG CCAGCCACCC 1080 TGTGAGCCTG CATGCTGTGG GGGTGAGCTA CTGGAAGGCC TCTGAGGGGG CTGAGTATGA 1140 TGACCAGACC AGCCAGAGGG AGAAGGAGGA TGACAAGGTG TTCCCTGGGG GCAGCCACAC 1200 CTATGTGTGG CAGGTGCTGA AGGAGAATGG CCCCATGGCC TCTGACCCCC TGTGCCTGAC 1260 CTACAGCTAC CTGAGCCATG TGGACCTGGT GAAGGACCTG AACTCTGGCC TGATTGGGGC 1320 CCTGCTGGTG TGCAGGGAGG GCAGCCTGGC CAAGGAGAAG ACCCAGACCC TGCACAAGTT 1380 CATCCTGCTG TTTGCTGTGT TTGATGAGGG CAAGAGCTGG CACTCTGAAA CCAAGAACAG 1440 CCTGATGCAG GACAGGGATG CTGCCTCTGC CAGGGCCTGG CCCAAGATGC ACACTGTGAA 1500 TGGCTATGTG AACAGGAGCC TGCCTGGCCT GATTGGCTGC CACAGGAAGT CTGTGTACTG 1560 GCATGTGATT GGCATGGGCA CCACCCCTGA GGTGCACAGC ATCTTCCTGG AGGGCCACAC 1620 CTTCCTGGTC AGGAACCACA GGCAGGCCAG CCTGGAGATC AGCCCCATCA CCTTCCTGAC 1680 TGCCCAGACC CTGCTGATGG ACCTGGGCCA GTTCCTGCTG TTCTGCCACA TCAGCAGCCA 1740 CCAGCATGAT GGCATGGAGG CCTATGTGAA GGTGGACAGC TGCCCTGAGG AGCCCCAGCT 1800 GAGGATGAAG AACAATGAGG AGGCTGAGGA CTATGATGAT GACCTGACTG ACTCTGAGAT 1860 GGATGTGGTG AGGTTTGATG ATGACAACAG CCCCAGCTTC ATCCAGATCA GGTCTGTGGC 1920 CAAGAAGCAC CCCAAGACCT GGGTGCACTA CATTGCTGCT GAGGAGGAGG ACTGGGACTA 1980 TGCCCCCCTG GTGCTGGCCC CTGATGACAG GAGCTACAAG AGCCAGTACC TGAACAATGG 2040 CCCCCAGAGG ATTGGCAGGA AGTACAAGAA GGTCAGGTTC ATGGCCTACA CTGATGAAAC 2100 CTTCAAGACC AGGGAGGCCA TCCAGCATGA GTCTGGCATC CTGGGCCCCC TGCTGTATGG 2160 GGAGGTGGGG GACACCCTGC TGATCATCTT CAAGAACCAG GCCAGCAGGC CCTACAACAT 2220 CTACCCCCAT GGCATCACTG ATGTGAGGCC CCTGTACAGC AGGAGGCTGC CCAAGGGGGT 2280 GAAGCACCTG AAGGACTTCC CCATCCTGCC TGGGGAGATC TTCAAGTACA AGTGGACTGT 2340 GACTGTGGAG GATGGCCCCA CCAAGTCTGA CCCCAGGTGC CTGACCAGAT ACTACAGCAG 2400 CTTTGTGAAC ATGGAGAGGG ACCTGGCCTC TGGCCTGATT GGCCCCCTGC TGATCTGCTA 2460 CAAGGAGTCT GTGGACCAGA GGGGCAACCA GATCATGTCT GACAAGAGGA ATGTGATCCT 2520 GTTCTCTGTG TTTGATGAGA ACAGGAGCTG GTACCTGACT GAGAACATCC AGAGGTTCCT 2580 GCCCAACCCT GCTGGGGTGC AGCTGGAGGA CCCTGAGTTC CAGGCCAGCA ACATCATGCA 2640 CAGCATCAAT GGCTATGTGT TTGACAGCCT GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC 2700 CTACTGGTAC ATCCTGAGCA TTGGGGCCCA GACTGACTTC CTGTCTGTGT TCTTCTCTGG 2760 CTACACCTTC AAGCACAAGA TGGTGTATGA GGACACCCTG ACCCTGTTCC CCTTCTCTGG 2820 GGAGACTGTG TTCATGAGCA TGGAGAACCC TGGCCTGTGG ATTCTGGGCT GCCACAACTC 2880 TGACTTCAGG AACAGGGGCA TGACTGCCCT GCTGAAAGTC TCCAGCTGTG ACAAGAACAC 2940 TGGGGACTAC TATGAGGACA GCTATGAGGA CATCTCTGCC TACCTGCTGA GCAAGAACAA 3000 TGCCATTGAG CCCAGGAGCT TCAGCCAGAA CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA 3060 GATCACCAGG ACCACCCTGC AGTCTGACCA GGAGGAGATT GACTATGATG ACACCATCTC 3120 TGTGGAGATG AAGAAGGAGG ACTTTGACAT CTACGACGAG GACGAGAACC AGAGCCCCAG 3180 GAGCTTCCAG AAGAAGACCA GGCACTACTT CATTGCTGCT GTGGAGAGGC TGTGGGACTA 3240 TGGCATGAGC AGCAGCCCCC ATGTGCTGAG GAACAGGGCC CAGTCTGGCT CTGTGCCCCA 3300 GTTCAAGAAG GTGGTGTTCC AGGAGTTCAC TGATGGCAGC TTCACCCAGC CCCTGTACAG 3360 AGGGGAGCTG AATGAGCACC TGGGCCTGCT GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA 3420 CAACATCATG GTGACCTTCA GGAACCAGGC CAGCAGGCCC TACAGCTTCT ACAGCAGCCT 3480 GATCAGCTAT GAGGAGGACC AGAGGCAGGG GGCTGAGCCC AGGAAGAACT TTGTGAAGCC 3540 CAATGAAACC AAGACCTACT TCTGGAAGGT GCAGCACCAC ATGGCCCCCA CCAAGGATGA 3600 GTTTGACTGC AAGGCCTGGG CCTACTTCTC TGATGTGGAC CTGGAGAAGG ATGTGCACTC 3660 TGGCCTGATT GGCCCCCTGC TGGTGTGCCA CACCAACACC CTGAACCCTG CCCATGGCAG 3720 GCAGGTGACT GTGCAGGAGT TTGCCCTGTT CTTCACCATC TTTGATGAAA CCAAGAGCTG 3780 GTACTTCACT GAGAACATGG AGAGGAACTG CAGGGCCCCC TGCAACATCC AGATGGAGGA 3840 CCCCACCTTC AAGGAGAACT ACAGGTTCCA TGCCATCAAT GGCTACATCA TGGACACCCT 3900 GCCTGGCCTG GTGATGGCCC AGGACCAGAG GATCAGGTGG TACCTGCTGA GCATGGGCAG 3960 CAATGAGAAC ATCCACAGCA TCCACTTCTC TGGCCATGTG TTCACTGTGA GGAAGAAGGA 4020 GGAGTACAAG ATGGCCCTGT ACAACCTGTA CCCTGGGGTG TTTGAGACTG TGGAGATGCT 4080 GCCCAGCAAG GCTGGCATCT GGAGGGTGGA GTGCCTGATT GGGGAGCACC TGCATGCTGG 4140 CATGAGCACC CTGTTCCTGG TGTACAGCAA CAAGTGCCAG ACCCCCCTGG GCATGGCCTC 4200 TGGCCACATC AGGGACTTCC AGATCACTGC CTCTGGCCAG TATGGCCAGT GGGCCCCCAA 4260 GCTGGCCAGG CTGCACTACT CTGGCAGCAT CAATGCCTGG AGCACCAAGG AGCCCTTCAG 4320 CTGGATCAAG GTGGACCTGC TGGCCCCCAT GATCATCCAT GGCATCAAGA CCCAGGGGGC 4380 CAGGCAGAAG TTCAGCAGCC TGTACATCAG CCAGTTCATC ATCATGTACA GCCTGGATGG 4440 CAAGAAGTGG CAGACCTACA GGGGCAACAG CACTGGCACC CTGATGGTGT TCTTTGGCAA 4500 TGTGGACAGC TCTGGCATCA AGCACAACAT CTTCAACCCC CCCATCATTG CCAGATACAT 4560 CAGGCTGCAC CCCACCCACT ACAGCATCAG GAGCACCCTG AGGATGGAGC TGATGGGCTG 4620 TGACCTGAAC AGCTGCAGCA TGCCCCTGGG CATGGAGAGC AAGGCCATCT CTGATGCCCA 4680 GATCACTGCC AGCAGCTACT TCACCAACAT GTTTGCCACC TGGAGCCCCA GCAAGGCCAG 4740 GCTGCACCTG CAGGGCAGGA GCAATGCCTG GAGGCCCCAG GTCAACAACC CCAAGGAGTG 4800 GCTGCAGGTG GACTTCCAGA AGACCATGAA GGTGACTGGG GTGACCACCC AGGGGGTGAA 4860 GAGCCTGCTG ACCAGCATGT ATGTGAAGGA GTTCCTGATC AGCAGCAGCC AGGATGGCCA 4920 CCAGTGGACC CTGTTCTTCC AGAATGGCAA GGTGAAGGTG TTCCAGGGCA ACCAGGACAG 4980 CTTCACCCCT GTGGTGAACA GCCTGGACCC CCCCCTGCTG ACCAGATACC TGAGGATTCA 5040 CCCCCAGAGC TGGGTGCACC AGATTGCCCT GAGGATGGAG GTGCTGGGCT GTGAGGCCCA 5100 GGACCTGTAC TGACCTCGAG GCACTGTCCT TTCCTAATAA AATGAGGAAA TTGCATCGCA 5160 TTGTCTGAGT AGGTGTCATT CTATTCTGGG GGGTGGGGTG GGGCAGGACA GCAAGGGGGA 5220 GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG GGCTCTATGG GCACTCGACA 5280 GGTTAATTTT TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT 5340 GTTTGCTCTG GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA 5400 ACATCCTGGA CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTCA GGTTAATTTT 5460 TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT GTTTGCTCTG 5520 GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA ACATCCTGGA 5580 CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTGT CGAGTGGCGG CCGCAGGAAC 5640 CCCTAGTGAT GGAGTTGGCC ACTCCCTCTC TGCGCGCTCG CTCGCTCACT GAGGCCGGGC 5700 GACCAAAGGT CGCCCGACGC CCGGGCTTTG CCCGGGCGGC CTCAGTGAGC GAGCGAGCGC 5760 GCAGAGAGGG AGTGGCCAA 5779 SEQ ID NO: 22 <211> 5962 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 22 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGTAA GTACTAGCAG CTACAATCCA GCTACCATTC TGCTTTTATT TTATGGTTGG 780 GATAAGGCTG GATTATTCTG AGTCCAAGCT AGGCCCTTTT GCTAATCATG TTCATACCTC 840 TTATCTTCCT CCCACAGCTC CTGGGCAACG TGCTGGTCTG TGTGCTGGCC CATCACTTTG 900 GCAAAGAATT GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT TCCTGTGCCT 960 GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG AGCTGAGCTG 1020 GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC CCCCCAGAGT 1080 GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT TTGTGGAGTT 1140 CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC TGCTGGGCCC 1200 CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA TGGCCAGCCA 1260 CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG GGGCTGAGTA 1320 TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG GGGGCAGCCA 1380 CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC CCCTGTGCCT 1440 GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG GCCTGATTGG 1500 GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA CCCTGCACAA 1560 GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG AAACCAAGAA 1620 CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA TGCACACTGT 1680 GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA AGTCTGTGTA 1740 CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC TGGAGGGCCA 1800 CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA TCACCTTCCT 1860 GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC ACATCAGCAG 1920 CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG AGGAGCCCCA 1980 GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA CTGACTCTGA 2040 GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA TCAGGTCTGT 2100 GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG AGGACTGGGA 2160 CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT ACCTGAACAA 2220 TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT ACACTGATGA 2280 AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC CCCTGCTGTA 2340 TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA GGCCCTACAA 2400 CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC TGCCCAAGGG 2460 GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT ACAAGTGGAC 2520 TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA GATACTACAG 2580 CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC TGCTGATCTG 2640 CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA GGAATGTGAT 2700 CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA TCCAGAGGTT 2760 CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA GCAACATCAT 2820 GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC TGCATGAGGT 2880 GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG TGTTCTTCTC 2940 TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT TCCCCTTCTC 3000 TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG GCTGCCACAA 3060 CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT GTGACAAGAA 3120 CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC TGAGCAAGAA 3180 CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA GGCACCAGAG 3240 GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG ATGACACCAT 3300 CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA ACCAGAGCCC 3360 CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA GGCTGTGGGA 3420 CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG GCTCTGTGCC 3480 CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC AGCCCCTGTA 3540 CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG CTGAGGTGGA 3600 GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT TCTACAGCAG 3660 CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA ACTTTGTGAA 3720 GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC CCACCAAGGA 3780 TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA AGGATGTGCA 3840 CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC CTGCCCATGG 3900 CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG AAACCAAGAG 3960 CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA TCCAGATGGA 4020 GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA TCATGGACAC 4080 CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC TGAGCATGGG 4140 CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG TGAGGAAGAA 4200 GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA CTGTGGAGAT 4260 GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC ACCTGCATGC 4320 TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC TGGGCATGGC 4380 CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC AGTGGGCCCC 4440 CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA AGGAGCCCTT 4500 CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA AGACCCAGGG 4560 GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT ACAGCCTGGA 4620 TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG TGTTCTTTGG 4680 CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA TTGCCAGATA 4740 CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG AGCTGATGGG 4800 CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA TCTCTGATGC 4860 CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC CCAGCAAGGC 4920 CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA ACCCCAAGGA 4980 GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA CCCAGGGGGT 5040 GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA GCCAGGATGG 5100 CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG GCAACCAGGA 5160 CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT ACCTGAGGAT 5220 TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG GCTGTGAGGC 5280 CCAGGACCTG TACTGACCTC GAGGCACTGT CCTTTCCTAA TAAAATGAGG AAATTGCATC 5340 GCATTGTCTG AGTAGGTGTC ATTCTATTCT GGGGGGTGGG GTGGGGCAGG ACAGCAAGGG 5400 GGAGGATTGG GAAGACAATA GCAGGCATGC TGGGGATGCG GTGGGCTCTA TGGGCACTCG 5460 ACAGGTTAAT TTTTAAAAAG CAGTCAAAAG TCCAAGTGGC CCTTGGCAGC ATTTACTCTC 5520 TCTGTTTGCT CTGGTTAATA ATCTCAGGAG CACAAACATT CCTGGAGGCA GGAGAAGAAA 5580 TCAACATCCT GGACTTATCC TCTGGGCCTC TCCCCACCCC CAGGAGAGGC TCAGGTTAAT 5640 TTTTAAAAAG CAGTCAAAAG TCCAAGTGGC CCTTGGCAGC ATTTACTCTC TCTGTTTGCT 5700 CTGGTTAATA ATCTCAGGAG CACAAACATT CCTGGAGGCA GGAGAAGAAA TCAACATCCT 5760 GGACTTATCC TCTGGGCCTC TCCCCACCCC CAGGAGAGGC TGTCGAGTGG CGGCCGCAGG 5820 AACCCCTAGT GATGGAGTTG GCCACTCCCT CTCTGCGCGC TCGCTCGCTC ACTGAGGCCG 5880 GGCGACCAAA GGTCGCCCGA CGCCCGGGCT TTGCCCGGGC GGCCTCAGTG AGCGAGCGAG 5940 CGCGCAGAGA GGGAGTGGCC AA 5962 SEQ ID NO: 23 <211> 5919 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 23 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTA GGCTCAGAGG CACACAGGAG 180 TTTCTGGGCT CACCCTGCCC CCTTCCAACC CCTCAGTTCC CATCCTCCAG CAGCTGTTTG 240 TGTGCTGCCT CTGAAGTCCA CACTGAACAA ACTTCAGCCT ACTCATGTCC CTAAAATGGG 300 CAAACATTGC AAGCAGCAAA CAGCAAACAC ACAGCCCTCC CTGCCTGCTG ACCTTGGAGC 360 TGGGGCAGAG GTCAGAGACC TCTCTGGGCC CATGCCACCT CCAACATCCA CTCGACCCCT 420 TGGAATTTCG GTGGAGAGGA GCAGAGGTTG TCCTGGCGTG GTTTAGGTAG TGTGAGAGGG 480 GTCGACGATC TTGCTACCAG TGGAACAGCC ACTAAGGATT CTGCAGTGAG AGCAGAGGGC 540 CAGCTAAGTG GTACTCTCCC AGAGACTGTC TGACTCACGC CACCCCCTCC ACCTTGGACA 600 CAGGACGCTG TGGTTTCTGA GCCAGGTACA ATGACTCCTT TCGGTAAGTG CAGTGGAAGC 660 TGTACACTGC CCAGGCAAAG CGTCCGGGCA GCGTAGGCGG GCGACTCAGA TCCCAGCCAG 720 TGGACTTAGC CCCTGTTTGC TCCTCCGATA ACTGGGGTGA CCTTGGTTAA TATTCACCAG 780 CAGCCTCCCC CGTTGCCCCT CTGGATCCAC TGCTTAAATA CGGACGAGGA CAGGGCCCTG 840 TCTCCTCAGC TTCAGGCACC ACCACTGACC TGGGACAGTG AATCGTAAGT ATGCCTTTCA 900 CTGCGAGAGG TTCTGGAGAG GCTTCTGAGC TCCCCATGGC CCAGGCAGGC AGCAGGTCTG 960 GGGCAGGAGG GGGGTTGTGG AGTGGGTATC CGCCTGCTGA GGTGCAGGGC AGATCATCAT 1020 GTGCCTTGAC TCGGGGCCTG GCCCCCCCAT CTCTGTCTTG CAGGACAATT GCCGTCTTCT 1080 GTCTCGTGGG GCATCCTCCT GCTGGCAGGC CTGTGCTGCC TGGTCCCTGT CTCCCTGGCT 1140 GAGGACCGGC CACCATGCAG ATTGAGCTGA GCACCTGCTT CTTCCTGTGC CTGCTGAGGT 1200 TCTGCTTCTC TGCCACCAGG AGATACTACC TGGGGGCTGT GGAGCTGAGC TGGGACTACA 1260 TGCAGTCTGA CCTGGGGGAG CTGCCTGTGG ATGCCAGGTT CCCCCCCAGA GTGCCCAAGA 1320 GCTTCCCCTT CAACACCTCT GTGGTGTACA AGAAGACCCT GTTTGTGGAG TTCACTGACC 1380 ACCTGTTCAA CATTGCCAAG CCCAGGCCCC CCTGGATGGG CCTGCTGGGC CCCACCATCC 1440 AGGCTGAGGT GTATGACACT GTGGTGATCA CCCTGAAGAA CATGGCCAGC CACCCTGTGA 1500 GCCTGCATGC TGTGGGGGTG AGCTACTGGA AGGCCTCTGA GGGGGCTGAG TATGATGACC 1560 AGACCAGCCA GAGGGAGAAG GAGGATGACA AGGTGTTCCC TGGGGGCAGC CACACCTATG 1620 TGTGGCAGGT GCTGAAGGAG AATGGCCCCA TGGCCTCTGA CCCCCTGTGC CTGACCTACA 1680 GCTACCTGAG CCATGTGGAC CTGGTGAAGG ACCTGAACTC TGGCCTGATT GGGGCCCTGC 1740 TGGTGTGCAG GGAGGGCAGC CTGGCCAAGG AGAAGACCCA GACCCTGCAC AAGTTCATCC 1800 TGCTGTTTGC TGTGTTTGAT GAGGGCAAGA GCTGGCACTC TGAAACCAAG AACAGCCTGA 1860 TGCAGGACAG GGATGCTGCC TCTGCCAGGG CCTGGCCCAA GATGCACACT GTGAATGGCT 1920 ATGTGAACAG GAGCCTGCCT GGCCTGATTG GCTGCCACAG GAAGTCTGTG TACTGGCATG 1980 TGATTGGCAT GGGCACCACC CCTGAGGTGC ACAGCATCTT CCTGGAGGGC CACACCTTCC 2040 TGGTCAGGAA CCACAGGCAG GCCAGCCTGG AGATCAGCCC CATCACCTTC CTGACTGCCC 2100 AGACCCTGCT GATGGACCTG GGCCAGTTCC TGCTGTTCTG CCACATCAGC AGCCACCAGC 2160 ATGATGGCAT GGAGGCCTAT GTGAAGGTGG ACAGCTGCCC TGAGGAGCCC CAGCTGAGGA 2220 TGAAGAACAA TGAGGAGGCT GAGGACTATG ATGATGACCT GACTGACTCT GAGATGGATG 2280 TGGTGAGGTT TGATGATGAC AACAGCCCCA GCTTCATCCA GATCAGGTCT GTGGCCAAGA 2340 AGCACCCCAA GACCTGGGTG CACTACATTG CTGCTGAGGA GGAGGACTGG GACTATGCCC 2400 CCCTGGTGCT GGCCCCTGAT GACAGGAGCT ACAAGAGCCA GTACCTGAAC AATGGCCCCC 2460 AGAGGATTGG CAGGAAGTAC AAGAAGGTCA GGTTCATGGC CTACACTGAT GAAACCTTCA 2520 AGACCAGGGA GGCCATCCAG CATGAGTCTG GCATCCTGGG CCCCCTGCTG TATGGGGAGG 2580 TGGGGGACAC CCTGCTGATC ATCTTCAAGA ACCAGGCCAG CAGGCCCTAC AACATCTACC 2640 CCCATGGCAT CACTGATGTG AGGCCCCTGT ACAGCAGGAG GCTGCCCAAG GGGGTGAAGC 2700 ACCTGAAGGA CTTCCCCATC CTGCCTGGGG AGATCTTCAA GTACAAGTGG ACTGTGACTG 2760 TGGAGGATGG CCCCACCAAG TCTGACCCCA GGTGCCTGAC CAGATACTAC AGCAGCTTTG 2820 TGAACATGGA GAGGGACCTG GCCTCTGGCC TGATTGGCCC CCTGCTGATC TGCTACAAGG 2880 AGTCTGTGGA CCAGAGGGGC AACCAGATCA TGTCTGACAA GAGGAATGTG ATCCTGTTCT 2940 CTGTGTTTGA TGAGAACAGG AGCTGGTACC TGACTGAGAA CATCCAGAGG TTCCTGCCCA 3000 ACCCTGCTGG GGTGCAGCTG GAGGACCCTG AGTTCCAGGC CAGCAACATC ATGCACAGCA 3060 TCAATGGCTA TGTGTTTGAC AGCCTGCAGC TGTCTGTGTG CCTGCATGAG GTGGCCTACT 3120 GGTACATCCT GAGCATTGGG GCCCAGACTG ACTTCCTGTC TGTGTTCTTC TCTGGCTACA 3180 CCTTCAAGCA CAAGATGGTG TATGAGGACA CCCTGACCCT GTTCCCCTTC TCTGGGGAGA 3240 CTGTGTTCAT GAGCATGGAG AACCCTGGCC TGTGGATTCT GGGCTGCCAC AACTCTGACT 3300 TCAGGAACAG GGGCATGACT GCCCTGCTGA AAGTCTCCAG CTGTGACAAG AACACTGGGG 3360 ACTACTATGA GGACAGCTAT GAGGACATCT CTGCCTACCT GCTGAGCAAG AACAATGCCA 3420 TTGAGCCCAG GAGCTTCAGC CAGAACCCCC CAGTGCTGAA GAGGCACCAG AGGGAGATCA 3480 CCAGGACCAC CCTGCAGTCT GACCAGGAGG AGATTGACTA TGATGACACC ATCTCTGTGG 3540 AGATGAAGAA GGAGGACTTT GACATCTACG ACGAGGACGA GAACCAGAGC CCCAGGAGCT 3600 TCCAGAAGAA GACCAGGCAC TACTTCATTG CTGCTGTGGA GAGGCTGTGG GACTATGGCA 3660 TGAGCAGCAG CCCCCATGTG CTGAGGAACA GGGCCCAGTC TGGCTCTGTG CCCCAGTTCA 3720 AGAAGGTGGT GTTCCAGGAG TTCACTGATG GCAGCTTCAC CCAGCCCCTG TACAGAGGGG 3780 AGCTGAATGA GCACCTGGGC CTGCTGGGCC CCTACATCAG GGCTGAGGTG GAGGACAACA 3840 TCATGGTGAC CTTCAGGAAC CAGGCCAGCA GGCCCTACAG CTTCTACAGC AGCCTGATCA 3900 GCTATGAGGA GGACCAGAGG CAGGGGGCTG AGCCCAGGAA GAACTTTGTG AAGCCCAATG 3960 AAACCAAGAC CTACTTCTGG AAGGTGCAGC ACCACATGGC CCCCACCAAG GATGAGTTTG 4020 ACTGCAAGGC CTGGGCCTAC TTCTCTGATG TGGACCTGGA GAAGGATGTG CACTCTGGCC 4080 TGATTGGCCC CCTGCTGGTG TGCCACACCA ACACCCTGAA CCCTGCCCAT GGCAGGCAGG 4140 TGACTGTGCA GGAGTTTGCC CTGTTCTTCA CCATCTTTGA TGAAACCAAG AGCTGGTACT 4200 TCACTGAGAA CATGGAGAGG AACTGCAGGG CCCCCTGCAA CATCCAGATG GAGGACCCCA 4260 CCTTCAAGGA GAACTACAGG TTCCATGCCA TCAATGGCTA CATCATGGAC ACCCTGCCTG 4320 GCCTGGTGAT GGCCCAGGAC CAGAGGATCA GGTGGTACCT GCTGAGCATG GGCAGCAATG 4380 AGAACATCCA CAGCATCCAC TTCTCTGGCC ATGTGTTCAC TGTGAGGAAG AAGGAGGAGT 4440 ACAAGATGGC CCTGTACAAC CTGTACCCTG GGGTGTTTGA GACTGTGGAG ATGCTGCCCA 4500 GCAAGGCTGG CATCTGGAGG GTGGAGTGCC TGATTGGGGA GCACCTGCAT GCTGGCATGA 4560 GCACCCTGTT CCTGGTGTAC AGCAACAAGT GCCAGACCCC CCTGGGCATG GCCTCTGGCC 4620 ACATCAGGGA CTTCCAGATC ACTGCCTCTG GCCAGTATGG CCAGTGGGCC CCCAAGCTGG 4680 CCAGGCTGCA CTACTCTGGC AGCATCAATG CCTGGAGCAC CAAGGAGCCC TTCAGCTGGA 4740 TCAAGGTGGA CCTGCTGGCC CCCATGATCA TCCATGGCAT CAAGACCCAG GGGGCCAGGC 4800 AGAAGTTCAG CAGCCTGTAC ATCAGCCAGT TCATCATCAT GTACAGCCTG GATGGCAAGA 4860 AGTGGCAGAC CTACAGGGGC AACAGCACTG GCACCCTGAT GGTGTTCTTT GGCAATGTGG 4920 ACAGCTCTGG CATCAAGCAC AACATCTTCA ACCCCCCCAT CATTGCCAGA TACATCAGGC 4980 TGCACCCCAC CCACTACAGC ATCAGGAGCA CCCTGAGGAT GGAGCTGATG GGCTGTGACC 5040 TGAACAGCTG CAGCATGCCC CTGGGCATGG AGAGCAAGGC CATCTCTGAT GCCCAGATCA 5100 CTGCCAGCAG CTACTTCACC AACATGTTTG CCACCTGGAG CCCCAGCAAG GCCAGGCTGC 5160 ACCTGCAGGG CAGGAGCAAT GCCTGGAGGC CCCAGGTCAA CAACCCCAAG GAGTGGCTGC 5220 AGGTGGACTT CCAGAAGACC ATGAAGGTGA CTGGGGTGAC CACCCAGGGG GTGAAGAGCC 5280 TGCTGACCAG CATGTATGTG AAGGAGTTCC TGATCAGCAG CAGCCAGGAT GGCCACCAGT 5340 GGACCCTGTT CTTCCAGAAT GGCAAGGTGA AGGTGTTCCA GGGCAACCAG GACAGCTTCA 5400 CCCCTGTGGT GAACAGCCTG GACCCCCCCC TGCTGACCAG ATACCTGAGG ATTCACCCCC 5460 AGAGCTGGGT GCACCAGATT GCCCTGAGGA TGGAGGTGCT GGGCTGTGAG GCCCAGGACC 5520 TGTACTGAGC TCGAGCTGTG CCTTCTAGTT GCCAGCCATC TGTTGTTTGC CCCTCCCCCG 5580 TGCCTTCCTT GACCCTGGAA GGTGCCACTC CCACTGTCCT TTCCTAATAA AATGAGGAAA 5640 TTGCATCGCA TTGTCTGAGT AGGTGTCATT CTATTCTGGG GGGTGGGGTG GGGCAGGACA 5700 GCAAGGGGGA GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG GGCTCTATGG 5760 ACCGGTGCGG CCGCAGGAAC CCCTAGTGAT GGAGTTGGCC ACTCCCTCTC TGCGCGCTCG 5820 CTCGCTCACT GAGGCCGGGC GACCAAAGGT CGCCCGACGC CCGGGCTTTG CCCGGGCGGC 5880 CTCAGTGAGC GAGCGAGCGC GCAGAGAGGG AGTGGCCAA 5919 SEQ ID NO: 24 <211> 5306 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 24 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTAAACGT CGACCCTAAA 180 ATGGGCAAAC ATTGCAAGCA GCAAACAGCA AACTGACCTT GGAGCTGGGG CAGAGGTCAG 240 AGACCTCTCT GGGCACTCGA CCCCTTGGAA TTTCGGTGGA GAGGAGCAGA GGTACACAGC 300 CCTCCCTGCC TGCCCCATGC CACCTCCAAC ATCTGTCCTG GCGTGGTTTA GGTAGTGTGA 360 GAGGGGAATG ACTCCTTTCG GTAAGTGCAG TGGAAGCTGT ACACTGCCCA GGCAAAGCGT 420 CCGGGCAGCG TAGGCGGGCG ACTCAGATCC CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC 480 TCCGATAACT GGGGTGACCT TGGTTAATAT TCACCAGCAG CCTCCCCCGT TGCCCCTCTG 540 GATCCACTGC TTAAATACGG ACGAGGACAG GGCCCTGTCT CCTCAGCTTC AGGCACCACC 600 ACTGACCTGG GACAGTGAAT CGCGATCGCA CTGCTTAAAT ACGGACGAGG ACAGGGCCCT 660 GTCTCCTCAG CTTCAGGCAC CACCACTGAC CTGGGACAGT GAATCGCGAT CGCCACCATG 720 CAGATTGAGC TGAGCACCTG CTTCTTCCTG TGCCTGCTGA GGTTCTGCTT CTCTGCCACC 780 AGGAGATACT ACCTGGGGGC TGTGGAGCTG AGCTGGGACT ACATGCAGTC TGACCTGGGG 840 GAGCTGCCTG TGGATGCCAG GTTCCCCCCC AGAGTGCCCA AGAGCTTCCC CTTCAACACC 900 TCTGTGGTGT ACAAGAAGAC CCTGTTTGTG GAGTTCACTG ACCACCTGTT CAACATTGCC 960 AAGCCCAGGC CCCCCTGGAT GGGCCTGCTG GGCCCCACCA TCCAGGCTGA GGTGTATGAC 1020 ACTGTGGTGA TCACCCTGAA GAACATGGCC AGCCACCCTG TGAGCCTGCA TGCTGTGGGG 1080 GTGAGCTACT GGAAGGCCTC TGAGGGGGCT GAGTATGATG ACCAGACCAG CCAGAGGGAG 1140 AAGGAGGATG ACAAGGTGTT CCCTGGGGGC AGCCACACCT ATGTGTGGCA GGTGCTGAAG 1200 GAGAATGGCC CCATGGCCTC TGACCCCCTG TGCCTGACCT ACAGCTACCT GAGCCATGTG 1260 GACCTGGTGA AGGACCTGAA CTCTGGCCTG ATTGGGGCCC TGCTGGTGTG CAGGGAGGGC 1320 AGCCTGGCCA AGGAGAAGAC CCAGACCCTG CACAAGTTCA TCCTGCTGTT TGCTGTGTTT 1380 GATGAGGGCA AGAGCTGGCA CTCTGAAACC AAGAACAGCC TGATGCAGGA CAGGGATGCT 1440 GCCTCTGCCA GGGCCTGGCC CAAGATGCAC ACTGTGAATG GCTATGTGAA CAGGAGCCTG 1500 CCTGGCCTGA TTGGCTGCCA CAGGAAGTCT GTGTACTGGC ATGTGATTGG CATGGGCACC 1560 ACCCCTGAGG TGCACAGCAT CTTCCTGGAG GGCCACACCT TCCTGGTCAG GAACCACAGG 1620 CAGGCCAGCC TGGAGATCAG CCCCATCACC TTCCTGACTG CCCAGACCCT GCTGATGGAC 1680 CTGGGCCAGT TCCTGCTGTT CTGCCACATC AGCAGCCACC AGCATGATGG CATGGAGGCC 1740 TATGTGAAGG TGGACAGCTG CCCTGAGGAG CCCCAGCTGA GGATGAAGAA CAATGAGGAG 1800 GCTGAGGACT ATGATGATGA CCTGACTGAC TCTGAGATGG ATGTGGTGAG GTTTGATGAT 1860 GACAACAGCC CCAGCTTCAT CCAGATCAGG TCTGTGGCCA AGAAGCACCC CAAGACCTGG 1920 GTGCACTACA TTGCTGCTGA GGAGGAGGAC TGGGACTATG CCCCCCTGGT GCTGGCCCCT 1980 GATGACAGGA GCTACAAGAG CCAGTACCTG AACAATGGCC CCCAGAGGAT TGGCAGGAAG 2040 TACAAGAAGG TCAGGTTCAT GGCCTACACT GATGAAACCT TCAAGACCAG GGAGGCCATC 2100 CAGCATGAGT CTGGCATCCT GGGCCCCCTG CTGTATGGGG AGGTGGGGGA CACCCTGCTG 2160 ATCATCTTCA AGAACCAGGC CAGCAGGCCC TACAACATCT ACCCCCATGG CATCACTGAT 2220 GTGAGGCCCC TGTACAGCAG GAGGCTGCCC AAGGGGGTGA AGCACCTGAA GGACTTCCCC 2280 ATCCTGCCTG GGGAGATCTT CAAGTACAAG TGGACTGTGA CTGTGGAGGA TGGCCCCACC 2340 AAGTCTGACC CCAGGTGCCT GACCAGATAC TACAGCAGCT TTGTGAACAT GGAGAGGGAC 2400 CTGGCCTCTG GCCTGATTGG CCCCCTGCTG ATCTGCTACA AGGAGTCTGT GGACCAGAGG 2460 GGCAACCAGA TCATGTCTGA CAAGAGGAAT GTGATCCTGT TCTCTGTGTT TGATGAGAAC 2520 AGGAGCTGGT ACCTGACTGA GAACATCCAG AGGTTCCTGC CCAACCCTGC TGGGGTGCAG 2580 CTGGAGGACC CTGAGTTCCA GGCCAGCAAC ATCATGCACA GCATCAATGG CTATGTGTTT 2640 GACAGCCTGC AGCTGTCTGT GTGCCTGCAT GAGGTGGCCT ACTGGTACAT CCTGAGCATT 2700 GGGGCCCAGA CTGACTTCCT GTCTGTGTTC TTCTCTGGCT ACACCTTCAA GCACAAGATG 2760 GTGTATGAGG ACACCCTGAC CCTGTTCCCC TTCTCTGGGG AGACTGTGTT CATGAGCATG 2820 GAGAACCCTG GCCTGTGGAT TCTGGGCTGC CACAACTCTG ACTTCAGGAA CAGGGGCATG 2880 ACTGCCCTGC TGAAAGTCTC CAGCTGTGAC AAGAACACTG GGGACTACTA TGAGGACAGC 2940 TATGAGGACA TCTCTGCCTA CCTGCTGAGC AAGAACAATG CCATTGAGCC CAGGAGCTTC 3000 AGCCAGAACC CCCCAGTGCT GAAGAGGCAC CAGAGGGAGA TCACCAGGAC CACCCTGCAG 3060 TCTGACCAGG AGGAGATTGA CTATGATGAC ACCATCTCTG TGGAGATGAA GAAGGAGGAC 3120 TTTGACATCT ACGACGAGGA CGAGAACCAG AGCCCCAGGA GCTTCCAGAA GAAGACCAGG 3180 CACTACTTCA TTGCTGCTGT GGAGAGGCTG TGGGACTATG GCATGAGCAG CAGCCCCCAT 3240 GTGCTGAGGA ACAGGGCCCA GTCTGGCTCT GTGCCCCAGT TCAAGAAGGT GGTGTTCCAG 3300 GAGTTCACTG ATGGCAGCTT CACCCAGCCC CTGTACAGAG GGGAGCTGAA TGAGCACCTG 3360 GGCCTGCTGG GCCCCTACAT CAGGGCTGAG GTGGAGGACA ACATCATGGT GACCTTCAGG 3420 AACCAGGCCA GCAGGCCCTA CAGCTTCTAC AGCAGCCTGA TCAGCTATGA GGAGGACCAG 3480 AGGCAGGGGG CTGAGCCCAG GAAGAACTTT GTGAAGCCCA ATGAAACCAA GACCTACTTC 3540 TGGAAGGTGC AGCACCACAT GGCCCCCACC AAGGATGAGT TTGACTGCAA GGCCTGGGCC 3600 TACTTCTCTG ATGTGGACCT GGAGAAGGAT GTGCACTCTG GCCTGATTGG CCCCCTGCTG 3660 GTGTGCCACA CCAACACCCT GAACCCTGCC CATGGCAGGC AGGTGACTGT GCAGGAGTTT 3720 GCCCTGTTCT TCACCATCTT TGATGAAACC AAGAGCTGGT ACTTCACTGA GAACATGGAG 3780 AGGAACTGCA GGGCCCCCTG CAACATCCAG ATGGAGGACC CCACCTTCAA GGAGAACTAC 3840 AGGTTCCATG CCATCAATGG CTACATCATG GACACCCTGC CTGGCCTGGT GATGGCCCAG 3900 GACCAGAGGA TCAGGTGGTA CCTGCTGAGC ATGGGCAGCA ATGAGAACAT CCACAGCATC 3960 CACTTCTCTG GCCATGTGTT CACTGTGAGG AAGAAGGAGG AGTACAAGAT GGCCCTGTAC 4020 AACCTGTACC CTGGGGTGTT TGAGACTGTG GAGATGCTGC CCAGCAAGGC TGGCATCTGG 4080 AGGGTGGAGT GCCTGATTGG GGAGCACCTG CATGCTGGCA TGAGCACCCT GTTCCTGGTG 4140 TACAGCAACA AGTGCCAGAC CCCCCTGGGC ATGGCCTCTG GCCACATCAG GGACTTCCAG 4200 ATCACTGCCT CTGGCCAGTA TGGCCAGTGG GCCCCCAAGC TGGCCAGGCT GCACTACTCT 4260 GGCAGCATCA ATGCCTGGAG CACCAAGGAG CCCTTCAGCT GGATCAAGGT GGACCTGCTG 4320 GCCCCCATGA TCATCCATGG CATCAAGACC CAGGGGGCCA GGCAGAAGTT CAGCAGCCTG 4380 TACATCAGCC AGTTCATCAT CATGTACAGC CTGGATGGCA AGAAGTGGCA GACCTACAGG 4440 GGCAACAGCA CTGGCACCCT GATGGTGTTC TTTGGCAATG TGGACAGCTC TGGCATCAAG 4500 CACAACATCT TCAACCCCCC CATCATTGCC AGATACATCA GGCTGCACCC CACCCACTAC 4560 AGCATCAGGA GCACCCTGAG GATGGAGCTG ATGGGCTGTG ACCTGAACAG CTGCAGCATG 4620 CCCCTGGGCA TGGAGAGCAA GGCCATCTCT GATGCCCAGA TCACTGCCAG CAGCTACTTC 4680 ACCAACATGT TTGCCACCTG GAGCCCCAGC AAGGCCAGGC TGCACCTGCA GGGCAGGAGC 4740 AATGCCTGGA GGCCCCAGGT CAACAACCCC AAGGAGTGGC TGCAGGTGGA CTTCCAGAAG 4800 ACCATGAAGG TGACTGGGGT GACCACCCAG GGGGTGAAGA GCCTGCTGAC CAGCATGTAT 4860 GTGAAGGAGT TCCTGATCAG CAGCAGCCAG GATGGCCACC AGTGGACCCT GTTCTTCCAG 4920 AATGGCAAGG TGAAGGTGTT CCAGGGCAAC CAGGACAGCT TCACCCCTGT GGTGAACAGC 4980 CTGGACCCCC CCCTGCTGAC CAGATACCTG AGGATTCACC CCCAGAGCTG GGTGCACCAG 5040 ATTGCCCTGA GGATGGAGGT GCTGGGCTGT GAGGCCCAGG ACCTGTACTG ACCTCGAGGA 5100 ATAAAGGAAA TTTATTTTCA TTGCAATAGT GTGTTGGTTT TTTGTGTCAC GTGGCGGCCG 5160 CAGGAACCCC TAGTGATGGA GTTGGCCACT CCCTCTCTGC GCGCTCGCTC GCTCACTGAG 5220 GCCGGGCGAC CAAAGGTCGC CCGACGCCCG GGCTTTGCCC GGGCGGCCTC AGTGAGCGAG 5280 CGAGCGCGCA GAGAGGGAGT GGCCAA 5306 SEQ ID NO: 25 <211> 5461 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 25 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTT TATTTGCCAC 180 AAAAACCCTA TCAGATGGGC GTCTTTATCA TTTCCATTGT ACAGATGGGG AAACAGGCTT 240 CGGGGTCGGG GCATAGCCAC TTACTGACGA CTCCCCACCC AGCAAGTGGT TTTGAACCCG 300 GACCCTCTCA CACTACCTAA ACCACGCCAG GACAACCTCT GCTCCTCTCC ACCGAAATTC 360 CAAGGGGTCG AGTGGATGTT GGAGGTGGCA TGGGCCCAGA GAGGTCTCTG ACCTCTGCCC 420 CAGCTCCAAG GTCAGCAGGC AGGGAGGGCT GTGTGTTTGC TGTTTGCTGC TTGCAATGTT 480 TGCCCATTTT AGGGACATGA GTAGGCTGAA GTTTGTTCAG TGTGGACTTC AGAGGCAGCA 540 CACAAACAGC TGCTGGAGGA TGGGAACTGA GGGGTTGGAA GGGGGCAGGG TGAGCCCAGA 600 AACTCCTGTG TGCCTCTGAG CCTGCAGACG CGAAACGTCG ACTGGACACA GGACGCTGTG 660 GTTTCTGAGC CAGGGGGCGA CTCAGATCCC AGCCAGTGGA CTTAGCCCCT GTTTGCTCCT 720 CCGATAACTG GGGTGACCTT GGTTAATATT CACCAGCAGC CTCCCCCGTT GCCCCTCTGG 780 ATCCACTGCT TAAATACGGA CGAGGACAGG GCCCTGTCTC CTCAGCTTCA GGCACCACCA 840 CTGACCTGGG ACAGTGAATC GCGATCGCCA CCATGCAGAT TGAGCTGAGC ACCTGCTTCT 900 TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG CCACCAGGAG ATACTACCTG GGGGCTGTGG 960 AGCTGAGCTG GGACTACATG CAGTCTGACC TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC 1020 CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA ACACCTCTGT GGTGTACAAG AAGACCCTGT 1080 TTGTGGAGTT CACTGACCAC CTGTTCAACA TTGCCAAGCC CAGGCCCCCC TGGATGGGCC 1140 TGCTGGGCCC CACCATCCAG GCTGAGGTGT ATGACACTGT GGTGATCACC CTGAAGAACA 1200 TGGCCAGCCA CCCTGTGAGC CTGCATGCTG TGGGGGTGAG CTACTGGAAG GCCTCTGAGG 1260 GGGCTGAGTA TGATGACCAG ACCAGCCAGA GGGAGAAGGA GGATGACAAG GTGTTCCCTG 1320 GGGGCAGCCA CACCTATGTG TGGCAGGTGC TGAAGGAGAA TGGCCCCATG GCCTCTGACC 1380 CCCTGTGCCT GACCTACAGC TACCTGAGCC ATGTGGACCT GGTGAAGGAC CTGAACTCTG 1440 GCCTGATTGG GGCCCTGCTG GTGTGCAGGG AGGGCAGCCT GGCCAAGGAG AAGACCCAGA 1500 CCCTGCACAA GTTCATCCTG CTGTTTGCTG TGTTTGATGA GGGCAAGAGC TGGCACTCTG 1560 AAACCAAGAA CAGCCTGATG CAGGACAGGG ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA 1620 TGCACACTGT GAATGGCTAT GTGAACAGGA GCCTGCCTGG CCTGATTGGC TGCCACAGGA 1680 AGTCTGTGTA CTGGCATGTG ATTGGCATGG GCACCACCCC TGAGGTGCAC AGCATCTTCC 1740 TGGAGGGCCA CACCTTCCTG GTCAGGAACC ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA 1800 TCACCTTCCT GACTGCCCAG ACCCTGCTGA TGGACCTGGG CCAGTTCCTG CTGTTCTGCC 1860 ACATCAGCAG CCACCAGCAT GATGGCATGG AGGCCTATGT GAAGGTGGAC AGCTGCCCTG 1920 AGGAGCCCCA GCTGAGGATG AAGAACAATG AGGAGGCTGA GGACTATGAT GATGACCTGA 1980 CTGACTCTGA GATGGATGTG GTGAGGTTTG ATGATGACAA CAGCCCCAGC TTCATCCAGA 2040 TCAGGTCTGT GGCCAAGAAG CACCCCAAGA CCTGGGTGCA CTACATTGCT GCTGAGGAGG 2100 AGGACTGGGA CTATGCCCCC CTGGTGCTGG CCCCTGATGA CAGGAGCTAC AAGAGCCAGT 2160 ACCTGAACAA TGGCCCCCAG AGGATTGGCA GGAAGTACAA GAAGGTCAGG TTCATGGCCT 2220 ACACTGATGA AACCTTCAAG ACCAGGGAGG CCATCCAGCA TGAGTCTGGC ATCCTGGGCC 2280 CCCTGCTGTA TGGGGAGGTG GGGGACACCC TGCTGATCAT CTTCAAGAAC CAGGCCAGCA 2340 GGCCCTACAA CATCTACCCC CATGGCATCA CTGATGTGAG GCCCCTGTAC AGCAGGAGGC 2400 TGCCCAAGGG GGTGAAGCAC CTGAAGGACT TCCCCATCCT GCCTGGGGAG ATCTTCAAGT 2460 ACAAGTGGAC TGTGACTGTG GAGGATGGCC CCACCAAGTC TGACCCCAGG TGCCTGACCA 2520 GATACTACAG CAGCTTTGTG AACATGGAGA GGGACCTGGC CTCTGGCCTG ATTGGCCCCC 2580 TGCTGATCTG CTACAAGGAG TCTGTGGACC AGAGGGGCAA CCAGATCATG TCTGACAAGA 2640 GGAATGTGAT CCTGTTCTCT GTGTTTGATG AGAACAGGAG CTGGTACCTG ACTGAGAACA 2700 TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG TGCAGCTGGA GGACCCTGAG TTCCAGGCCA 2760 GCAACATCAT GCACAGCATC AATGGCTATG TGTTTGACAG CCTGCAGCTG TCTGTGTGCC 2820 TGCATGAGGT GGCCTACTGG TACATCCTGA GCATTGGGGC CCAGACTGAC TTCCTGTCTG 2880 TGTTCTTCTC TGGCTACACC TTCAAGCACA AGATGGTGTA TGAGGACACC CTGACCCTGT 2940 TCCCCTTCTC TGGGGAGACT GTGTTCATGA GCATGGAGAA CCCTGGCCTG TGGATTCTGG 3000 GCTGCCACAA CTCTGACTTC AGGAACAGGG GCATGACTGC CCTGCTGAAA GTCTCCAGCT 3060 GTGACAAGAA CACTGGGGAC TACTATGAGG ACAGCTATGA GGACATCTCT GCCTACCTGC 3120 TGAGCAAGAA CAATGCCATT GAGCCCAGGA GCTTCAGCCA GAACCCCCCA GTGCTGAAGA 3180 GGCACCAGAG GGAGATCACC AGGACCACCC TGCAGTCTGA CCAGGAGGAG ATTGACTATG 3240 ATGACACCAT CTCTGTGGAG ATGAAGAAGG AGGACTTTGA CATCTACGAC GAGGACGAGA 3300 ACCAGAGCCC CAGGAGCTTC CAGAAGAAGA CCAGGCACTA CTTCATTGCT GCTGTGGAGA 3360 GGCTGTGGGA CTATGGCATG AGCAGCAGCC CCCATGTGCT GAGGAACAGG GCCCAGTCTG 3420 GCTCTGTGCC CCAGTTCAAG AAGGTGGTGT TCCAGGAGTT CACTGATGGC AGCTTCACCC 3480 AGCCCCTGTA CAGAGGGGAG CTGAATGAGC ACCTGGGCCT GCTGGGCCCC TACATCAGGG 3540 CTGAGGTGGA GGACAACATC ATGGTGACCT TCAGGAACCA GGCCAGCAGG CCCTACAGCT 3600 TCTACAGCAG CCTGATCAGC TATGAGGAGG ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA 3660 ACTTTGTGAA GCCCAATGAA ACCAAGACCT ACTTCTGGAA GGTGCAGCAC CACATGGCCC 3720 CCACCAAGGA TGAGTTTGAC TGCAAGGCCT GGGCCTACTT CTCTGATGTG GACCTGGAGA 3780 AGGATGTGCA CTCTGGCCTG ATTGGCCCCC TGCTGGTGTG CCACACCAAC ACCCTGAACC 3840 CTGCCCATGG CAGGCAGGTG ACTGTGCAGG AGTTTGCCCT GTTCTTCACC ATCTTTGATG 3900 AAACCAAGAG CTGGTACTTC ACTGAGAACA TGGAGAGGAA CTGCAGGGCC CCCTGCAACA 3960 TCCAGATGGA GGACCCCACC TTCAAGGAGA ACTACAGGTT CCATGCCATC AATGGCTACA 4020 TCATGGACAC CCTGCCTGGC CTGGTGATGG CCCAGGACCA GAGGATCAGG TGGTACCTGC 4080 TGAGCATGGG CAGCAATGAG AACATCCACA GCATCCACTT CTCTGGCCAT GTGTTCACTG 4140 TGAGGAAGAA GGAGGAGTAC AAGATGGCCC TGTACAACCT GTACCCTGGG GTGTTTGAGA 4200 CTGTGGAGAT GCTGCCCAGC AAGGCTGGCA TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC 4260 ACCTGCATGC TGGCATGAGC ACCCTGTTCC TGGTGTACAG CAACAAGTGC CAGACCCCCC 4320 TGGGCATGGC CTCTGGCCAC ATCAGGGACT TCCAGATCAC TGCCTCTGGC CAGTATGGCC 4380 AGTGGGCCCC CAAGCTGGCC AGGCTGCACT ACTCTGGCAG CATCAATGCC TGGAGCACCA 4440 AGGAGCCCTT CAGCTGGATC AAGGTGGACC TGCTGGCCCC CATGATCATC CATGGCATCA 4500 AGACCCAGGG GGCCAGGCAG AAGTTCAGCA GCCTGTACAT CAGCCAGTTC ATCATCATGT 4560 ACAGCCTGGA TGGCAAGAAG TGGCAGACCT ACAGGGGCAA CAGCACTGGC ACCCTGATGG 4620 TGTTCTTTGG CAATGTGGAC AGCTCTGGCA TCAAGCACAA CATCTTCAAC CCCCCCATCA 4680 TTGCCAGATA CATCAGGCTG CACCCCACCC ACTACAGCAT CAGGAGCACC CTGAGGATGG 4740 AGCTGATGGG CTGTGACCTG AACAGCTGCA GCATGCCCCT GGGCATGGAG AGCAAGGCCA 4800 TCTCTGATGC CCAGATCACT GCCAGCAGCT ACTTCACCAA CATGTTTGCC ACCTGGAGCC 4860 CCAGCAAGGC CAGGCTGCAC CTGCAGGGCA GGAGCAATGC CTGGAGGCCC CAGGTCAACA 4920 ACCCCAAGGA GTGGCTGCAG GTGGACTTCC AGAAGACCAT GAAGGTGACT GGGGTGACCA 4980 CCCAGGGGGT GAAGAGCCTG CTGACCAGCA TGTATGTGAA GGAGTTCCTG ATCAGCAGCA 5040 GCCAGGATGG CCACCAGTGG ACCCTGTTCT TCCAGAATGG CAAGGTGAAG GTGTTCCAGG 5100 GCAACCAGGA CAGCTTCACC CCTGTGGTGA ACAGCCTGGA CCCCCCCCTG CTGACCAGAT 5160 ACCTGAGGAT TCACCCCCAG AGCTGGGTGC ACCAGATTGC CCTGAGGATG GAGGTGCTGG 5220 GCTGTGAGGC CCAGGACCTG TACTGACCTC GAGGAATAAA GGAAATTTAT TTTCATTGCA 5280 ATAGTGTGTT GGTTTTTTGT GTCACGTGGC GGCCGCAGGA ACCCCTAGTG ATGGAGTTGG 5340 CCACTCCCTC TCTGCGCGCT CGCTCGCTCA CTGAGGCCGG GCGACCAAAG GTCGCCCGAC 5400 GCCCGGGCTT TGCCCGGGCG GCCTCAGTGA GCGAGCGAGC GCGCAGAGAG GGAGTGGCCA 5460 A 5461 SEQ ID NO: 26 <211> 5327 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 26 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT GTGCCTGCTG 780 AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT GAGCTGGGAC 840 TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC CAGAGTGCCC 900 AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT GGAGTTCACT 960 GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT GGGCCCCACC 1020 ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC CAGCCACCCT 1080 GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC TGAGTATGAT 1140 GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG CAGCCACACC 1200 TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT GTGCCTGACC 1260 TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT GATTGGGGCC 1320 CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT GCACAAGTTC 1380 ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC CAAGAACAGC 1440 CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA CACTGTGAAT 1500 GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC TGTGTACTGG 1560 CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA GGGCCACACC 1620 TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC CTTCCTGACT 1680 GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT CAGCAGCCAC 1740 CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA GCCCCAGCTG 1800 AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA CTCTGAGATG 1860 GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG GTCTGTGGCC 1920 AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA CTGGGACTAT 1980 GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT GAACAATGGC 2040 CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC TGATGAAACC 2100 TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT GCTGTATGGG 2160 GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC CTACAACATC 2220 TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC CAAGGGGGTG 2280 AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA GTGGACTGTG 2340 ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA CTACAGCAGC 2400 TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT GATCTGCTAC 2460 AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA TGTGATCCTG 2520 TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA GAGGTTCCTG 2580 CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA CATCATGCAC 2640 AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA TGAGGTGGCC 2700 TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT CTTCTCTGGC 2760 TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC CTTCTCTGGG 2820 GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG CCACAACTCT 2880 GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA CAAGAACACT 2940 GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG CAAGAACAAT 3000 GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA CCAGAGGGAG 3060 ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA CACCATCTCT 3120 GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA GAGCCCCAGG 3180 AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT GTGGGACTAT 3240 GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC TGTGCCCCAG 3300 TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC CCTGTACAGA 3360 GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA GGTGGAGGAC 3420 AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA CAGCAGCCTG 3480 ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT TGTGAAGCCC 3540 AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC CAAGGATGAG 3600 TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA TGTGCACTCT 3660 GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC CCATGGCAGG 3720 CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC CAAGAGCTGG 3780 TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA GATGGAGGAC 3840 CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT GGACACCCTG 3900 CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG CATGGGCAGC 3960 AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG GAAGAAGGAG 4020 GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT GGAGATGCTG 4080 CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT GCATGCTGGC 4140 ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG CATGGCCTCT 4200 GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG GGCCCCCAAG 4260 CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA GCCCTTCAGC 4320 TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC CCAGGGGGCC 4380 AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG CCTGGATGGC 4440 AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT CTTTGGCAAT 4500 GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC CAGATACATC 4560 AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT GATGGGCTGT 4620 GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC TGATGCCCAG 4680 ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG CAAGGCCAGG 4740 CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC CAAGGAGTGG 4800 CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA GGGGGTGAAG 4860 AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA GGATGGCCAC 4920 CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA CCAGGACAGC 4980 TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT GAGGATTCAC 5040 CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG TGAGGCCCAG 5100 GACCTGTACT GACCTCGAGG AATAAAGGAA ATTTATTTTC ATTGCAATAG TGTGTTGGTT 5160 TTTTGTGTCA CGTGGCGGCC GCAGGAACCC CTAGTGATGG AGTTGGCCAC TCCCTCTCTG 5220 CGCGCTCGCT CGCTCACTGA GGCCGGGCGA CCAAAGGTCG CCCGACGCCC GGGCTTTGCC 5280 CGGGCGGCCT CAGTGAGCGA GCGAGCGCGC AGAGAGGGAG TGGCCAA 5327 SEQ ID NO: 27 <211> 5309 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 27 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTC TGCAGGCTCA GAGGCACACA 180 GGAGTTTCTG GGCTCACCCT GCCCCCTTCC AACCCCTCAG TTCCCATCCT CCAGCAGCTG 240 TTTGTGTGCT GCCTCTGAAG TCCACACTGA ACAAACTTCA GCCTACTCAT GTCCCTAAAA 300 TGGGCAAACA TTGCAAGCAG CAAACAGCAA ACACACAGCC CTCCCTGCCT GCTGACCTTG 360 GAGCTGGGGC AGAGGTCAGA GACCTCTCTG GGCCCATGCC ACCTCCAACA TCCACTCGAC 420 CCCTTGGAAT TTCGGTGGAG AGGAGCAGAG GTTGTCCTGG CGTGGTTTAG GTAGTGTGAG 480 AGGGGTCGAC TGGACACAGG ACGCTGTGGT TTCTGAGCCA GGGGGCGACT CAGATCCCAG 540 CCAGTGGACT TAGCCCCTGT TTGCTCCTCC GATAACTGGG GTGACCTTGG TTAATATTCA 600 CCAGCAGCCT CCCCCGTTGC CCCTCTGGAT CCACTGCTTA AATACGGACG AGGACAGGGC 660 CCTGTCTCCT CAGCTTCAGG CACCACCACT GACCTGGGAC AGTGAATCGC GATCGCCACC 720 ATGCAGATTG AGCTGAGCAC CTGCTTCTTC CTGTGCCTGC TGAGGTTCTG CTTCTCTGCC 780 ACCAGGAGAT ACTACCTGGG GGCTGTGGAG CTGAGCTGGG ACTACATGCA GTCTGACCTG 840 GGGGAGCTGC CTGTGGATGC CAGGTTCCCC CCCAGAGTGC CCAAGAGCTT CCCCTTCAAC 900 ACCTCTGTGG TGTACAAGAA GACCCTGTTT GTGGAGTTCA CTGACCACCT GTTCAACATT 960 GCCAAGCCCA GGCCCCCCTG GATGGGCCTG CTGGGCCCCA CCATCCAGGC TGAGGTGTAT 1020 GACACTGTGG TGATCACCCT GAAGAACATG GCCAGCCACC CTGTGAGCCT GCATGCTGTG 1080 GGGGTGAGCT ACTGGAAGGC CTCTGAGGGG GCTGAGTATG ATGACCAGAC CAGCCAGAGG 1140 GAGAAGGAGG ATGACAAGGT GTTCCCTGGG GGCAGCCACA CCTATGTGTG GCAGGTGCTG 1200 AAGGAGAATG GCCCCATGGC CTCTGACCCC CTGTGCCTGA CCTACAGCTA CCTGAGCCAT 1260 GTGGACCTGG TGAAGGACCT GAACTCTGGC CTGATTGGGG CCCTGCTGGT GTGCAGGGAG 1320 GGCAGCCTGG CCAAGGAGAA GACCCAGACC CTGCACAAGT TCATCCTGCT GTTTGCTGTG 1380 TTTGATGAGG GCAAGAGCTG GCACTCTGAA ACCAAGAACA GCCTGATGCA GGACAGGGAT 1440 GCTGCCTCTG CCAGGGCCTG GCCCAAGATG CACACTGTGA ATGGCTATGT GAACAGGAGC 1500 CTGCCTGGCC TGATTGGCTG CCACAGGAAG TCTGTGTACT GGCATGTGAT TGGCATGGGC 1560 ACCACCCCTG AGGTGCACAG CATCTTCCTG GAGGGCCACA CCTTCCTGGT CAGGAACCAC 1620 AGGCAGGCCA GCCTGGAGAT CAGCCCCATC ACCTTCCTGA CTGCCCAGAC CCTGCTGATG 1680 GACCTGGGCC AGTTCCTGCT GTTCTGCCAC ATCAGCAGCC ACCAGCATGA TGGCATGGAG 1740 GCCTATGTGA AGGTGGACAG CTGCCCTGAG GAGCCCCAGC TGAGGATGAA GAACAATGAG 1800 GAGGCTGAGG ACTATGATGA TGACCTGACT GACTCTGAGA TGGATGTGGT GAGGTTTGAT 1860 GATGACAACA GCCCCAGCTT CATCCAGATC AGGTCTGTGG CCAAGAAGCA CCCCAAGACC 1920 TGGGTGCACT ACATTGCTGC TGAGGAGGAG GACTGGGACT ATGCCCCCCT GGTGCTGGCC 1980 CCTGATGACA GGAGCTACAA GAGCCAGTAC CTGAACAATG GCCCCCAGAG GATTGGCAGG 2040 AAGTACAAGA AGGTCAGGTT CATGGCCTAC ACTGATGAAA CCTTCAAGAC CAGGGAGGCC 2100 ATCCAGCATG AGTCTGGCAT CCTGGGCCCC CTGCTGTATG GGGAGGTGGG GGACACCCTG 2160 CTGATCATCT TCAAGAACCA GGCCAGCAGG CCCTACAACA TCTACCCCCA TGGCATCACT 2220 GATGTGAGGC CCCTGTACAG CAGGAGGCTG CCCAAGGGGG TGAAGCACCT GAAGGACTTC 2280 CCCATCCTGC CTGGGGAGAT CTTCAAGTAC AAGTGGACTG TGACTGTGGA GGATGGCCCC 2340 ACCAAGTCTG ACCCCAGGTG CCTGACCAGA TACTACAGCA GCTTTGTGAA CATGGAGAGG 2400 GACCTGGCCT CTGGCCTGAT TGGCCCCCTG CTGATCTGCT ACAAGGAGTC TGTGGACCAG 2460 AGGGGCAACC AGATCATGTC TGACAAGAGG AATGTGATCC TGTTCTCTGT GTTTGATGAG 2520 AACAGGAGCT GGTACCTGAC TGAGAACATC CAGAGGTTCC TGCCCAACCC TGCTGGGGTG 2580 CAGCTGGAGG ACCCTGAGTT CCAGGCCAGC AACATCATGC ACAGCATCAA TGGCTATGTG 2640 TTTGACAGCC TGCAGCTGTC TGTGTGCCTG CATGAGGTGG CCTACTGGTA CATCCTGAGC 2700 ATTGGGGCCC AGACTGACTT CCTGTCTGTG TTCTTCTCTG GCTACACCTT CAAGCACAAG 2760 ATGGTGTATG AGGACACCCT GACCCTGTTC CCCTTCTCTG GGGAGACTGT GTTCATGAGC 2820 ATGGAGAACC CTGGCCTGTG GATTCTGGGC TGCCACAACT CTGACTTCAG GAACAGGGGC 2880 ATGACTGCCC TGCTGAAAGT CTCCAGCTGT GACAAGAACA CTGGGGACTA CTATGAGGAC 2940 AGCTATGAGG ACATCTCTGC CTACCTGCTG AGCAAGAACA ATGCCATTGA GCCCAGGAGC 3000 TTCAGCCAGA ACCCCCCAGT GCTGAAGAGG CACCAGAGGG AGATCACCAG GACCACCCTG 3060 CAGTCTGACC AGGAGGAGAT TGACTATGAT GACACCATCT CTGTGGAGAT GAAGAAGGAG 3120 GACTTTGACA TCTACGACGA GGACGAGAAC CAGAGCCCCA GGAGCTTCCA GAAGAAGACC 3180 AGGCACTACT TCATTGCTGC TGTGGAGAGG CTGTGGGACT ATGGCATGAG CAGCAGCCCC 3240 CATGTGCTGA GGAACAGGGC CCAGTCTGGC TCTGTGCCCC AGTTCAAGAA GGTGGTGTTC 3300 CAGGAGTTCA CTGATGGCAG CTTCACCCAG CCCCTGTACA GAGGGGAGCT GAATGAGCAC 3360 CTGGGCCTGC TGGGCCCCTA CATCAGGGCT GAGGTGGAGG ACAACATCAT GGTGACCTTC 3420 AGGAACCAGG CCAGCAGGCC CTACAGCTTC TACAGCAGCC TGATCAGCTA TGAGGAGGAC 3480 CAGAGGCAGG GGGCTGAGCC CAGGAAGAAC TTTGTGAAGC CCAATGAAAC CAAGACCTAC 3540 TTCTGGAAGG TGCAGCACCA CATGGCCCCC ACCAAGGATG AGTTTGACTG CAAGGCCTGG 3600 GCCTACTTCT CTGATGTGGA CCTGGAGAAG GATGTGCACT CTGGCCTGAT TGGCCCCCTG 3660 CTGGTGTGCC ACACCAACAC CCTGAACCCT GCCCATGGCA GGCAGGTGAC TGTGCAGGAG 3720 TTTGCCCTGT TCTTCACCAT CTTTGATGAA ACCAAGAGCT GGTACTTCAC TGAGAACATG 3780 GAGAGGAACT GCAGGGCCCC CTGCAACATC CAGATGGAGG ACCCCACCTT CAAGGAGAAC 3840 TACAGGTTCC ATGCCATCAA TGGCTACATC ATGGACACCC TGCCTGGCCT GGTGATGGCC 3900 CAGGACCAGA GGATCAGGTG GTACCTGCTG AGCATGGGCA GCAATGAGAA CATCCACAGC 3960 ATCCACTTCT CTGGCCATGT GTTCACTGTG AGGAAGAAGG AGGAGTACAA GATGGCCCTG 4020 TACAACCTGT ACCCTGGGGT GTTTGAGACT GTGGAGATGC TGCCCAGCAA GGCTGGCATC 4080 TGGAGGGTGG AGTGCCTGAT TGGGGAGCAC CTGCATGCTG GCATGAGCAC CCTGTTCCTG 4140 GTGTACAGCA ACAAGTGCCA GACCCCCCTG GGCATGGCCT CTGGCCACAT CAGGGACTTC 4200 CAGATCACTG CCTCTGGCCA GTATGGCCAG TGGGCCCCCA AGCTGGCCAG GCTGCACTAC 4260 TCTGGCAGCA TCAATGCCTG GAGCACCAAG GAGCCCTTCA GCTGGATCAA GGTGGACCTG 4320 CTGGCCCCCA TGATCATCCA TGGCATCAAG ACCCAGGGGG CCAGGCAGAA GTTCAGCAGC 4380 CTGTACATCA GCCAGTTCAT CATCATGTAC AGCCTGGATG GCAAGAAGTG GCAGACCTAC 4440 AGGGGCAACA GCACTGGCAC CCTGATGGTG TTCTTTGGCA ATGTGGACAG CTCTGGCATC 4500 AAGCACAACA TCTTCAACCC CCCCATCATT GCCAGATACA TCAGGCTGCA CCCCACCCAC 4560 TACAGCATCA GGAGCACCCT GAGGATGGAG CTGATGGGCT GTGACCTGAA CAGCTGCAGC 4620 ATGCCCCTGG GCATGGAGAG CAAGGCCATC TCTGATGCCC AGATCACTGC CAGCAGCTAC 4680 TTCACCAACA TGTTTGCCAC CTGGAGCCCC AGCAAGGCCA GGCTGCACCT GCAGGGCAGG 4740 AGCAATGCCT GGAGGCCCCA GGTCAACAAC CCCAAGGAGT GGCTGCAGGT GGACTTCCAG 4800 AAGACCATGA AGGTGACTGG GGTGACCACC CAGGGGGTGA AGAGCCTGCT GACCAGCATG 4860 TATGTGAAGG AGTTCCTGAT CAGCAGCAGC CAGGATGGCC ACCAGTGGAC CCTGTTCTTC 4920 CAGAATGGCA AGGTGAAGGT GTTCCAGGGC AACCAGGACA GCTTCACCCC TGTGGTGAAC 4980 AGCCTGGACC CCCCCCTGCT GACCAGATAC CTGAGGATTC ACCCCCAGAG CTGGGTGCAC 5040 CAGATTGCCC TGAGGATGGA GGTGCTGGGC TGTGAGGCCC AGGACCTGTA CTGACCTCGA 5100 GGAATAAAGG AAATTTATTT TCATTGCAAT AGTGTGTTGG TTTTTTGTGT CACGTGGCGG 5160 CCGCAGGAAC CCCTAGTGAT GGAGTTGGCC ACTCCCTCTC TGCGCGCTCG CTCGCTCACT 5220 GAGGCCGGGC GACCAAAGGT CGCCCGACGC CCGGGCTTTG CCCGGGCGGC CTCAGTGAGC 5280 GAGCGAGCGC GCAGAGAGGG AGTGGCCAA 5309 SEQ ID NO: 28 <211> 5532 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 28 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGTAA GTATGCCTTT CACTGCGAGA GGTTCTGGAG AGGCTTCTGA GCTCCCCATG 780 GCCCAGGCAG GCAGCAGGTC TGGGGCAGGA GGGGGGTTGT GGAGTGCCTT GACTCGGGGC 840 CTGGCCCCCC CATCTCTGTC TTGCAGGACA ATTGCCGTCT TCTGTCTCGT GGGGCATCCT 900 CCTGCTGGCA GGCCTGTGCT GCCTGGTCCC TGCGATCGCC ACCATGCAGA TTGAGCTGAG 960 CACCTGCTTC TTCCTGTGCC TGCTGAGGTT CTGCTTCTCT GCCACCAGGA GATACTACCT 1020 GGGGGCTGTG GAGCTGAGCT GGGACTACAT GCAGTCTGAC CTGGGGGAGC TGCCTGTGGA 1080 TGCCAGGTTC CCCCCCAGAG TGCCCAAGAG CTTCCCCTTC AACACCTCTG TGGTGTACAA 1140 GAAGACCCTG TTTGTGGAGT TCACTGACCA CCTGTTCAAC ATTGCCAAGC CCAGGCCCCC 1200 CTGGATGGGC CTGCTGGGCC CCACCATCCA GGCTGAGGTG TATGACACTG TGGTGATCAC 1260 CCTGAAGAAC ATGGCCAGCC ACCCTGTGAG CCTGCATGCT GTGGGGGTGA GCTACTGGAA 1320 GGCCTCTGAG GGGGCTGAGT ATGATGACCA GACCAGCCAG AGGGAGAAGG AGGATGACAA 1380 GGTGTTCCCT GGGGGCAGCC ACACCTATGT GTGGCAGGTG CTGAAGGAGA ATGGCCCCAT 1440 GGCCTCTGAC CCCCTGTGCC TGACCTACAG CTACCTGAGC CATGTGGACC TGGTGAAGGA 1500 CCTGAACTCT GGCCTGATTG GGGCCCTGCT GGTGTGCAGG GAGGGCAGCC TGGCCAAGGA 1560 GAAGACCCAG ACCCTGCACA AGTTCATCCT GCTGTTTGCT GTGTTTGATG AGGGCAAGAG 1620 CTGGCACTCT GAAACCAAGA ACAGCCTGAT GCAGGACAGG GATGCTGCCT CTGCCAGGGC 1680 CTGGCCCAAG ATGCACACTG TGAATGGCTA TGTGAACAGG AGCCTGCCTG GCCTGATTGG 1740 CTGCCACAGG AAGTCTGTGT ACTGGCATGT GATTGGCATG GGCACCACCC CTGAGGTGCA 1800 CAGCATCTTC CTGGAGGGCC ACACCTTCCT GGTCAGGAAC CACAGGCAGG CCAGCCTGGA 1860 GATCAGCCCC ATCACCTTCC TGACTGCCCA GACCCTGCTG ATGGACCTGG GCCAGTTCCT 1920 GCTGTTCTGC CACATCAGCA GCCACCAGCA TGATGGCATG GAGGCCTATG TGAAGGTGGA 1980 CAGCTGCCCT GAGGAGCCCC AGCTGAGGAT GAAGAACAAT GAGGAGGCTG AGGACTATGA 2040 TGATGACCTG ACTGACTCTG AGATGGATGT GGTGAGGTTT GATGATGACA ACAGCCCCAG 2100 CTTCATCCAG ATCAGGTCTG TGGCCAAGAA GCACCCCAAG ACCTGGGTGC ACTACATTGC 2160 TGCTGAGGAG GAGGACTGGG ACTATGCCCC CCTGGTGCTG GCCCCTGATG ACAGGAGCTA 2220 CAAGAGCCAG TACCTGAACA ATGGCCCCCA GAGGATTGGC AGGAAGTACA AGAAGGTCAG 2280 GTTCATGGCC TACACTGATG AAACCTTCAA GACCAGGGAG GCCATCCAGC ATGAGTCTGG 2340 CATCCTGGGC CCCCTGCTGT ATGGGGAGGT GGGGGACACC CTGCTGATCA TCTTCAAGAA 2400 CCAGGCCAGC AGGCCCTACA ACATCTACCC CCATGGCATC ACTGATGTGA GGCCCCTGTA 2460 CAGCAGGAGG CTGCCCAAGG GGGTGAAGCA CCTGAAGGAC TTCCCCATCC TGCCTGGGGA 2520 GATCTTCAAG TACAAGTGGA CTGTGACTGT GGAGGATGGC CCCACCAAGT CTGACCCCAG 2580 GTGCCTGACC AGATACTACA GCAGCTTTGT GAACATGGAG AGGGACCTGG CCTCTGGCCT 2640 GATTGGCCCC CTGCTGATCT GCTACAAGGA GTCTGTGGAC CAGAGGGGCA ACCAGATCAT 2700 GTCTGACAAG AGGAATGTGA TCCTGTTCTC TGTGTTTGAT GAGAACAGGA GCTGGTACCT 2760 GACTGAGAAC ATCCAGAGGT TCCTGCCCAA CCCTGCTGGG GTGCAGCTGG AGGACCCTGA 2820 GTTCCAGGCC AGCAACATCA TGCACAGCAT CAATGGCTAT GTGTTTGACA GCCTGCAGCT 2880 GTCTGTGTGC CTGCATGAGG TGGCCTACTG GTACATCCTG AGCATTGGGG CCCAGACTGA 2940 CTTCCTGTCT GTGTTCTTCT CTGGCTACAC CTTCAAGCAC AAGATGGTGT ATGAGGACAC 3000 CCTGACCCTG TTCCCCTTCT CTGGGGAGAC TGTGTTCATG AGCATGGAGA ACCCTGGCCT 3060 GTGGATTCTG GGCTGCCACA ACTCTGACTT CAGGAACAGG GGCATGACTG CCCTGCTGAA 3120 AGTCTCCAGC TGTGACAAGA ACACTGGGGA CTACTATGAG GACAGCTATG AGGACATCTC 3180 TGCCTACCTG CTGAGCAAGA ACAATGCCAT TGAGCCCAGG AGCTTCAGCC AGAACCCCCC 3240 AGTGCTGAAG AGGCACCAGA GGGAGATCAC CAGGACCACC CTGCAGTCTG ACCAGGAGGA 3300 GATTGACTAT GATGACACCA TCTCTGTGGA GATGAAGAAG GAGGACTTTG ACATCTACGA 3360 CGAGGACGAG AACCAGAGCC CCAGGAGCTT CCAGAAGAAG ACCAGGCACT ACTTCATTGC 3420 TGCTGTGGAG AGGCTGTGGG ACTATGGCAT GAGCAGCAGC CCCCATGTGC TGAGGAACAG 3480 GGCCCAGTCT GGCTCTGTGC CCCAGTTCAA GAAGGTGGTG TTCCAGGAGT TCACTGATGG 3540 CAGCTTCACC CAGCCCCTGT ACAGAGGGGA GCTGAATGAG CACCTGGGCC TGCTGGGCCC 3600 CTACATCAGG GCTGAGGTGG AGGACAACAT CATGGTGACC TTCAGGAACC AGGCCAGCAG 3660 GCCCTACAGC TTCTACAGCA GCCTGATCAG CTATGAGGAG GACCAGAGGC AGGGGGCTGA 3720 GCCCAGGAAG AACTTTGTGA AGCCCAATGA AACCAAGACC TACTTCTGGA AGGTGCAGCA 3780 CCACATGGCC CCCACCAAGG ATGAGTTTGA CTGCAAGGCC TGGGCCTACT TCTCTGATGT 3840 GGACCTGGAG AAGGATGTGC ACTCTGGCCT GATTGGCCCC CTGCTGGTGT GCCACACCAA 3900 CACCCTGAAC CCTGCCCATG GCAGGCAGGT GACTGTGCAG GAGTTTGCCC TGTTCTTCAC 3960 CATCTTTGAT GAAACCAAGA GCTGGTACTT CACTGAGAAC ATGGAGAGGA ACTGCAGGGC 4020 CCCCTGCAAC ATCCAGATGG AGGACCCCAC CTTCAAGGAG AACTACAGGT TCCATGCCAT 4080 CAATGGCTAC ATCATGGACA CCCTGCCTGG CCTGGTGATG GCCCAGGACC AGAGGATCAG 4140 GTGGTACCTG CTGAGCATGG GCAGCAATGA GAACATCCAC AGCATCCACT TCTCTGGCCA 4200 TGTGTTCACT GTGAGGAAGA AGGAGGAGTA CAAGATGGCC CTGTACAACC TGTACCCTGG 4260 GGTGTTTGAG ACTGTGGAGA TGCTGCCCAG CAAGGCTGGC ATCTGGAGGG TGGAGTGCCT 4320 GATTGGGGAG CACCTGCATG CTGGCATGAG CACCCTGTTC CTGGTGTACA GCAACAAGTG 4380 CCAGACCCCC CTGGGCATGG CCTCTGGCCA CATCAGGGAC TTCCAGATCA CTGCCTCTGG 4440 CCAGTATGGC CAGTGGGCCC CCAAGCTGGC CAGGCTGCAC TACTCTGGCA GCATCAATGC 4500 CTGGAGCACC AAGGAGCCCT TCAGCTGGAT CAAGGTGGAC CTGCTGGCCC CCATGATCAT 4560 CCATGGCATC AAGACCCAGG GGGCCAGGCA GAAGTTCAGC AGCCTGTACA TCAGCCAGTT 4620 CATCATCATG TACAGCCTGG ATGGCAAGAA GTGGCAGACC TACAGGGGCA ACAGCACTGG 4680 CACCCTGATG GTGTTCTTTG GCAATGTGGA CAGCTCTGGC ATCAAGCACA ACATCTTCAA 4740 CCCCCCCATC ATTGCCAGAT ACATCAGGCT GCACCCCACC CACTACAGCA TCAGGAGCAC 4800 CCTGAGGATG GAGCTGATGG GCTGTGACCT GAACAGCTGC AGCATGCCCC TGGGCATGGA 4860 GAGCAAGGCC ATCTCTGATG CCCAGATCAC TGCCAGCAGC TACTTCACCA ACATGTTTGC 4920 CACCTGGAGC CCCAGCAAGG CCAGGCTGCA CCTGCAGGGC AGGAGCAATG CCTGGAGGCC 4980 CCAGGTCAAC AACCCCAAGG AGTGGCTGCA GGTGGACTTC CAGAAGACCA TGAAGGTGAC 5040 TGGGGTGACC ACCCAGGGGG TGAAGAGCCT GCTGACCAGC ATGTATGTGA AGGAGTTCCT 5100 GATCAGCAGC AGCCAGGATG GCCACCAGTG GACCCTGTTC TTCCAGAATG GCAAGGTGAA 5160 GGTGTTCCAG GGCAACCAGG ACAGCTTCAC CCCTGTGGTG AACAGCCTGG ACCCCCCCCT 5220 GCTGACCAGA TACCTGAGGA TTCACCCCCA GAGCTGGGTG CACCAGATTG CCCTGAGGAT 5280 GGAGGTGCTG GGCTGTGAGG CCCAGGACCT GTACTGACCT CGAGGAATAA AGGAAATTTA 5340 TTTTCATTGC AATAGTGTGT TGGTTTTTTG TGTCACGTGG CGGCCGCAGG AACCCCTAGT 5400 GATGGAGTTG GCCACTCCCT CTCTGCGCGC TCGCTCGCTC ACTGAGGCCG GGCGACCAAA 5460 GGTCGCCCGA CGCCCGGGCT TTGCCCGGGC GGCCTCAGTG AGCGAGCGAG CGCGCAGAGA 5520 GGGAGTGGCC AA 5532 SEQ ID NO: 29 <211> 5877 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 29 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACAG GTTAATTTTT AAAAAGCAGT CAAAAGTCCA 540 AGTGGCCCTT GGCAGCATTT ACTCTCTCTG TTTGCTCTGG TTAATAATCT CAGGAGCACA 600 AACATTCCTG GAGGCAGGAG AAGAAATCAA CATCCTGGAC TTATCCTCTG GGCCTCTCCC 660 CACCCCCAGG AGAGGCTCAG GTTAATTTTT AAAAAGCAGT CAAAAGTCCA AGTGGCCCTT 720 GGCAGCATTT ACTCTCTCTG TTTGCTCTGG TTAATAATCT CAGGAGCACA AACATTCCTG 780 GAGGCAGGAG AAGAAATCAA CATCCTGGAC TTATCCTCTG GGCCTCTCCC CACCCCCAGG 840 AGAGGCTGTC GACTGGACAC AGGACGCTGT GGTTTCTGAG CCAGGGGGCG ACTCAGATCC 900 CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC TCCGATAACT GGGGTGACCT TGGTTAATAT 960 TCACCAGCAG CCTCCCCCGT TGCCCCTCTG GATCCACTGC TTAAATACGG ACGAGGACAG 1020 GGCCCTGTCT CCTCAGCTTC AGGCACCACC ACTGACCTGG GACAGTGAAT CGTAAGTATG 1080 CCTTTCACTG CGAGAGGTTC TGGAGAGGCT TCTGAGCTCC CCATGGCCCA GGCAGGCAGC 1140 AGGTCTGGGG CAGGAGGGGG GTTGTGGAGT GCCTTGACTC GGGGCCTGGC CCCCCCATCT 1200 CTGTCTTGCA GGACAATTGC CGTCTTCTGT CTCGTGGGGC ATCCTCCTGC TGGCAGGCCT 1260 GTGCTGCCTG GTCCCTGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT 1320 GTGCCTGCTG AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT 1380 GAGCTGGGAC TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC 1440 CAGAGTGCCC AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT 1500 GGAGTTCACT GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT 1560 GGGCCCCACC ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC 1620 CAGCCACCCT GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC 1680 TGAGTATGAT GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG 1740 CAGCCACACC TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT 1800 GTGCCTGACC TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT 1860 GATTGGGGCC CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT 1920 GCACAAGTTC ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC 1980 CAAGAACAGC CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA 2040 CACTGTGAAT GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC 2100 TGTGTACTGG CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA 2160 GGGCCACACC TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC 2220 CTTCCTGACT GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT 2280 CAGCAGCCAC CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA 2340 GCCCCAGCTG AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA 2400 CTCTGAGATG GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG 2460 GTCTGTGGCC AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA 2520 CTGGGACTAT GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT 2580 GAACAATGGC CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC 2640 TGATGAAACC TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT 2700 GCTGTATGGG GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC 2760 CTACAACATC TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC 2820 CAAGGGGGTG AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA 2880 GTGGACTGTG ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA 2940 CTACAGCAGC TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT 3000 GATCTGCTAC AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA 3060 TGTGATCCTG TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA 3120 GAGGTTCCTG CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA 3180 CATCATGCAC AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA 3240 TGAGGTGGCC TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT 3300 CTTCTCTGGC TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC 3360 CTTCTCTGGG GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG 3420 CCACAACTCT GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA 3480 CAAGAACACT GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG 3540 CAAGAACAAT GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA 3600 CCAGAGGGAG ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA 3660 CACCATCTCT GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA 3720 GAGCCCCAGG AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT 3780 GTGGGACTAT GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC 3840 TGTGCCCCAG TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC 3900 CCTGTACAGA GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA 3960 GGTGGAGGAC AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA 4020 CAGCAGCCTG ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT 4080 TGTGAAGCCC AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC 4140 CAAGGATGAG TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA 4200 TGTGCACTCT GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC 4260 CCATGGCAGG CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC 4320 CAAGAGCTGG TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA 4380 GATGGAGGAC CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT 4440 GGACACCCTG CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG 4500 CATGGGCAGC AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG 4560 GAAGAAGGAG GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT 4620 GGAGATGCTG CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT 4680 GCATGCTGGC ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG 4740 CATGGCCTCT GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG 4800 GGCCCCCAAG CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA 4860 GCCCTTCAGC TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC 4920 CCAGGGGGCC AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG 4980 CCTGGATGGC AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT 5040 CTTTGGCAAT GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC 5100 CAGATACATC AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT 5160 GATGGGCTGT GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC 5220 TGATGCCCAG ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG 5280 CAAGGCCAGG CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC 5340 CAAGGAGTGG CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA 5400 GGGGGTGAAG AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA 5460 GGATGGCCAC CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA 5520 CCAGGACAGC TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT 5580 GAGGATTCAC CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG 5640 TGAGGCCCAG GACCTGTACT GACCTCGAGG AATAAAGGAA ATTTATTTTC ATTGCAATAG 5700 TGTGTTGGTT TTTTGTGTCA CGTGGCGGCC GCAGGAACCC CTAGTGATGG AGTTGGCCAC 5760 TCCCTCTCTG CGCGCTCGCT CGCTCACTGA GGCCGGGCGA CCAAAGGTCG CCCGACGCCC 5820 GGGCTTTGCC CGGGCGGCCT CAGTGAGCGA GCGAGCGCGC AGAGAGGGAG TGGCCAA 5877 SEQ ID NO: 30 <211> 6054 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 30 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACAG GTTAATTTTT AAAAAGCAGT CAAAAGTCCA 540 AGTGGCCCTT GGCAGCATTT ACTCTCTCTG TTTGCTCTGG TTAATAATCT CAGGAGCACA 600 AACATTCCTG GAGGCAGGAG AAGAAATCAA CATCCTGGAC TTATCCTCTG GGCCTCTCCC 660 CACCCCCAGG AGAGGCTCAG GTTAATTTTT AAAAAGCAGT CAAAAGTCCA AGTGGCCCTT 720 GGCAGCATTT ACTCTCTCTG TTTGCTCTGG TTAATAATCT CAGGAGCACA AACATTCCTG 780 GAGGCAGGAG AAGAAATCAA CATCCTGGAC TTATCCTCTG GGCCTCTCCC CACCCCCAGG 840 AGAGGCTGTC GACTGGACAC AGGACGCTGT GGTTTCTGAG CCAGGGGGCG ACTCAGATCC 900 CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC TCCGATAACT GGGGTGACCT TGGTTAATAT 960 TCACCAGCAG CCTCCCCCGT TGCCCCTCTG GATCCACTGC TTAAATACGG ACGAGGACAG 1020 GGCCCTGTCT CCTCAGCTTC AGGCACCACC ACTGACCTGG GACAGTGAAT CGTAAGTATG 1080 CCTTTCACTG CGAGAGGTTC TGGAGAGGCT TCTGAGCTCC CCATGGCCCA GGCAGGCAGC 1140 AGGTCTGGGG CAGGAGGGGG GTTGTGGAGT GCCTTGACTC GGGGCCTGGC CCCCCCATCT 1200 CTGTCTTGCA GGACAATTGC CGTCTTCTGT CTCGTGGGGC ATCCTCCTGC TGGCAGGCCT 1260 GTGCTGCCTG GTCCCTGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT 1320 GTGCCTGCTG AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT 1380 GAGCTGGGAC TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC 1440 CAGAGTGCCC AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT 1500 GGAGTTCACT GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT 1560 GGGCCCCACC ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC 1620 CAGCCACCCT GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC 1680 TGAGTATGAT GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG 1740 CAGCCACACC TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT 1800 GTGCCTGACC TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT 1860 GATTGGGGCC CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT 1920 GCACAAGTTC ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC 1980 CAAGAACAGC CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA 2040 CACTGTGAAT GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC 2100 TGTGTACTGG CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA 2160 GGGCCACACC TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC 2220 CTTCCTGACT GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT 2280 CAGCAGCCAC CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA 2340 GCCCCAGCTG AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA 2400 CTCTGAGATG GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG 2460 GTCTGTGGCC AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA 2520 CTGGGACTAT GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT 2580 GAACAATGGC CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC 2640 TGATGAAACC TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT 2700 GCTGTATGGG GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC 2760 CTACAACATC TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC 2820 CAAGGGGGTG AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA 2880 GTGGACTGTG ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA 2940 CTACAGCAGC TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT 3000 GATCTGCTAC AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA 3060 TGTGATCCTG TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA 3120 GAGGTTCCTG CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA 3180 CATCATGCAC AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA 3240 TGAGGTGGCC TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT 3300 CTTCTCTGGC TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC 3360 CTTCTCTGGG GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG 3420 CCACAACTCT GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA 3480 CAAGAACACT GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG 3540 CAAGAACAAT GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA 3600 CCAGAGGGAG ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA 3660 CACCATCTCT GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA 3720 GAGCCCCAGG AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT 3780 GTGGGACTAT GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC 3840 TGTGCCCCAG TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC 3900 CCTGTACAGA GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA 3960 GGTGGAGGAC AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA 4020 CAGCAGCCTG ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT 4080 TGTGAAGCCC AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC 4140 CAAGGATGAG TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA 4200 TGTGCACTCT GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC 4260 CCATGGCAGG CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC 4320 CAAGAGCTGG TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA 4380 GATGGAGGAC CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT 4440 GGACACCCTG CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG 4500 CATGGGCAGC AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG 4560 GAAGAAGGAG GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT 4620 GGAGATGCTG CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT 4680 GCATGCTGGC ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG 4740 CATGGCCTCT GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG 4800 GGCCCCCAAG CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA 4860 GCCCTTCAGC TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC 4920 CCAGGGGGCC AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG 4980 CCTGGATGGC AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT 5040 CTTTGGCAAT GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC 5100 CAGATACATC AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT 5160 GATGGGCTGT GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC 5220 TGATGCCCAG ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG 5280 CAAGGCCAGG CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC 5340 CAAGGAGTGG CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA 5400 GGGGGTGAAG AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA 5460 GGATGGCCAC CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA 5520 CCAGGACAGC TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT 5580 GAGGATTCAC CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG 5640 TGAGGCCCAG GACCTGTACT GACCTCGAGG TGTGCCTTCT AGTTGCCAGC CATCTGTTGT 5700 TTGCCCCTCC CCCGTGCCTT CCTTGACCCT GGAAGGTGCC ACTCCCACTG TCCTTTCCTA 5760 ATAAAATGAG GAAATTGCAT CGCATTGTCT GAGTAGGTGT CATTCTATTC TGGGGGGTGG 5820 GGTGGGGCAG GACAGCAAGG GGGAGGATTG GGAAGACAAT AGCAGGCATG CTGGGGATGC 5880 GGTGGGCTCT ATGGGCACGT GGCGGCCGCA GGAACCCCTA GTGATGGAGT TGGCCACTCC 5940 CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC GACGCCCGGG 6000 CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG CCAA 6054 SEQ ID NO: 31 <211> 6054 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 31 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGAAGC CTCTCCTGGG GGTGGGGAGA GGCCCAGAGG 540 ATAAGTCCAG GATGTTGATT TCTTCTCCTG CCTCCAGGAA TGTTTGTGCT CCTGAGATTA 600 TTAACCAGAG CAAACAGAGA GAGTAAATGC TGCCAAGGGC CACTTGGACT TTTGACTGCT 660 TTTTAAAAAT TAACCTGAGC CTCTCCTGGG GGTGGGGAGA GGCCCAGAGG ATAAGTCCAG 720 GATGTTGATT TCTTCTCCTG CCTCCAGGAA TGTTTGTGCT CCTGAGATTA TTAACCAGAG 780 CAAACAGAGA GAGTAAATGC TGCCAAGGGC CACTTGGACT TTTGACTGCT TTTTAAAAAT 840 TAACCTGGTC GACTGGACAC AGGACGCTGT GGTTTCTGAG CCAGGGGGCG ACTCAGATCC 900 CAGCCAGTGG ACTTAGCCCC TGTTTGCTCC TCCGATAACT GGGGTGACCT TGGTTAATAT 960 TCACCAGCAG CCTCCCCCGT TGCCCCTCTG GATCCACTGC TTAAATACGG ACGAGGACAG 1020 GGCCCTGTCT CCTCAGCTTC AGGCACCACC ACTGACCTGG GACAGTGAAT CGTAAGTATG 1080 CCTTTCACTG CGAGAGGTTC TGGAGAGGCT TCTGAGCTCC CCATGGCCCA GGCAGGCAGC 1140 AGGTCTGGGG CAGGAGGGGG GTTGTGGAGT GCCTTGACTC GGGGCCTGGC CCCCCCATCT 1200 CTGTCTTGCA GGACAATTGC CGTCTTCTGT CTCGTGGGGC ATCCTCCTGC TGGCAGGCCT 1260 GTGCTGCCTG GTCCCTGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT 1320 GTGCCTGCTG AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT 1380 GAGCTGGGAC TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC 1440 CAGAGTGCCC AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT 1500 GGAGTTCACT GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT 1560 GGGCCCCACC ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC 1620 CAGCCACCCT GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC 1680 TGAGTATGAT GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG 1740 CAGCCACACC TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT 1800 GTGCCTGACC TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT 1860 GATTGGGGCC CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT 1920 GCACAAGTTC ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC 1980 CAAGAACAGC CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA 2040 CACTGTGAAT GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC 2100 TGTGTACTGG CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA 2160 GGGCCACACC TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC 2220 CTTCCTGACT GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT 2280 CAGCAGCCAC CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA 2340 GCCCCAGCTG AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA 2400 CTCTGAGATG GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG 2460 GTCTGTGGCC AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA 2520 CTGGGACTAT GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT 2580 GAACAATGGC CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC 2640 TGATGAAACC TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT 2700 GCTGTATGGG GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC 2760 CTACAACATC TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC 2820 CAAGGGGGTG AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA 2880 GTGGACTGTG ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA 2940 CTACAGCAGC TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT 3000 GATCTGCTAC AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA 3060 TGTGATCCTG TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA 3120 GAGGTTCCTG CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA 3180 CATCATGCAC AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA 3240 TGAGGTGGCC TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT 3300 CTTCTCTGGC TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC 3360 CTTCTCTGGG GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG 3420 CCACAACTCT GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA 3480 CAAGAACACT GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG 3540 CAAGAACAAT GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA 3600 CCAGAGGGAG ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA 3660 CACCATCTCT GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA 3720 GAGCCCCAGG AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT 3780 GTGGGACTAT GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC 3840 TGTGCCCCAG TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC 3900 CCTGTACAGA GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA 3960 GGTGGAGGAC AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA 4020 CAGCAGCCTG ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT 4080 TGTGAAGCCC AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC 4140 CAAGGATGAG TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA 4200 TGTGCACTCT GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC 4260 CCATGGCAGG CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC 4320 CAAGAGCTGG TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA 4380 GATGGAGGAC CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT 4440 GGACACCCTG CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG 4500 CATGGGCAGC AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG 4560 GAAGAAGGAG GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT 4620 GGAGATGCTG CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT 4680 GCATGCTGGC ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG 4740 CATGGCCTCT GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG 4800 GGCCCCCAAG CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA 4860 GCCCTTCAGC TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC 4920 CCAGGGGGCC AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG 4980 CCTGGATGGC AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT 5040 CTTTGGCAAT GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC 5100 CAGATACATC AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT 5160 GATGGGCTGT GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC 5220 TGATGCCCAG ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG 5280 CAAGGCCAGG CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC 5340 CAAGGAGTGG CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA 5400 GGGGGTGAAG AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA 5460 GGATGGCCAC CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA 5520 CCAGGACAGC TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT 5580 GAGGATTCAC CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG 5640 TGAGGCCCAG GACCTGTACT GACCTCGAGG TGTGCCTTCT AGTTGCCAGC CATCTGTTGT 5700 TTGCCCCTCC CCCGTGCCTT CCTTGACCCT GGAAGGTGCC ACTCCCACTG TCCTTTCCTA 5760 ATAAAATGAG GAAATTGCAT CGCATTGTCT GAGTAGGTGT CATTCTATTC TGGGGGGTGG 5820 GGTGGGGCAG GACAGCAAGG GGGAGGATTG GGAAGACAAT AGCAGGCATG CTGGGGATGC 5880 GGTGGGCTCT ATGGGCACGT GGCGGCCGCA GGAACCCCTA GTGATGGAGT TGGCCACTCC 5940 CTCTCTGCGC GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC GACGCCCGGG 6000 CTTTGCCCGG GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG CCAA 6054 SEQ ID NO: 32 <211> 5504 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 32 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACTG GACACAGGAC GCTGTGGTTT CTGAGCCAGG 540 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 600 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 660 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 720 TGAATCGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT GTGCCTGCTG 780 AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT GAGCTGGGAC 840 TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC CAGAGTGCCC 900 AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT GGAGTTCACT 960 GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT GGGCCCCACC 1020 ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC CAGCCACCCT 1080 GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC TGAGTATGAT 1140 GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG CAGCCACACC 1200 TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT GTGCCTGACC 1260 TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT GATTGGGGCC 1320 CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT GCACAAGTTC 1380 ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC CAAGAACAGC 1440 CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA CACTGTGAAT 1500 GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC TGTGTACTGG 1560 CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA GGGCCACACC 1620 TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC CTTCCTGACT 1680 GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT CAGCAGCCAC 1740 CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA GCCCCAGCTG 1800 AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA CTCTGAGATG 1860 GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG GTCTGTGGCC 1920 AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA CTGGGACTAT 1980 GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT GAACAATGGC 2040 CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC TGATGAAACC 2100 TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT GCTGTATGGG 2160 GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC CTACAACATC 2220 TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC CAAGGGGGTG 2280 AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA GTGGACTGTG 2340 ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA CTACAGCAGC 2400 TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT GATCTGCTAC 2460 AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA TGTGATCCTG 2520 TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA GAGGTTCCTG 2580 CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA CATCATGCAC 2640 AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA TGAGGTGGCC 2700 TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT CTTCTCTGGC 2760 TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC CTTCTCTGGG 2820 GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG CCACAACTCT 2880 GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA CAAGAACACT 2940 GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG CAAGAACAAT 3000 GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA CCAGAGGGAG 3060 ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA CACCATCTCT 3120 GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA GAGCCCCAGG 3180 AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT GTGGGACTAT 3240 GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC TGTGCCCCAG 3300 TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC CCTGTACAGA 3360 GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA GGTGGAGGAC 3420 AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA CAGCAGCCTG 3480 ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT TGTGAAGCCC 3540 AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC CAAGGATGAG 3600 TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA TGTGCACTCT 3660 GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC CCATGGCAGG 3720 CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC CAAGAGCTGG 3780 TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA GATGGAGGAC 3840 CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT GGACACCCTG 3900 CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG CATGGGCAGC 3960 AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG GAAGAAGGAG 4020 GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT GGAGATGCTG 4080 CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT GCATGCTGGC 4140 ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG CATGGCCTCT 4200 GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG GGCCCCCAAG 4260 CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA GCCCTTCAGC 4320 TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC CCAGGGGGCC 4380 AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG CCTGGATGGC 4440 AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT CTTTGGCAAT 4500 GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC CAGATACATC 4560 AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT GATGGGCTGT 4620 GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC TGATGCCCAG 4680 ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG CAAGGCCAGG 4740 CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC CAAGGAGTGG 4800 CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA GGGGGTGAAG 4860 AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA GGATGGCCAC 4920 CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA CCAGGACAGC 4980 TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT GAGGATTCAC 5040 CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG TGAGGCCCAG 5100 GACCTGTACT GACCTCGAGG TGTGCCTTCT AGTTGCCAGC CATCTGTTGT TTGCCCCTCC 5160 CCCGTGCCTT CCTTGACCCT GGAAGGTGCC ACTCCCACTG TCCTTTCCTA ATAAAATGAG 5220 GAAATTGCAT CGCATTGTCT GAGTAGGTGT CATTCTATTC TGGGGGGTGG GGTGGGGCAG 5280 GACAGCAAGG GGGAGGATTG GGAAGACAAT AGCAGGCATG CTGGGGATGC GGTGGGCTCT 5340 ATGGGCACGT GGCGGCCGCA GGAACCCCTA GTGATGGAGT TGGCCACTCC CTCTCTGCGC 5400 GCTCGCTCGC TCACTGAGGC CGGGCGACCA AAGGTCGCCC GACGCCCGGG CTTTGCCCGG 5460 GCGGCCTCAG TGAGCGAGCG AGCGCGCAGA GAGGGAGTGG CCAA 5504 SEQ ID NO: 33 <211> 5507 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 33 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCC CTCTCACACT 180 ACCTAAACCA CGCCAGGACA ACCTCTGCTC CTCTCCACCG AAATTCCAAG GGGTCGAGTG 240 GATGTTGGAG GTGGCATGGG CCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 300 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 360 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCTGCT 420 GGAGGATGGG AACTGAGGGG TTGGAAGGGG GCAGGGTGAG CCCAGAAACT CCTGTGTGCC 480 TCTGAGCCTG CAGACGCGAA ACGTCGACGA TCTTGCTACC AGTGGAACAG CCACTAAGGA 540 TTCTGCAGTG AGAGCAGAGG GCCAGCTAAG TGGTACTCTC CCAGAGACTG TCTGACTCAC 600 GCCACCCCCT CCACCTTGGA CACAGGACGC TGTGGTTTCT GAGCCAGGTA CAATGACTCC 660 TTTCGGTAAG TGCAGTGGAA GCTGTACACT GCCCAGGCAA AGCGTCCGGG CAGCGTAGGC 720 GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA TAACTGGGGT 780 GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC ACTGCTTAAA 840 TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA CCTGGGACAG 900 TGAATCGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT GTGCCTGCTG 960 AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT GAGCTGGGAC 1020 TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC CAGAGTGCCC 1080 AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT GGAGTTCACT 1140 GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT GGGCCCCACC 1200 ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC CAGCCACCCT 1260 GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC TGAGTATGAT 1320 GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG CAGCCACACC 1380 TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT GTGCCTGACC 1440 TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT GATTGGGGCC 1500 CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT GCACAAGTTC 1560 ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC CAAGAACAGC 1620 CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA CACTGTGAAT 1680 GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC TGTGTACTGG 1740 CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA GGGCCACACC 1800 TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC CTTCCTGACT 1860 GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT CAGCAGCCAC 1920 CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA GCCCCAGCTG 1980 AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA CTCTGAGATG 2040 GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG GTCTGTGGCC 2100 AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA CTGGGACTAT 2160 GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT GAACAATGGC 2220 CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC TGATGAAACC 2280 TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT GCTGTATGGG 2340 GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC CTACAACATC 2400 TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC CAAGGGGGTG 2460 AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA GTGGACTGTG 2520 ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA CTACAGCAGC 2580 TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT GATCTGCTAC 2640 AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA TGTGATCCTG 2700 TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA GAGGTTCCTG 2760 CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA CATCATGCAC 2820 AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA TGAGGTGGCC 2880 TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT CTTCTCTGGC 2940 TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC CTTCTCTGGG 3000 GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG CCACAACTCT 3060 GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA CAAGAACACT 3120 GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG CAAGAACAAT 3180 GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA CCAGAGGGAG 3240 ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA CACCATCTCT 3300 GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA GAGCCCCAGG 3360 AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT GTGGGACTAT 3420 GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC TGTGCCCCAG 3480 TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC CCTGTACAGA 3540 GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA GGTGGAGGAC 3600 AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA CAGCAGCCTG 3660 ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT TGTGAAGCCC 3720 AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC CAAGGATGAG 3780 TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA TGTGCACTCT 3840 GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC CCATGGCAGG 3900 CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC CAAGAGCTGG 3960 TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA GATGGAGGAC 4020 CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT GGACACCCTG 4080 CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG CATGGGCAGC 4140 AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG GAAGAAGGAG 4200 GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT GGAGATGCTG 4260 CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT GCATGCTGGC 4320 ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG CATGGCCTCT 4380 GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG GGCCCCCAAG 4440 CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA GCCCTTCAGC 4500 TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC CCAGGGGGCC 4560 AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG CCTGGATGGC 4620 AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT CTTTGGCAAT 4680 GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC CAGATACATC 4740 AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT GATGGGCTGT 4800 GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC TGATGCCCAG 4860 ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG CAAGGCCAGG 4920 CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC CAAGGAGTGG 4980 CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA GGGGGTGAAG 5040 AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA GGATGGCCAC 5100 CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA CCAGGACAGC 5160 TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT GAGGATTCAC 5220 CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG TGAGGCCCAG 5280 GACCTGTACT GACCTCGAGG AATAAAGGAA ATTTATTTTC ATTGCAATAG TGTGTTGGTT 5340 TTTTGTGTCA CGTGGCGGCC GCAGGAACCC CTAGTGATGG AGTTGGCCAC TCCCTCTCTG 5400 CGCGCTCGCT CGCTCACTGA GGCCGGGCGA CCAAAGGTCG CCCGACGCCC GGGCTTTGCC 5460 CGGGCGGCCT CAGTGAGCGA GCGAGCGCGC AGAGAGGGAG TGGCCAA 5507 SEQ ID NO: 34 <211> 5311 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 34 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACGC AGAGAGGTCT 180 CTGACCTCTG CCCCAGCTCC AAGGTCAGCA GGCAGGGAGG GCTGTGTGTT TGCTGTTTGC 240 TGCTTGCAAT GTTTGCCCAT TTTAGGGACA TGAGTAGGCT GAAGTTTGTT CAGTGTGGAC 300 TTCAGAGGCA GCACACAAAC AGCCAGAGAG GTCTCTGACC TCTGCCCCAG CTCCAAGGTC 360 AGCAGGCAGG GAGGGCTGTG TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG 420 GACATGAGTA GGCTGAAGTT TGTTCAGTGT GGACTTCAGA GGCAGCACAC AAACAGCACG 480 CGAAACGTCG ACTGGACACA GGACGCTGTG GTTTCTGAGC CAGGGGGCGA CTCAGATCCC 540 AGCCAGTGGA CTTAGCCCCT GTTTGCTCCT CCGATAACTG GGGTGACCTT GGTTAATATT 600 CACCAGCAGC CTCCCCCGTT GCCCCTCTGG ATCCACTGCT TAAATACGGA CGAGGACAGG 660 GCCCTGTCTC CTCAGCTTCA GGCACCACCA CTGACCTGGG ACAGTGAATC GCGATCGCCA 720 CCATGCAGAT TGAGCTGAGC ACCTGCTTCT TCCTGTGCCT GCTGAGGTTC TGCTTCTCTG 780 CCACCAGGAG ATACTACCTG GGGGCTGTGG AGCTGAGCTG GGACTACATG CAGTCTGACC 840 TGGGGGAGCT GCCTGTGGAT GCCAGGTTCC CCCCCAGAGT GCCCAAGAGC TTCCCCTTCA 900 ACACCTCTGT GGTGTACAAG AAGACCCTGT TTGTGGAGTT CACTGACCAC CTGTTCAACA 960 TTGCCAAGCC CAGGCCCCCC TGGATGGGCC TGCTGGGCCC CACCATCCAG GCTGAGGTGT 1020 ATGACACTGT GGTGATCACC CTGAAGAACA TGGCCAGCCA CCCTGTGAGC CTGCATGCTG 1080 TGGGGGTGAG CTACTGGAAG GCCTCTGAGG GGGCTGAGTA TGATGACCAG ACCAGCCAGA 1140 GGGAGAAGGA GGATGACAAG GTGTTCCCTG GGGGCAGCCA CACCTATGTG TGGCAGGTGC 1200 TGAAGGAGAA TGGCCCCATG GCCTCTGACC CCCTGTGCCT GACCTACAGC TACCTGAGCC 1260 ATGTGGACCT GGTGAAGGAC CTGAACTCTG GCCTGATTGG GGCCCTGCTG GTGTGCAGGG 1320 AGGGCAGCCT GGCCAAGGAG AAGACCCAGA CCCTGCACAA GTTCATCCTG CTGTTTGCTG 1380 TGTTTGATGA GGGCAAGAGC TGGCACTCTG AAACCAAGAA CAGCCTGATG CAGGACAGGG 1440 ATGCTGCCTC TGCCAGGGCC TGGCCCAAGA TGCACACTGT GAATGGCTAT GTGAACAGGA 1500 GCCTGCCTGG CCTGATTGGC TGCCACAGGA AGTCTGTGTA CTGGCATGTG ATTGGCATGG 1560 GCACCACCCC TGAGGTGCAC AGCATCTTCC TGGAGGGCCA CACCTTCCTG GTCAGGAACC 1620 ACAGGCAGGC CAGCCTGGAG ATCAGCCCCA TCACCTTCCT GACTGCCCAG ACCCTGCTGA 1680 TGGACCTGGG CCAGTTCCTG CTGTTCTGCC ACATCAGCAG CCACCAGCAT GATGGCATGG 1740 AGGCCTATGT GAAGGTGGAC AGCTGCCCTG AGGAGCCCCA GCTGAGGATG AAGAACAATG 1800 AGGAGGCTGA GGACTATGAT GATGACCTGA CTGACTCTGA GATGGATGTG GTGAGGTTTG 1860 ATGATGACAA CAGCCCCAGC TTCATCCAGA TCAGGTCTGT GGCCAAGAAG CACCCCAAGA 1920 CCTGGGTGCA CTACATTGCT GCTGAGGAGG AGGACTGGGA CTATGCCCCC CTGGTGCTGG 1980 CCCCTGATGA CAGGAGCTAC AAGAGCCAGT ACCTGAACAA TGGCCCCCAG AGGATTGGCA 2040 GGAAGTACAA GAAGGTCAGG TTCATGGCCT ACACTGATGA AACCTTCAAG ACCAGGGAGG 2100 CCATCCAGCA TGAGTCTGGC ATCCTGGGCC CCCTGCTGTA TGGGGAGGTG GGGGACACCC 2160 TGCTGATCAT CTTCAAGAAC CAGGCCAGCA GGCCCTACAA CATCTACCCC CATGGCATCA 2220 CTGATGTGAG GCCCCTGTAC AGCAGGAGGC TGCCCAAGGG GGTGAAGCAC CTGAAGGACT 2280 TCCCCATCCT GCCTGGGGAG ATCTTCAAGT ACAAGTGGAC TGTGACTGTG GAGGATGGCC 2340 CCACCAAGTC TGACCCCAGG TGCCTGACCA GATACTACAG CAGCTTTGTG AACATGGAGA 2400 GGGACCTGGC CTCTGGCCTG ATTGGCCCCC TGCTGATCTG CTACAAGGAG TCTGTGGACC 2460 AGAGGGGCAA CCAGATCATG TCTGACAAGA GGAATGTGAT CCTGTTCTCT GTGTTTGATG 2520 AGAACAGGAG CTGGTACCTG ACTGAGAACA TCCAGAGGTT CCTGCCCAAC CCTGCTGGGG 2580 TGCAGCTGGA GGACCCTGAG TTCCAGGCCA GCAACATCAT GCACAGCATC AATGGCTATG 2640 TGTTTGACAG CCTGCAGCTG TCTGTGTGCC TGCATGAGGT GGCCTACTGG TACATCCTGA 2700 GCATTGGGGC CCAGACTGAC TTCCTGTCTG TGTTCTTCTC TGGCTACACC TTCAAGCACA 2760 AGATGGTGTA TGAGGACACC CTGACCCTGT TCCCCTTCTC TGGGGAGACT GTGTTCATGA 2820 GCATGGAGAA CCCTGGCCTG TGGATTCTGG GCTGCCACAA CTCTGACTTC AGGAACAGGG 2880 GCATGACTGC CCTGCTGAAA GTCTCCAGCT GTGACAAGAA CACTGGGGAC TACTATGAGG 2940 ACAGCTATGA GGACATCTCT GCCTACCTGC TGAGCAAGAA CAATGCCATT GAGCCCAGGA 3000 GCTTCAGCCA GAACCCCCCA GTGCTGAAGA GGCACCAGAG GGAGATCACC AGGACCACCC 3060 TGCAGTCTGA CCAGGAGGAG ATTGACTATG ATGACACCAT CTCTGTGGAG ATGAAGAAGG 3120 AGGACTTTGA CATCTACGAC GAGGACGAGA ACCAGAGCCC CAGGAGCTTC CAGAAGAAGA 3180 CCAGGCACTA CTTCATTGCT GCTGTGGAGA GGCTGTGGGA CTATGGCATG AGCAGCAGCC 3240 CCCATGTGCT GAGGAACAGG GCCCAGTCTG GCTCTGTGCC CCAGTTCAAG AAGGTGGTGT 3300 TCCAGGAGTT CACTGATGGC AGCTTCACCC AGCCCCTGTA CAGAGGGGAG CTGAATGAGC 3360 ACCTGGGCCT GCTGGGCCCC TACATCAGGG CTGAGGTGGA GGACAACATC ATGGTGACCT 3420 TCAGGAACCA GGCCAGCAGG CCCTACAGCT TCTACAGCAG CCTGATCAGC TATGAGGAGG 3480 ACCAGAGGCA GGGGGCTGAG CCCAGGAAGA ACTTTGTGAA GCCCAATGAA ACCAAGACCT 3540 ACTTCTGGAA GGTGCAGCAC CACATGGCCC CCACCAAGGA TGAGTTTGAC TGCAAGGCCT 3600 GGGCCTACTT CTCTGATGTG GACCTGGAGA AGGATGTGCA CTCTGGCCTG ATTGGCCCCC 3660 TGCTGGTGTG CCACACCAAC ACCCTGAACC CTGCCCATGG CAGGCAGGTG ACTGTGCAGG 3720 AGTTTGCCCT GTTCTTCACC ATCTTTGATG AAACCAAGAG CTGGTACTTC ACTGAGAACA 3780 TGGAGAGGAA CTGCAGGGCC CCCTGCAACA TCCAGATGGA GGACCCCACC TTCAAGGAGA 3840 ACTACAGGTT CCATGCCATC AATGGCTACA TCATGGACAC CCTGCCTGGC CTGGTGATGG 3900 CCCAGGACCA GAGGATCAGG TGGTACCTGC TGAGCATGGG CAGCAATGAG AACATCCACA 3960 GCATCCACTT CTCTGGCCAT GTGTTCACTG TGAGGAAGAA GGAGGAGTAC AAGATGGCCC 4020 TGTACAACCT GTACCCTGGG GTGTTTGAGA CTGTGGAGAT GCTGCCCAGC AAGGCTGGCA 4080 TCTGGAGGGT GGAGTGCCTG ATTGGGGAGC ACCTGCATGC TGGCATGAGC ACCCTGTTCC 4140 TGGTGTACAG CAACAAGTGC CAGACCCCCC TGGGCATGGC CTCTGGCCAC ATCAGGGACT 4200 TCCAGATCAC TGCCTCTGGC CAGTATGGCC AGTGGGCCCC CAAGCTGGCC AGGCTGCACT 4260 ACTCTGGCAG CATCAATGCC TGGAGCACCA AGGAGCCCTT CAGCTGGATC AAGGTGGACC 4320 TGCTGGCCCC CATGATCATC CATGGCATCA AGACCCAGGG GGCCAGGCAG AAGTTCAGCA 4380 GCCTGTACAT CAGCCAGTTC ATCATCATGT ACAGCCTGGA TGGCAAGAAG TGGCAGACCT 4440 ACAGGGGCAA CAGCACTGGC ACCCTGATGG TGTTCTTTGG CAATGTGGAC AGCTCTGGCA 4500 TCAAGCACAA CATCTTCAAC CCCCCCATCA TTGCCAGATA CATCAGGCTG CACCCCACCC 4560 ACTACAGCAT CAGGAGCACC CTGAGGATGG AGCTGATGGG CTGTGACCTG AACAGCTGCA 4620 GCATGCCCCT GGGCATGGAG AGCAAGGCCA TCTCTGATGC CCAGATCACT GCCAGCAGCT 4680 ACTTCACCAA CATGTTTGCC ACCTGGAGCC CCAGCAAGGC CAGGCTGCAC CTGCAGGGCA 4740 GGAGCAATGC CTGGAGGCCC CAGGTCAACA ACCCCAAGGA GTGGCTGCAG GTGGACTTCC 4800 AGAAGACCAT GAAGGTGACT GGGGTGACCA CCCAGGGGGT GAAGAGCCTG CTGACCAGCA 4860 TGTATGTGAA GGAGTTCCTG ATCAGCAGCA GCCAGGATGG CCACCAGTGG ACCCTGTTCT 4920 TCCAGAATGG CAAGGTGAAG GTGTTCCAGG GCAACCAGGA CAGCTTCACC CCTGTGGTGA 4980 ACAGCCTGGA CCCCCCCCTG CTGACCAGAT ACCTGAGGAT TCACCCCCAG AGCTGGGTGC 5040 ACCAGATTGC CCTGAGGATG GAGGTGCTGG GCTGTGAGGC CCAGGACCTG TACTGACCTC 5100 GAGGAATAAA GGAAATTTAT TTTCATTGCA ATAGTGTGTT GGTTTTTTGT GTCACGTGGC 5160 GGCCGCAGGA ACCCCTAGTG ATGGAGTTGG CCACTCCCTC TCTGCGCGCT CGCTCGCTCA 5220 CTGAGGCCGG GCGACCAAAG GTCGCCCGAC GCCCGGGCTT TGCCCGGGCG GCCTCAGTGA 5280 GCGAGCGAGC GCGCAGAGAG GGAGTGGCCA A 5311 SEQ ID NO: 35 <211> 5156 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 35 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCA GAGAGGTCTC 180 TGACCTCTGC CCCAGCTCCA AGGTCAGCAG GCAGGGAGGG CTGTGTGTTT GCTGTTTGCT 240 GCTTGCAATG TTTGCCCATT TTAGGGACAT GAGTAGGCTG AAGTTTGTTC AGTGTGGACT 300 TCAGAGGCAG CACACAAACA GCACGCGAAA CGTCGACTGG ACACAGGACG CTGTGGTTTC 360 TGAGCCAGGG GGCGACTCAG ATCCCAGCCA GTGGACTTAG CCCCTGTTTG CTCCTCCGAT 420 AACTGGGGTG ACCTTGGTTA ATATTCACCA GCAGCCTCCC CCGTTGCCCC TCTGGATCCA 480 CTGCTTAAAT ACGGACGAGG ACAGGGCCCT GTCTCCTCAG CTTCAGGCAC CACCACTGAC 540 CTGGGACAGT GAATCGCGAT CGCCACCATG CAGATTGAGC TGAGCACCTG CTTCTTCCTG 600 TGCCTGCTGA GGTTCTGCTT CTCTGCCACC AGGAGATACT ACCTGGGGGC TGTGGAGCTG 660 AGCTGGGACT ACATGCAGTC TGACCTGGGG GAGCTGCCTG TGGATGCCAG GTTCCCCCCC 720 AGAGTGCCCA AGAGCTTCCC CTTCAACACC TCTGTGGTGT ACAAGAAGAC CCTGTTTGTG 780 GAGTTCACTG ACCACCTGTT CAACATTGCC AAGCCCAGGC CCCCCTGGAT GGGCCTGCTG 840 GGCCCCACCA TCCAGGCTGA GGTGTATGAC ACTGTGGTGA TCACCCTGAA GAACATGGCC 900 AGCCACCCTG TGAGCCTGCA TGCTGTGGGG GTGAGCTACT GGAAGGCCTC TGAGGGGGCT 960 GAGTATGATG ACCAGACCAG CCAGAGGGAG AAGGAGGATG ACAAGGTGTT CCCTGGGGGC 1020 AGCCACACCT ATGTGTGGCA GGTGCTGAAG GAGAATGGCC CCATGGCCTC TGACCCCCTG 1080 TGCCTGACCT ACAGCTACCT GAGCCATGTG GACCTGGTGA AGGACCTGAA CTCTGGCCTG 1140 ATTGGGGCCC TGCTGGTGTG CAGGGAGGGC AGCCTGGCCA AGGAGAAGAC CCAGACCCTG 1200 CACAAGTTCA TCCTGCTGTT TGCTGTGTTT GATGAGGGCA AGAGCTGGCA CTCTGAAACC 1260 AAGAACAGCC TGATGCAGGA CAGGGATGCT GCCTCTGCCA GGGCCTGGCC CAAGATGCAC 1320 ACTGTGAATG GCTATGTGAA CAGGAGCCTG CCTGGCCTGA TTGGCTGCCA CAGGAAGTCT 1380 GTGTACTGGC ATGTGATTGG CATGGGCACC ACCCCTGAGG TGCACAGCAT CTTCCTGGAG 1440 GGCCACACCT TCCTGGTCAG GAACCACAGG CAGGCCAGCC TGGAGATCAG CCCCATCACC 1500 TTCCTGACTG CCCAGACCCT GCTGATGGAC CTGGGCCAGT TCCTGCTGTT CTGCCACATC 1560 AGCAGCCACC AGCATGATGG CATGGAGGCC TATGTGAAGG TGGACAGCTG CCCTGAGGAG 1620 CCCCAGCTGA GGATGAAGAA CAATGAGGAG GCTGAGGACT ATGATGATGA CCTGACTGAC 1680 TCTGAGATGG ATGTGGTGAG GTTTGATGAT GACAACAGCC CCAGCTTCAT CCAGATCAGG 1740 TCTGTGGCCA AGAAGCACCC CAAGACCTGG GTGCACTACA TTGCTGCTGA GGAGGAGGAC 1800 TGGGACTATG CCCCCCTGGT GCTGGCCCCT GATGACAGGA GCTACAAGAG CCAGTACCTG 1860 AACAATGGCC CCCAGAGGAT TGGCAGGAAG TACAAGAAGG TCAGGTTCAT GGCCTACACT 1920 GATGAAACCT TCAAGACCAG GGAGGCCATC CAGCATGAGT CTGGCATCCT GGGCCCCCTG 1980 CTGTATGGGG AGGTGGGGGA CACCCTGCTG ATCATCTTCA AGAACCAGGC CAGCAGGCCC 2040 TACAACATCT ACCCCCATGG CATCACTGAT GTGAGGCCCC TGTACAGCAG GAGGCTGCCC 2100 AAGGGGGTGA AGCACCTGAA GGACTTCCCC ATCCTGCCTG GGGAGATCTT CAAGTACAAG 2160 TGGACTGTGA CTGTGGAGGA TGGCCCCACC AAGTCTGACC CCAGGTGCCT GACCAGATAC 2220 TACAGCAGCT TTGTGAACAT GGAGAGGGAC CTGGCCTCTG GCCTGATTGG CCCCCTGCTG 2280 ATCTGCTACA AGGAGTCTGT GGACCAGAGG GGCAACCAGA TCATGTCTGA CAAGAGGAAT 2340 GTGATCCTGT TCTCTGTGTT TGATGAGAAC AGGAGCTGGT ACCTGACTGA GAACATCCAG 2400 AGGTTCCTGC CCAACCCTGC TGGGGTGCAG CTGGAGGACC CTGAGTTCCA GGCCAGCAAC 2460 ATCATGCACA GCATCAATGG CTATGTGTTT GACAGCCTGC AGCTGTCTGT GTGCCTGCAT 2520 GAGGTGGCCT ACTGGTACAT CCTGAGCATT GGGGCCCAGA CTGACTTCCT GTCTGTGTTC 2580 TTCTCTGGCT ACACCTTCAA GCACAAGATG GTGTATGAGG ACACCCTGAC CCTGTTCCCC 2640 TTCTCTGGGG AGACTGTGTT CATGAGCATG GAGAACCCTG GCCTGTGGAT TCTGGGCTGC 2700 CACAACTCTG ACTTCAGGAA CAGGGGCATG ACTGCCCTGC TGAAAGTCTC CAGCTGTGAC 2760 AAGAACACTG GGGACTACTA TGAGGACAGC TATGAGGACA TCTCTGCCTA CCTGCTGAGC 2820 AAGAACAATG CCATTGAGCC CAGGAGCTTC AGCCAGAACC CCCCAGTGCT GAAGAGGCAC 2880 CAGAGGGAGA TCACCAGGAC CACCCTGCAG TCTGACCAGG AGGAGATTGA CTATGATGAC 2940 ACCATCTCTG TGGAGATGAA GAAGGAGGAC TTTGACATCT ACGACGAGGA CGAGAACCAG 3000 AGCCCCAGGA GCTTCCAGAA GAAGACCAGG CACTACTTCA TTGCTGCTGT GGAGAGGCTG 3060 TGGGACTATG GCATGAGCAG CAGCCCCCAT GTGCTGAGGA ACAGGGCCCA GTCTGGCTCT 3120 GTGCCCCAGT TCAAGAAGGT GGTGTTCCAG GAGTTCACTG ATGGCAGCTT CACCCAGCCC 3180 CTGTACAGAG GGGAGCTGAA TGAGCACCTG GGCCTGCTGG GCCCCTACAT CAGGGCTGAG 3240 GTGGAGGACA ACATCATGGT GACCTTCAGG AACCAGGCCA GCAGGCCCTA CAGCTTCTAC 3300 AGCAGCCTGA TCAGCTATGA GGAGGACCAG AGGCAGGGGG CTGAGCCCAG GAAGAACTTT 3360 GTGAAGCCCA ATGAAACCAA GACCTACTTC TGGAAGGTGC AGCACCACAT GGCCCCCACC 3420 AAGGATGAGT TTGACTGCAA GGCCTGGGCC TACTTCTCTG ATGTGGACCT GGAGAAGGAT 3480 GTGCACTCTG GCCTGATTGG CCCCCTGCTG GTGTGCCACA CCAACACCCT GAACCCTGCC 3540 CATGGCAGGC AGGTGACTGT GCAGGAGTTT GCCCTGTTCT TCACCATCTT TGATGAAACC 3600 AAGAGCTGGT ACTTCACTGA GAACATGGAG AGGAACTGCA GGGCCCCCTG CAACATCCAG 3660 ATGGAGGACC CCACCTTCAA GGAGAACTAC AGGTTCCATG CCATCAATGG CTACATCATG 3720 GACACCCTGC CTGGCCTGGT GATGGCCCAG GACCAGAGGA TCAGGTGGTA CCTGCTGAGC 3780 ATGGGCAGCA ATGAGAACAT CCACAGCATC CACTTCTCTG GCCATGTGTT CACTGTGAGG 3840 AAGAAGGAGG AGTACAAGAT GGCCCTGTAC AACCTGTACC CTGGGGTGTT TGAGACTGTG 3900 GAGATGCTGC CCAGCAAGGC TGGCATCTGG AGGGTGGAGT GCCTGATTGG GGAGCACCTG 3960 CATGCTGGCA TGAGCACCCT GTTCCTGGTG TACAGCAACA AGTGCCAGAC CCCCCTGGGC 4020 ATGGCCTCTG GCCACATCAG GGACTTCCAG ATCACTGCCT CTGGCCAGTA TGGCCAGTGG 4080 GCCCCCAAGC TGGCCAGGCT GCACTACTCT GGCAGCATCA ATGCCTGGAG CACCAAGGAG 4140 CCCTTCAGCT GGATCAAGGT GGACCTGCTG GCCCCCATGA TCATCCATGG CATCAAGACC 4200 CAGGGGGCCA GGCAGAAGTT CAGCAGCCTG TACATCAGCC AGTTCATCAT CATGTACAGC 4260 CTGGATGGCA AGAAGTGGCA GACCTACAGG GGCAACAGCA CTGGCACCCT GATGGTGTTC 4320 TTTGGCAATG TGGACAGCTC TGGCATCAAG CACAACATCT TCAACCCCCC CATCATTGCC 4380 AGATACATCA GGCTGCACCC CACCCACTAC AGCATCAGGA GCACCCTGAG GATGGAGCTG 4440 ATGGGCTGTG ACCTGAACAG CTGCAGCATG CCCCTGGGCA TGGAGAGCAA GGCCATCTCT 4500 GATGCCCAGA TCACTGCCAG CAGCTACTTC ACCAACATGT TTGCCACCTG GAGCCCCAGC 4560 AAGGCCAGGC TGCACCTGCA GGGCAGGAGC AATGCCTGGA GGCCCCAGGT CAACAACCCC 4620 AAGGAGTGGC TGCAGGTGGA CTTCCAGAAG ACCATGAAGG TGACTGGGGT GACCACCCAG 4680 GGGGTGAAGA GCCTGCTGAC CAGCATGTAT GTGAAGGAGT TCCTGATCAG CAGCAGCCAG 4740 GATGGCCACC AGTGGACCCT GTTCTTCCAG AATGGCAAGG TGAAGGTGTT CCAGGGCAAC 4800 CAGGACAGCT TCACCCCTGT GGTGAACAGC CTGGACCCCC CCCTGCTGAC CAGATACCTG 4860 AGGATTCACC CCCAGAGCTG GGTGCACCAG ATTGCCCTGA GGATGGAGGT GCTGGGCTGT 4920 GAGGCCCAGG ACCTGTACTG ACCTCGAGGA ATAAAGGAAA TTTATTTTCA TTGCAATAGT 4980 GTGTTGGTTT TTTGTGTCAC GTGGCGGCCG CAGGAACCCC TAGTGATGGA GTTGGCCACT 5040 CCCTCTCTGC GCGCTCGCTC GCTCACTGAG GCCGGGCGAC CAAAGGTCGC CCGACGCCCG 5100 GGCTTTGCCC GGGCGGCCTC AGTGAGCGAG CGAGCGCGCA GAGAGGGAGT GGCCAA 5156 SEQ ID NO: 36 <211> 5178 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 36 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACT 360 GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC AGATCCCAGC CAGTGGACTT 420 AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC 480 CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC 540 AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGCG ATCGCCACCA TGCAGATTGA 600 GCTGAGCACC TGCTTCTTCC TGTGCCTGCT GAGGTTCTGC TTCTCTGCCA CCAGGAGATA 660 CTACCTGGGG GCTGTGGAGC TGAGCTGGGA CTACATGCAG TCTGACCTGG GGGAGCTGCC 720 TGTGGATGCC AGGTTCCCCC CCAGAGTGCC CAAGAGCTTC CCCTTCAACA CCTCTGTGGT 780 GTACAAGAAG ACCCTGTTTG TGGAGTTCAC TGACCACCTG TTCAACATTG CCAAGCCCAG 840 GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC CATCCAGGCT GAGGTGTATG ACACTGTGGT 900 GATCACCCTG AAGAACATGG CCAGCCACCC TGTGAGCCTG CATGCTGTGG GGGTGAGCTA 960 CTGGAAGGCC TCTGAGGGGG CTGAGTATGA TGACCAGACC AGCCAGAGGG AGAAGGAGGA 1020 TGACAAGGTG TTCCCTGGGG GCAGCCACAC CTATGTGTGG CAGGTGCTGA AGGAGAATGG 1080 CCCCATGGCC TCTGACCCCC TGTGCCTGAC CTACAGCTAC CTGAGCCATG TGGACCTGGT 1140 GAAGGACCTG AACTCTGGCC TGATTGGGGC CCTGCTGGTG TGCAGGGAGG GCAGCCTGGC 1200 CAAGGAGAAG ACCCAGACCC TGCACAAGTT CATCCTGCTG TTTGCTGTGT TTGATGAGGG 1260 CAAGAGCTGG CACTCTGAAA CCAAGAACAG CCTGATGCAG GACAGGGATG CTGCCTCTGC 1320 CAGGGCCTGG CCCAAGATGC ACACTGTGAA TGGCTATGTG AACAGGAGCC TGCCTGGCCT 1380 GATTGGCTGC CACAGGAAGT CTGTGTACTG GCATGTGATT GGCATGGGCA CCACCCCTGA 1440 GGTGCACAGC ATCTTCCTGG AGGGCCACAC CTTCCTGGTC AGGAACCACA GGCAGGCCAG 1500 CCTGGAGATC AGCCCCATCA CCTTCCTGAC TGCCCAGACC CTGCTGATGG ACCTGGGCCA 1560 GTTCCTGCTG TTCTGCCACA TCAGCAGCCA CCAGCATGAT GGCATGGAGG CCTATGTGAA 1620 GGTGGACAGC TGCCCTGAGG AGCCCCAGCT GAGGATGAAG AACAATGAGG AGGCTGAGGA 1680 CTATGATGAT GACCTGACTG ACTCTGAGAT GGATGTGGTG AGGTTTGATG ATGACAACAG 1740 CCCCAGCTTC ATCCAGATCA GGTCTGTGGC CAAGAAGCAC CCCAAGACCT GGGTGCACTA 1800 CATTGCTGCT GAGGAGGAGG ACTGGGACTA TGCCCCCCTG GTGCTGGCCC CTGATGACAG 1860 GAGCTACAAG AGCCAGTACC TGAACAATGG CCCCCAGAGG ATTGGCAGGA AGTACAAGAA 1920 GGTCAGGTTC ATGGCCTACA CTGATGAAAC CTTCAAGACC AGGGAGGCCA TCCAGCATGA 1980 GTCTGGCATC CTGGGCCCCC TGCTGTATGG GGAGGTGGGG GACACCCTGC TGATCATCTT 2040 CAAGAACCAG GCCAGCAGGC CCTACAACAT CTACCCCCAT GGCATCACTG ATGTGAGGCC 2100 CCTGTACAGC AGGAGGCTGC CCAAGGGGGT GAAGCACCTG AAGGACTTCC CCATCCTGCC 2160 TGGGGAGATC TTCAAGTACA AGTGGACTGT GACTGTGGAG GATGGCCCCA CCAAGTCTGA 2220 CCCCAGGTGC CTGACCAGAT ACTACAGCAG CTTTGTGAAC ATGGAGAGGG ACCTGGCCTC 2280 TGGCCTGATT GGCCCCCTGC TGATCTGCTA CAAGGAGTCT GTGGACCAGA GGGGCAACCA 2340 GATCATGTCT GACAAGAGGA ATGTGATCCT GTTCTCTGTG TTTGATGAGA ACAGGAGCTG 2400 GTACCTGACT GAGAACATCC AGAGGTTCCT GCCCAACCCT GCTGGGGTGC AGCTGGAGGA 2460 CCCTGAGTTC CAGGCCAGCA ACATCATGCA CAGCATCAAT GGCTATGTGT TTGACAGCCT 2520 GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC CTACTGGTAC ATCCTGAGCA TTGGGGCCCA 2580 GACTGACTTC CTGTCTGTGT TCTTCTCTGG CTACACCTTC AAGCACAAGA TGGTGTATGA 2640 GGACACCCTG ACCCTGTTCC CCTTCTCTGG GGAGACTGTG TTCATGAGCA TGGAGAACCC 2700 TGGCCTGTGG ATTCTGGGCT GCCACAACTC TGACTTCAGG AACAGGGGCA TGACTGCCCT 2760 GCTGAAAGTC TCCAGCTGTG ACAAGAACAC TGGGGACTAC TATGAGGACA GCTATGAGGA 2820 CATCTCTGCC TACCTGCTGA GCAAGAACAA TGCCATTGAG CCCAGGAGCT TCAGCCAGAA 2880 CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA GATCACCAGG ACCACCCTGC AGTCTGACCA 2940 GGAGGAGATT GACTATGATG ACACCATCTC TGTGGAGATG AAGAAGGAGG ACTTTGACAT 3000 CTACGACGAG GACGAGAACC AGAGCCCCAG GAGCTTCCAG AAGAAGACCA GGCACTACTT 3060 CATTGCTGCT GTGGAGAGGC TGTGGGACTA TGGCATGAGC AGCAGCCCCC ATGTGCTGAG 3120 GAACAGGGCC CAGTCTGGCT CTGTGCCCCA GTTCAAGAAG GTGGTGTTCC AGGAGTTCAC 3180 TGATGGCAGC TTCACCCAGC CCCTGTACAG AGGGGAGCTG AATGAGCACC TGGGCCTGCT 3240 GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA CAACATCATG GTGACCTTCA GGAACCAGGC 3300 CAGCAGGCCC TACAGCTTCT ACAGCAGCCT GATCAGCTAT GAGGAGGACC AGAGGCAGGG 3360 GGCTGAGCCC AGGAAGAACT TTGTGAAGCC CAATGAAACC AAGACCTACT TCTGGAAGGT 3420 GCAGCACCAC ATGGCCCCCA CCAAGGATGA GTTTGACTGC AAGGCCTGGG CCTACTTCTC 3480 TGATGTGGAC CTGGAGAAGG ATGTGCACTC TGGCCTGATT GGCCCCCTGC TGGTGTGCCA 3540 CACCAACACC CTGAACCCTG CCCATGGCAG GCAGGTGACT GTGCAGGAGT TTGCCCTGTT 3600 CTTCACCATC TTTGATGAAA CCAAGAGCTG GTACTTCACT GAGAACATGG AGAGGAACTG 3660 CAGGGCCCCC TGCAACATCC AGATGGAGGA CCCCACCTTC AAGGAGAACT ACAGGTTCCA 3720 TGCCATCAAT GGCTACATCA TGGACACCCT GCCTGGCCTG GTGATGGCCC AGGACCAGAG 3780 GATCAGGTGG TACCTGCTGA GCATGGGCAG CAATGAGAAC ATCCACAGCA TCCACTTCTC 3840 TGGCCATGTG TTCACTGTGA GGAAGAAGGA GGAGTACAAG ATGGCCCTGT ACAACCTGTA 3900 CCCTGGGGTG TTTGAGACTG TGGAGATGCT GCCCAGCAAG GCTGGCATCT GGAGGGTGGA 3960 GTGCCTGATT GGGGAGCACC TGCATGCTGG CATGAGCACC CTGTTCCTGG TGTACAGCAA 4020 CAAGTGCCAG ACCCCCCTGG GCATGGCCTC TGGCCACATC AGGGACTTCC AGATCACTGC 4080 CTCTGGCCAG TATGGCCAGT GGGCCCCCAA GCTGGCCAGG CTGCACTACT CTGGCAGCAT 4140 CAATGCCTGG AGCACCAAGG AGCCCTTCAG CTGGATCAAG GTGGACCTGC TGGCCCCCAT 4200 GATCATCCAT GGCATCAAGA CCCAGGGGGC CAGGCAGAAG TTCAGCAGCC TGTACATCAG 4260 CCAGTTCATC ATCATGTACA GCCTGGATGG CAAGAAGTGG CAGACCTACA GGGGCAACAG 4320 CACTGGCACC CTGATGGTGT TCTTTGGCAA TGTGGACAGC TCTGGCATCA AGCACAACAT 4380 CTTCAACCCC CCCATCATTG CCAGATACAT CAGGCTGCAC CCCACCCACT ACAGCATCAG 4440 GAGCACCCTG AGGATGGAGC TGATGGGCTG TGACCTGAAC AGCTGCAGCA TGCCCCTGGG 4500 CATGGAGAGC AAGGCCATCT CTGATGCCCA GATCACTGCC AGCAGCTACT TCACCAACAT 4560 GTTTGCCACC TGGAGCCCCA GCAAGGCCAG GCTGCACCTG CAGGGCAGGA GCAATGCCTG 4620 GAGGCCCCAG GTCAACAACC CCAAGGAGTG GCTGCAGGTG GACTTCCAGA AGACCATGAA 4680 GGTGACTGGG GTGACCACCC AGGGGGTGAA GAGCCTGCTG ACCAGCATGT ATGTGAAGGA 4740 GTTCCTGATC AGCAGCAGCC AGGATGGCCA CCAGTGGACC CTGTTCTTCC AGAATGGCAA 4800 GGTGAAGGTG TTCCAGGGCA ACCAGGACAG CTTCACCCCT GTGGTGAACA GCCTGGACCC 4860 CCCCCTGCTG ACCAGATACC TGAGGATTCA CCCCCAGAGC TGGGTGCACC AGATTGCCCT 4920 GAGGATGGAG GTGCTGGGCT GTGAGGCCCA GGACCTGTAC TGACCTCGAG GAATAAAGGA 4980 AATTTATTTT CATTGCAATA GTGTGTTGGT TTTTTGTGTC ACGTGGCGGC CGCAGGAACC 5040 CCTAGTGATG GAGTTGGCCA CTCCCTCTCT GCGCGCTCGC TCGCTCACTG AGGCCGGGCG 5100 ACCAAAGGTC GCCCGACGCC CGGGCTTTGC CCGGGCGGCC TCAGTGAGCG AGCGAGCGCG 5160 CAGAGAGGGA GTGGCCAA 5178 SEQ ID NO: 37 <211> 5160 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 37 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTT GTCCCTAAAA TGGGCAAACA 180 TTGCAAGCAG CAAACAGCAA ACATGTCCCT AAAATGGGCA AACATTGCAA GCAGCAAACA 240 GCAAACATGT CCCTAAAATG GGCAAACATT GCAAGCAGCA AACAGCAAAC ATGTCCCTAA 300 AATGGGCAAA CATTGCAAGC AGCAAACAGC AAACAGTCGA CTGGACACAG GACGCTGTGG 360 TTTCTGAGCC AGGGGGCGAC TCAGATCCCA GCCAGTGGAC TTAGCCCCTG TTTGCTCCTC 420 CGATAACTGG GGTGACCTTG GTTAATATTC ACCAGCAGCC TCCCCCGTTG CCCCTCTGGA 480 TCCACTGCTT AAATACGGAC GAGGACAGGG CCCTGTCTCC TCAGCTTCAG GCACCACCAC 540 TGACCTGGGA CAGTGAATCG CGATCGCCAC CATGCAGATT GAGCTGAGCA CCTGCTTCTT 600 CCTGTGCCTG CTGAGGTTCT GCTTCTCTGC CACCAGGAGA TACTACCTGG GGGCTGTGGA 660 GCTGAGCTGG GACTACATGC AGTCTGACCT GGGGGAGCTG CCTGTGGATG CCAGGTTCCC 720 CCCCAGAGTG CCCAAGAGCT TCCCCTTCAA CACCTCTGTG GTGTACAAGA AGACCCTGTT 780 TGTGGAGTTC ACTGACCACC TGTTCAACAT TGCCAAGCCC AGGCCCCCCT GGATGGGCCT 840 GCTGGGCCCC ACCATCCAGG CTGAGGTGTA TGACACTGTG GTGATCACCC TGAAGAACAT 900 GGCCAGCCAC CCTGTGAGCC TGCATGCTGT GGGGGTGAGC TACTGGAAGG CCTCTGAGGG 960 GGCTGAGTAT GATGACCAGA CCAGCCAGAG GGAGAAGGAG GATGACAAGG TGTTCCCTGG 1020 GGGCAGCCAC ACCTATGTGT GGCAGGTGCT GAAGGAGAAT GGCCCCATGG CCTCTGACCC 1080 CCTGTGCCTG ACCTACAGCT ACCTGAGCCA TGTGGACCTG GTGAAGGACC TGAACTCTGG 1140 CCTGATTGGG GCCCTGCTGG TGTGCAGGGA GGGCAGCCTG GCCAAGGAGA AGACCCAGAC 1200 CCTGCACAAG TTCATCCTGC TGTTTGCTGT GTTTGATGAG GGCAAGAGCT GGCACTCTGA 1260 AACCAAGAAC AGCCTGATGC AGGACAGGGA TGCTGCCTCT GCCAGGGCCT GGCCCAAGAT 1320 GCACACTGTG AATGGCTATG TGAACAGGAG CCTGCCTGGC CTGATTGGCT GCCACAGGAA 1380 GTCTGTGTAC TGGCATGTGA TTGGCATGGG CACCACCCCT GAGGTGCACA GCATCTTCCT 1440 GGAGGGCCAC ACCTTCCTGG TCAGGAACCA CAGGCAGGCC AGCCTGGAGA TCAGCCCCAT 1500 CACCTTCCTG ACTGCCCAGA CCCTGCTGAT GGACCTGGGC CAGTTCCTGC TGTTCTGCCA 1560 CATCAGCAGC CACCAGCATG ATGGCATGGA GGCCTATGTG AAGGTGGACA GCTGCCCTGA 1620 GGAGCCCCAG CTGAGGATGA AGAACAATGA GGAGGCTGAG GACTATGATG ATGACCTGAC 1680 TGACTCTGAG ATGGATGTGG TGAGGTTTGA TGATGACAAC AGCCCCAGCT TCATCCAGAT 1740 CAGGTCTGTG GCCAAGAAGC ACCCCAAGAC CTGGGTGCAC TACATTGCTG CTGAGGAGGA 1800 GGACTGGGAC TATGCCCCCC TGGTGCTGGC CCCTGATGAC AGGAGCTACA AGAGCCAGTA 1860 CCTGAACAAT GGCCCCCAGA GGATTGGCAG GAAGTACAAG AAGGTCAGGT TCATGGCCTA 1920 CACTGATGAA ACCTTCAAGA CCAGGGAGGC CATCCAGCAT GAGTCTGGCA TCCTGGGCCC 1980 CCTGCTGTAT GGGGAGGTGG GGGACACCCT GCTGATCATC TTCAAGAACC AGGCCAGCAG 2040 GCCCTACAAC ATCTACCCCC ATGGCATCAC TGATGTGAGG CCCCTGTACA GCAGGAGGCT 2100 GCCCAAGGGG GTGAAGCACC TGAAGGACTT CCCCATCCTG CCTGGGGAGA TCTTCAAGTA 2160 CAAGTGGACT GTGACTGTGG AGGATGGCCC CACCAAGTCT GACCCCAGGT GCCTGACCAG 2220 ATACTACAGC AGCTTTGTGA ACATGGAGAG GGACCTGGCC TCTGGCCTGA TTGGCCCCCT 2280 GCTGATCTGC TACAAGGAGT CTGTGGACCA GAGGGGCAAC CAGATCATGT CTGACAAGAG 2340 GAATGTGATC CTGTTCTCTG TGTTTGATGA GAACAGGAGC TGGTACCTGA CTGAGAACAT 2400 CCAGAGGTTC CTGCCCAACC CTGCTGGGGT GCAGCTGGAG GACCCTGAGT TCCAGGCCAG 2460 CAACATCATG CACAGCATCA ATGGCTATGT GTTTGACAGC CTGCAGCTGT CTGTGTGCCT 2520 GCATGAGGTG GCCTACTGGT ACATCCTGAG CATTGGGGCC CAGACTGACT TCCTGTCTGT 2580 GTTCTTCTCT GGCTACACCT TCAAGCACAA GATGGTGTAT GAGGACACCC TGACCCTGTT 2640 CCCCTTCTCT GGGGAGACTG TGTTCATGAG CATGGAGAAC CCTGGCCTGT GGATTCTGGG 2700 CTGCCACAAC TCTGACTTCA GGAACAGGGG CATGACTGCC CTGCTGAAAG TCTCCAGCTG 2760 TGACAAGAAC ACTGGGGACT ACTATGAGGA CAGCTATGAG GACATCTCTG CCTACCTGCT 2820 GAGCAAGAAC AATGCCATTG AGCCCAGGAG CTTCAGCCAG AACCCCCCAG TGCTGAAGAG 2880 GCACCAGAGG GAGATCACCA GGACCACCCT GCAGTCTGAC CAGGAGGAGA TTGACTATGA 2940 TGACACCATC TCTGTGGAGA TGAAGAAGGA GGACTTTGAC ATCTACGACG AGGACGAGAA 3000 CCAGAGCCCC AGGAGCTTCC AGAAGAAGAC CAGGCACTAC TTCATTGCTG CTGTGGAGAG 3060 GCTGTGGGAC TATGGCATGA GCAGCAGCCC CCATGTGCTG AGGAACAGGG CCCAGTCTGG 3120 CTCTGTGCCC CAGTTCAAGA AGGTGGTGTT CCAGGAGTTC ACTGATGGCA GCTTCACCCA 3180 GCCCCTGTAC AGAGGGGAGC TGAATGAGCA CCTGGGCCTG CTGGGCCCCT ACATCAGGGC 3240 TGAGGTGGAG GACAACATCA TGGTGACCTT CAGGAACCAG GCCAGCAGGC CCTACAGCTT 3300 CTACAGCAGC CTGATCAGCT ATGAGGAGGA CCAGAGGCAG GGGGCTGAGC CCAGGAAGAA 3360 CTTTGTGAAG CCCAATGAAA CCAAGACCTA CTTCTGGAAG GTGCAGCACC ACATGGCCCC 3420 CACCAAGGAT GAGTTTGACT GCAAGGCCTG GGCCTACTTC TCTGATGTGG ACCTGGAGAA 3480 GGATGTGCAC TCTGGCCTGA TTGGCCCCCT GCTGGTGTGC CACACCAACA CCCTGAACCC 3540 TGCCCATGGC AGGCAGGTGA CTGTGCAGGA GTTTGCCCTG TTCTTCACCA TCTTTGATGA 3600 AACCAAGAGC TGGTACTTCA CTGAGAACAT GGAGAGGAAC TGCAGGGCCC CCTGCAACAT 3660 CCAGATGGAG GACCCCACCT TCAAGGAGAA CTACAGGTTC CATGCCATCA ATGGCTACAT 3720 CATGGACACC CTGCCTGGCC TGGTGATGGC CCAGGACCAG AGGATCAGGT GGTACCTGCT 3780 GAGCATGGGC AGCAATGAGA ACATCCACAG CATCCACTTC TCTGGCCATG TGTTCACTGT 3840 GAGGAAGAAG GAGGAGTACA AGATGGCCCT GTACAACCTG TACCCTGGGG TGTTTGAGAC 3900 TGTGGAGATG CTGCCCAGCA AGGCTGGCAT CTGGAGGGTG GAGTGCCTGA TTGGGGAGCA 3960 CCTGCATGCT GGCATGAGCA CCCTGTTCCT GGTGTACAGC AACAAGTGCC AGACCCCCCT 4020 GGGCATGGCC TCTGGCCACA TCAGGGACTT CCAGATCACT GCCTCTGGCC AGTATGGCCA 4080 GTGGGCCCCC AAGCTGGCCA GGCTGCACTA CTCTGGCAGC ATCAATGCCT GGAGCACCAA 4140 GGAGCCCTTC AGCTGGATCA AGGTGGACCT GCTGGCCCCC ATGATCATCC ATGGCATCAA 4200 GACCCAGGGG GCCAGGCAGA AGTTCAGCAG CCTGTACATC AGCCAGTTCA TCATCATGTA 4260 CAGCCTGGAT GGCAAGAAGT GGCAGACCTA CAGGGGCAAC AGCACTGGCA CCCTGATGGT 4320 GTTCTTTGGC AATGTGGACA GCTCTGGCAT CAAGCACAAC ATCTTCAACC CCCCCATCAT 4380 TGCCAGATAC ATCAGGCTGC ACCCCACCCA CTACAGCATC AGGAGCACCC TGAGGATGGA 4440 GCTGATGGGC TGTGACCTGA ACAGCTGCAG CATGCCCCTG GGCATGGAGA GCAAGGCCAT 4500 CTCTGATGCC CAGATCACTG CCAGCAGCTA CTTCACCAAC ATGTTTGCCA CCTGGAGCCC 4560 CAGCAAGGCC AGGCTGCACC TGCAGGGCAG GAGCAATGCC TGGAGGCCCC AGGTCAACAA 4620 CCCCAAGGAG TGGCTGCAGG TGGACTTCCA GAAGACCATG AAGGTGACTG GGGTGACCAC 4680 CCAGGGGGTG AAGAGCCTGC TGACCAGCAT GTATGTGAAG GAGTTCCTGA TCAGCAGCAG 4740 CCAGGATGGC CACCAGTGGA CCCTGTTCTT CCAGAATGGC AAGGTGAAGG TGTTCCAGGG 4800 CAACCAGGAC AGCTTCACCC CTGTGGTGAA CAGCCTGGAC CCCCCCCTGC TGACCAGATA 4860 CCTGAGGATT CACCCCCAGA GCTGGGTGCA CCAGATTGCC CTGAGGATGG AGGTGCTGGG 4920 CTGTGAGGCC CAGGACCTGT ACTGACCTCG AGGAATAAAG GAAATTTATT TTCATTGCAA 4980 TAGTGTGTTG GTTTTTTGTG TCACGTGGCG GCCGCAGGAA CCCCTAGTGA TGGAGTTGGC 5040 CACTCCCTCT CTGCGCGCTC GCTCGCTCAC TGAGGCCGGG CGACCAAAGG TCGCCCGACG 5100 CCCGGGCTTT GCCCGGGCGG CCTCAGTGAG CGAGCGAGCG CGCAGAGAGG GAGTGGCCAA 5160 SEQ ID NO: 38 <211> 5383 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 38 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACT 360 GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC AGATCCCAGC CAGTGGACTT 420 AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC 480 CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC 540 AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGTA AGTATGCCTT TCACTGCGAG 600 AGGTTCTGGA GAGGCTTCTG AGCTCCCCAT GGCCCAGGCA GGCAGCAGGT CTGGGGCAGG 660 AGGGGGGTTG TGGAGTGCCT TGACTCGGGG CCTGGCCCCC CCATCTCTGT CTTGCAGGAC 720 AATTGCCGTC TTCTGTCTCG TGGGGCATCC TCCTGCTGGC AGGCCTGTGC TGCCTGGTCC 780 CTGCGATCGC CACCATGCAG ATTGAGCTGA GCACCTGCTT CTTCCTGTGC CTGCTGAGGT 840 TCTGCTTCTC TGCCACCAGG AGATACTACC TGGGGGCTGT GGAGCTGAGC TGGGACTACA 900 TGCAGTCTGA CCTGGGGGAG CTGCCTGTGG ATGCCAGGTT CCCCCCCAGA GTGCCCAAGA 960 GCTTCCCCTT CAACACCTCT GTGGTGTACA AGAAGACCCT GTTTGTGGAG TTCACTGACC 1020 ACCTGTTCAA CATTGCCAAG CCCAGGCCCC CCTGGATGGG CCTGCTGGGC CCCACCATCC 1080 AGGCTGAGGT GTATGACACT GTGGTGATCA CCCTGAAGAA CATGGCCAGC CACCCTGTGA 1140 GCCTGCATGC TGTGGGGGTG AGCTACTGGA AGGCCTCTGA GGGGGCTGAG TATGATGACC 1200 AGACCAGCCA GAGGGAGAAG GAGGATGACA AGGTGTTCCC TGGGGGCAGC CACACCTATG 1260 TGTGGCAGGT GCTGAAGGAG AATGGCCCCA TGGCCTCTGA CCCCCTGTGC CTGACCTACA 1320 GCTACCTGAG CCATGTGGAC CTGGTGAAGG ACCTGAACTC TGGCCTGATT GGGGCCCTGC 1380 TGGTGTGCAG GGAGGGCAGC CTGGCCAAGG AGAAGACCCA GACCCTGCAC AAGTTCATCC 1440 TGCTGTTTGC TGTGTTTGAT GAGGGCAAGA GCTGGCACTC TGAAACCAAG AACAGCCTGA 1500 TGCAGGACAG GGATGCTGCC TCTGCCAGGG CCTGGCCCAA GATGCACACT GTGAATGGCT 1560 ATGTGAACAG GAGCCTGCCT GGCCTGATTG GCTGCCACAG GAAGTCTGTG TACTGGCATG 1620 TGATTGGCAT GGGCACCACC CCTGAGGTGC ACAGCATCTT CCTGGAGGGC CACACCTTCC 1680 TGGTCAGGAA CCACAGGCAG GCCAGCCTGG AGATCAGCCC CATCACCTTC CTGACTGCCC 1740 AGACCCTGCT GATGGACCTG GGCCAGTTCC TGCTGTTCTG CCACATCAGC AGCCACCAGC 1800 ATGATGGCAT GGAGGCCTAT GTGAAGGTGG ACAGCTGCCC TGAGGAGCCC CAGCTGAGGA 1860 TGAAGAACAA TGAGGAGGCT GAGGACTATG ATGATGACCT GACTGACTCT GAGATGGATG 1920 TGGTGAGGTT TGATGATGAC AACAGCCCCA GCTTCATCCA GATCAGGTCT GTGGCCAAGA 1980 AGCACCCCAA GACCTGGGTG CACTACATTG CTGCTGAGGA GGAGGACTGG GACTATGCCC 2040 CCCTGGTGCT GGCCCCTGAT GACAGGAGCT ACAAGAGCCA GTACCTGAAC AATGGCCCCC 2100 AGAGGATTGG CAGGAAGTAC AAGAAGGTCA GGTTCATGGC CTACACTGAT GAAACCTTCA 2160 AGACCAGGGA GGCCATCCAG CATGAGTCTG GCATCCTGGG CCCCCTGCTG TATGGGGAGG 2220 TGGGGGACAC CCTGCTGATC ATCTTCAAGA ACCAGGCCAG CAGGCCCTAC AACATCTACC 2280 CCCATGGCAT CACTGATGTG AGGCCCCTGT ACAGCAGGAG GCTGCCCAAG GGGGTGAAGC 2340 ACCTGAAGGA CTTCCCCATC CTGCCTGGGG AGATCTTCAA GTACAAGTGG ACTGTGACTG 2400 TGGAGGATGG CCCCACCAAG TCTGACCCCA GGTGCCTGAC CAGATACTAC AGCAGCTTTG 2460 TGAACATGGA GAGGGACCTG GCCTCTGGCC TGATTGGCCC CCTGCTGATC TGCTACAAGG 2520 AGTCTGTGGA CCAGAGGGGC AACCAGATCA TGTCTGACAA GAGGAATGTG ATCCTGTTCT 2580 CTGTGTTTGA TGAGAACAGG AGCTGGTACC TGACTGAGAA CATCCAGAGG TTCCTGCCCA 2640 ACCCTGCTGG GGTGCAGCTG GAGGACCCTG AGTTCCAGGC CAGCAACATC ATGCACAGCA 2700 TCAATGGCTA TGTGTTTGAC AGCCTGCAGC TGTCTGTGTG CCTGCATGAG GTGGCCTACT 2760 GGTACATCCT GAGCATTGGG GCCCAGACTG ACTTCCTGTC TGTGTTCTTC TCTGGCTACA 2820 CCTTCAAGCA CAAGATGGTG TATGAGGACA CCCTGACCCT GTTCCCCTTC TCTGGGGAGA 2880 CTGTGTTCAT GAGCATGGAG AACCCTGGCC TGTGGATTCT GGGCTGCCAC AACTCTGACT 2940 TCAGGAACAG GGGCATGACT GCCCTGCTGA AAGTCTCCAG CTGTGACAAG AACACTGGGG 3000 ACTACTATGA GGACAGCTAT GAGGACATCT CTGCCTACCT GCTGAGCAAG AACAATGCCA 3060 TTGAGCCCAG GAGCTTCAGC CAGAACCCCC CAGTGCTGAA GAGGCACCAG AGGGAGATCA 3120 CCAGGACCAC CCTGCAGTCT GACCAGGAGG AGATTGACTA TGATGACACC ATCTCTGTGG 3180 AGATGAAGAA GGAGGACTTT GACATCTACG ACGAGGACGA GAACCAGAGC CCCAGGAGCT 3240 TCCAGAAGAA GACCAGGCAC TACTTCATTG CTGCTGTGGA GAGGCTGTGG GACTATGGCA 3300 TGAGCAGCAG CCCCCATGTG CTGAGGAACA GGGCCCAGTC TGGCTCTGTG CCCCAGTTCA 3360 AGAAGGTGGT GTTCCAGGAG TTCACTGATG GCAGCTTCAC CCAGCCCCTG TACAGAGGGG 3420 AGCTGAATGA GCACCTGGGC CTGCTGGGCC CCTACATCAG GGCTGAGGTG GAGGACAACA 3480 TCATGGTGAC CTTCAGGAAC CAGGCCAGCA GGCCCTACAG CTTCTACAGC AGCCTGATCA 3540 GCTATGAGGA GGACCAGAGG CAGGGGGCTG AGCCCAGGAA GAACTTTGTG AAGCCCAATG 3600 AAACCAAGAC CTACTTCTGG AAGGTGCAGC ACCACATGGC CCCCACCAAG GATGAGTTTG 3660 ACTGCAAGGC CTGGGCCTAC TTCTCTGATG TGGACCTGGA GAAGGATGTG CACTCTGGCC 3720 TGATTGGCCC CCTGCTGGTG TGCCACACCA ACACCCTGAA CCCTGCCCAT GGCAGGCAGG 3780 TGACTGTGCA GGAGTTTGCC CTGTTCTTCA CCATCTTTGA TGAAACCAAG AGCTGGTACT 3840 TCACTGAGAA CATGGAGAGG AACTGCAGGG CCCCCTGCAA CATCCAGATG GAGGACCCCA 3900 CCTTCAAGGA GAACTACAGG TTCCATGCCA TCAATGGCTA CATCATGGAC ACCCTGCCTG 3960 GCCTGGTGAT GGCCCAGGAC CAGAGGATCA GGTGGTACCT GCTGAGCATG GGCAGCAATG 4020 AGAACATCCA CAGCATCCAC TTCTCTGGCC ATGTGTTCAC TGTGAGGAAG AAGGAGGAGT 4080 ACAAGATGGC CCTGTACAAC CTGTACCCTG GGGTGTTTGA GACTGTGGAG ATGCTGCCCA 4140 GCAAGGCTGG CATCTGGAGG GTGGAGTGCC TGATTGGGGA GCACCTGCAT GCTGGCATGA 4200 GCACCCTGTT CCTGGTGTAC AGCAACAAGT GCCAGACCCC CCTGGGCATG GCCTCTGGCC 4260 ACATCAGGGA CTTCCAGATC ACTGCCTCTG GCCAGTATGG CCAGTGGGCC CCCAAGCTGG 4320 CCAGGCTGCA CTACTCTGGC AGCATCAATG CCTGGAGCAC CAAGGAGCCC TTCAGCTGGA 4380 TCAAGGTGGA CCTGCTGGCC CCCATGATCA TCCATGGCAT CAAGACCCAG GGGGCCAGGC 4440 AGAAGTTCAG CAGCCTGTAC ATCAGCCAGT TCATCATCAT GTACAGCCTG GATGGCAAGA 4500 AGTGGCAGAC CTACAGGGGC AACAGCACTG GCACCCTGAT GGTGTTCTTT GGCAATGTGG 4560 ACAGCTCTGG CATCAAGCAC AACATCTTCA ACCCCCCCAT CATTGCCAGA TACATCAGGC 4620 TGCACCCCAC CCACTACAGC ATCAGGAGCA CCCTGAGGAT GGAGCTGATG GGCTGTGACC 4680 TGAACAGCTG CAGCATGCCC CTGGGCATGG AGAGCAAGGC CATCTCTGAT GCCCAGATCA 4740 CTGCCAGCAG CTACTTCACC AACATGTTTG CCACCTGGAG CCCCAGCAAG GCCAGGCTGC 4800 ACCTGCAGGG CAGGAGCAAT GCCTGGAGGC CCCAGGTCAA CAACCCCAAG GAGTGGCTGC 4860 AGGTGGACTT CCAGAAGACC ATGAAGGTGA CTGGGGTGAC CACCCAGGGG GTGAAGAGCC 4920 TGCTGACCAG CATGTATGTG AAGGAGTTCC TGATCAGCAG CAGCCAGGAT GGCCACCAGT 4980 GGACCCTGTT CTTCCAGAAT GGCAAGGTGA AGGTGTTCCA GGGCAACCAG GACAGCTTCA 5040 CCCCTGTGGT GAACAGCCTG GACCCCCCCC TGCTGACCAG ATACCTGAGG ATTCACCCCC 5100 AGAGCTGGGT GCACCAGATT GCCCTGAGGA TGGAGGTGCT GGGCTGTGAG GCCCAGGACC 5160 TGTACTGACC TCGAGGAATA AAGGAAATTT ATTTTCATTG CAATAGTGTG TTGGTTTTTT 5220 GTGTCACGTG GCGGCCGCAG GAACCCCTAG TGATGGAGTT GGCCACTCCC TCTCTGCGCG 5280 CTCGCTCGCT CACTGAGGCC GGGCGACCAA AGGTCGCCCG ACGCCCGGGC TTTGCCCGGG 5340 CGGCCTCAGT GAGCGAGCGA GCGCGCAGAG AGGGAGTGGC CAA 5383 SEQ ID NO: 39 <211> 5728 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 39 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACA 360 GGTTAATTTT TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT 420 GTTTGCTCTG GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA 480 ACATCCTGGA CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTCA GGTTAATTTT 540 TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT GTTTGCTCTG 600 GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA ACATCCTGGA 660 CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTGT CGACTGGACA CAGGACGCTG 720 TGGTTTCTGA GCCAGGGGGC GACTCAGATC CCAGCCAGTG GACTTAGCCC CTGTTTGCTC 780 CTCCGATAAC TGGGGTGACC TTGGTTAATA TTCACCAGCA GCCTCCCCCG TTGCCCCTCT 840 GGATCCACTG CTTAAATACG GACGAGGACA GGGCCCTGTC TCCTCAGCTT CAGGCACCAC 900 CACTGACCTG GGACAGTGAA TCGTAAGTAT GCCTTTCACT GCGAGAGGTT CTGGAGAGGC 960 TTCTGAGCTC CCCATGGCCC AGGCAGGCAG CAGGTCTGGG GCAGGAGGGG GGTTGTGGAG 1020 TGCCTTGACT CGGGGCCTGG CCCCCCCATC TCTGTCTTGC AGGACAATTG CCGTCTTCTG 1080 TCTCGTGGGG CATCCTCCTG CTGGCAGGCC TGTGCTGCCT GGTCCCTGCG ATCGCCACCA 1140 TGCAGATTGA GCTGAGCACC TGCTTCTTCC TGTGCCTGCT GAGGTTCTGC TTCTCTGCCA 1200 CCAGGAGATA CTACCTGGGG GCTGTGGAGC TGAGCTGGGA CTACATGCAG TCTGACCTGG 1260 GGGAGCTGCC TGTGGATGCC AGGTTCCCCC CCAGAGTGCC CAAGAGCTTC CCCTTCAACA 1320 CCTCTGTGGT GTACAAGAAG ACCCTGTTTG TGGAGTTCAC TGACCACCTG TTCAACATTG 1380 CCAAGCCCAG GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC CATCCAGGCT GAGGTGTATG 1440 ACACTGTGGT GATCACCCTG AAGAACATGG CCAGCCACCC TGTGAGCCTG CATGCTGTGG 1500 GGGTGAGCTA CTGGAAGGCC TCTGAGGGGG CTGAGTATGA TGACCAGACC AGCCAGAGGG 1560 AGAAGGAGGA TGACAAGGTG TTCCCTGGGG GCAGCCACAC CTATGTGTGG CAGGTGCTGA 1620 AGGAGAATGG CCCCATGGCC TCTGACCCCC TGTGCCTGAC CTACAGCTAC CTGAGCCATG 1680 TGGACCTGGT GAAGGACCTG AACTCTGGCC TGATTGGGGC CCTGCTGGTG TGCAGGGAGG 1740 GCAGCCTGGC CAAGGAGAAG ACCCAGACCC TGCACAAGTT CATCCTGCTG TTTGCTGTGT 1800 TTGATGAGGG CAAGAGCTGG CACTCTGAAA CCAAGAACAG CCTGATGCAG GACAGGGATG 1860 CTGCCTCTGC CAGGGCCTGG CCCAAGATGC ACACTGTGAA TGGCTATGTG AACAGGAGCC 1920 TGCCTGGCCT GATTGGCTGC CACAGGAAGT CTGTGTACTG GCATGTGATT GGCATGGGCA 1980 CCACCCCTGA GGTGCACAGC ATCTTCCTGG AGGGCCACAC CTTCCTGGTC AGGAACCACA 2040 GGCAGGCCAG CCTGGAGATC AGCCCCATCA CCTTCCTGAC TGCCCAGACC CTGCTGATGG 2100 ACCTGGGCCA GTTCCTGCTG TTCTGCCACA TCAGCAGCCA CCAGCATGAT GGCATGGAGG 2160 CCTATGTGAA GGTGGACAGC TGCCCTGAGG AGCCCCAGCT GAGGATGAAG AACAATGAGG 2220 AGGCTGAGGA CTATGATGAT GACCTGACTG ACTCTGAGAT GGATGTGGTG AGGTTTGATG 2280 ATGACAACAG CCCCAGCTTC ATCCAGATCA GGTCTGTGGC CAAGAAGCAC CCCAAGACCT 2340 GGGTGCACTA CATTGCTGCT GAGGAGGAGG ACTGGGACTA TGCCCCCCTG GTGCTGGCCC 2400 CTGATGACAG GAGCTACAAG AGCCAGTACC TGAACAATGG CCCCCAGAGG ATTGGCAGGA 2460 AGTACAAGAA GGTCAGGTTC ATGGCCTACA CTGATGAAAC CTTCAAGACC AGGGAGGCCA 2520 TCCAGCATGA GTCTGGCATC CTGGGCCCCC TGCTGTATGG GGAGGTGGGG GACACCCTGC 2580 TGATCATCTT CAAGAACCAG GCCAGCAGGC CCTACAACAT CTACCCCCAT GGCATCACTG 2640 ATGTGAGGCC CCTGTACAGC AGGAGGCTGC CCAAGGGGGT GAAGCACCTG AAGGACTTCC 2700 CCATCCTGCC TGGGGAGATC TTCAAGTACA AGTGGACTGT GACTGTGGAG GATGGCCCCA 2760 CCAAGTCTGA CCCCAGGTGC CTGACCAGAT ACTACAGCAG CTTTGTGAAC ATGGAGAGGG 2820 ACCTGGCCTC TGGCCTGATT GGCCCCCTGC TGATCTGCTA CAAGGAGTCT GTGGACCAGA 2880 GGGGCAACCA GATCATGTCT GACAAGAGGA ATGTGATCCT GTTCTCTGTG TTTGATGAGA 2940 ACAGGAGCTG GTACCTGACT GAGAACATCC AGAGGTTCCT GCCCAACCCT GCTGGGGTGC 3000 AGCTGGAGGA CCCTGAGTTC CAGGCCAGCA ACATCATGCA CAGCATCAAT GGCTATGTGT 3060 TTGACAGCCT GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC CTACTGGTAC ATCCTGAGCA 3120 TTGGGGCCCA GACTGACTTC CTGTCTGTGT TCTTCTCTGG CTACACCTTC AAGCACAAGA 3180 TGGTGTATGA GGACACCCTG ACCCTGTTCC CCTTCTCTGG GGAGACTGTG TTCATGAGCA 3240 TGGAGAACCC TGGCCTGTGG ATTCTGGGCT GCCACAACTC TGACTTCAGG AACAGGGGCA 3300 TGACTGCCCT GCTGAAAGTC TCCAGCTGTG ACAAGAACAC TGGGGACTAC TATGAGGACA 3360 GCTATGAGGA CATCTCTGCC TACCTGCTGA GCAAGAACAA TGCCATTGAG CCCAGGAGCT 3420 TCAGCCAGAA CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA GATCACCAGG ACCACCCTGC 3480 AGTCTGACCA GGAGGAGATT GACTATGATG ACACCATCTC TGTGGAGATG AAGAAGGAGG 3540 ACTTTGACAT CTACGACGAG GACGAGAACC AGAGCCCCAG GAGCTTCCAG AAGAAGACCA 3600 GGCACTACTT CATTGCTGCT GTGGAGAGGC TGTGGGACTA TGGCATGAGC AGCAGCCCCC 3660 ATGTGCTGAG GAACAGGGCC CAGTCTGGCT CTGTGCCCCA GTTCAAGAAG GTGGTGTTCC 3720 AGGAGTTCAC TGATGGCAGC TTCACCCAGC CCCTGTACAG AGGGGAGCTG AATGAGCACC 3780 TGGGCCTGCT GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA CAACATCATG GTGACCTTCA 3840 GGAACCAGGC CAGCAGGCCC TACAGCTTCT ACAGCAGCCT GATCAGCTAT GAGGAGGACC 3900 AGAGGCAGGG GGCTGAGCCC AGGAAGAACT TTGTGAAGCC CAATGAAACC AAGACCTACT 3960 TCTGGAAGGT GCAGCACCAC ATGGCCCCCA CCAAGGATGA GTTTGACTGC AAGGCCTGGG 4020 CCTACTTCTC TGATGTGGAC CTGGAGAAGG ATGTGCACTC TGGCCTGATT GGCCCCCTGC 4080 TGGTGTGCCA CACCAACACC CTGAACCCTG CCCATGGCAG GCAGGTGACT GTGCAGGAGT 4140 TTGCCCTGTT CTTCACCATC TTTGATGAAA CCAAGAGCTG GTACTTCACT GAGAACATGG 4200 AGAGGAACTG CAGGGCCCCC TGCAACATCC AGATGGAGGA CCCCACCTTC AAGGAGAACT 4260 ACAGGTTCCA TGCCATCAAT GGCTACATCA TGGACACCCT GCCTGGCCTG GTGATGGCCC 4320 AGGACCAGAG GATCAGGTGG TACCTGCTGA GCATGGGCAG CAATGAGAAC ATCCACAGCA 4380 TCCACTTCTC TGGCCATGTG TTCACTGTGA GGAAGAAGGA GGAGTACAAG ATGGCCCTGT 4440 ACAACCTGTA CCCTGGGGTG TTTGAGACTG TGGAGATGCT GCCCAGCAAG GCTGGCATCT 4500 GGAGGGTGGA GTGCCTGATT GGGGAGCACC TGCATGCTGG CATGAGCACC CTGTTCCTGG 4560 TGTACAGCAA CAAGTGCCAG ACCCCCCTGG GCATGGCCTC TGGCCACATC AGGGACTTCC 4620 AGATCACTGC CTCTGGCCAG TATGGCCAGT GGGCCCCCAA GCTGGCCAGG CTGCACTACT 4680 CTGGCAGCAT CAATGCCTGG AGCACCAAGG AGCCCTTCAG CTGGATCAAG GTGGACCTGC 4740 TGGCCCCCAT GATCATCCAT GGCATCAAGA CCCAGGGGGC CAGGCAGAAG TTCAGCAGCC 4800 TGTACATCAG CCAGTTCATC ATCATGTACA GCCTGGATGG CAAGAAGTGG CAGACCTACA 4860 GGGGCAACAG CACTGGCACC CTGATGGTGT TCTTTGGCAA TGTGGACAGC TCTGGCATCA 4920 AGCACAACAT CTTCAACCCC CCCATCATTG CCAGATACAT CAGGCTGCAC CCCACCCACT 4980 ACAGCATCAG GAGCACCCTG AGGATGGAGC TGATGGGCTG TGACCTGAAC AGCTGCAGCA 5040 TGCCCCTGGG CATGGAGAGC AAGGCCATCT CTGATGCCCA GATCACTGCC AGCAGCTACT 5100 TCACCAACAT GTTTGCCACC TGGAGCCCCA GCAAGGCCAG GCTGCACCTG CAGGGCAGGA 5160 GCAATGCCTG GAGGCCCCAG GTCAACAACC CCAAGGAGTG GCTGCAGGTG GACTTCCAGA 5220 AGACCATGAA GGTGACTGGG GTGACCACCC AGGGGGTGAA GAGCCTGCTG ACCAGCATGT 5280 ATGTGAAGGA GTTCCTGATC AGCAGCAGCC AGGATGGCCA CCAGTGGACC CTGTTCTTCC 5340 AGAATGGCAA GGTGAAGGTG TTCCAGGGCA ACCAGGACAG CTTCACCCCT GTGGTGAACA 5400 GCCTGGACCC CCCCCTGCTG ACCAGATACC TGAGGATTCA CCCCCAGAGC TGGGTGCACC 5460 AGATTGCCCT GAGGATGGAG GTGCTGGGCT GTGAGGCCCA GGACCTGTAC TGACCTCGAG 5520 GAATAAAGGA AATTTATTTT CATTGCAATA GTGTGTTGGT TTTTTGTGTC ACGTGGCGGC 5580 CGCAGGAACC CCTAGTGATG GAGTTGGCCA CTCCCTCTCT GCGCGCTCGC TCGCTCACTG 5640 AGGCCGGGCG ACCAAAGGTC GCCCGACGCC CGGGCTTTGC CCGGGCGGCC TCAGTGAGCG 5700 AGCGAGCGCG CAGAGAGGGA GTGGCCAA 5728 SEQ ID NO: 40 <211> 5905 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 40 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACA 360 GGTTAATTTT TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT 420 GTTTGCTCTG GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA 480 ACATCCTGGA CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTCA GGTTAATTTT 540 TAAAAAGCAG TCAAAAGTCC AAGTGGCCCT TGGCAGCATT TACTCTCTCT GTTTGCTCTG 600 GTTAATAATC TCAGGAGCAC AAACATTCCT GGAGGCAGGA GAAGAAATCA ACATCCTGGA 660 CTTATCCTCT GGGCCTCTCC CCACCCCCAG GAGAGGCTGT CGACTGGACA CAGGACGCTG 720 TGGTTTCTGA GCCAGGGGGC GACTCAGATC CCAGCCAGTG GACTTAGCCC CTGTTTGCTC 780 CTCCGATAAC TGGGGTGACC TTGGTTAATA TTCACCAGCA GCCTCCCCCG TTGCCCCTCT 840 GGATCCACTG CTTAAATACG GACGAGGACA GGGCCCTGTC TCCTCAGCTT CAGGCACCAC 900 CACTGACCTG GGACAGTGAA TCGTAAGTAT GCCTTTCACT GCGAGAGGTT CTGGAGAGGC 960 TTCTGAGCTC CCCATGGCCC AGGCAGGCAG CAGGTCTGGG GCAGGAGGGG GGTTGTGGAG 1020 TGCCTTGACT CGGGGCCTGG CCCCCCCATC TCTGTCTTGC AGGACAATTG CCGTCTTCTG 1080 TCTCGTGGGG CATCCTCCTG CTGGCAGGCC TGTGCTGCCT GGTCCCTGCG ATCGCCACCA 1140 TGCAGATTGA GCTGAGCACC TGCTTCTTCC TGTGCCTGCT GAGGTTCTGC TTCTCTGCCA 1200 CCAGGAGATA CTACCTGGGG GCTGTGGAGC TGAGCTGGGA CTACATGCAG TCTGACCTGG 1260 GGGAGCTGCC TGTGGATGCC AGGTTCCCCC CCAGAGTGCC CAAGAGCTTC CCCTTCAACA 1320 CCTCTGTGGT GTACAAGAAG ACCCTGTTTG TGGAGTTCAC TGACCACCTG TTCAACATTG 1380 CCAAGCCCAG GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC CATCCAGGCT GAGGTGTATG 1440 ACACTGTGGT GATCACCCTG AAGAACATGG CCAGCCACCC TGTGAGCCTG CATGCTGTGG 1500 GGGTGAGCTA CTGGAAGGCC TCTGAGGGGG CTGAGTATGA TGACCAGACC AGCCAGAGGG 1560 AGAAGGAGGA TGACAAGGTG TTCCCTGGGG GCAGCCACAC CTATGTGTGG CAGGTGCTGA 1620 AGGAGAATGG CCCCATGGCC TCTGACCCCC TGTGCCTGAC CTACAGCTAC CTGAGCCATG 1680 TGGACCTGGT GAAGGACCTG AACTCTGGCC TGATTGGGGC CCTGCTGGTG TGCAGGGAGG 1740 GCAGCCTGGC CAAGGAGAAG ACCCAGACCC TGCACAAGTT CATCCTGCTG TTTGCTGTGT 1800 TTGATGAGGG CAAGAGCTGG CACTCTGAAA CCAAGAACAG CCTGATGCAG GACAGGGATG 1860 CTGCCTCTGC CAGGGCCTGG CCCAAGATGC ACACTGTGAA TGGCTATGTG AACAGGAGCC 1920 TGCCTGGCCT GATTGGCTGC CACAGGAAGT CTGTGTACTG GCATGTGATT GGCATGGGCA 1980 CCACCCCTGA GGTGCACAGC ATCTTCCTGG AGGGCCACAC CTTCCTGGTC AGGAACCACA 2040 GGCAGGCCAG CCTGGAGATC AGCCCCATCA CCTTCCTGAC TGCCCAGACC CTGCTGATGG 2100 ACCTGGGCCA GTTCCTGCTG TTCTGCCACA TCAGCAGCCA CCAGCATGAT GGCATGGAGG 2160 CCTATGTGAA GGTGGACAGC TGCCCTGAGG AGCCCCAGCT GAGGATGAAG AACAATGAGG 2220 AGGCTGAGGA CTATGATGAT GACCTGACTG ACTCTGAGAT GGATGTGGTG AGGTTTGATG 2280 ATGACAACAG CCCCAGCTTC ATCCAGATCA GGTCTGTGGC CAAGAAGCAC CCCAAGACCT 2340 GGGTGCACTA CATTGCTGCT GAGGAGGAGG ACTGGGACTA TGCCCCCCTG GTGCTGGCCC 2400 CTGATGACAG GAGCTACAAG AGCCAGTACC TGAACAATGG CCCCCAGAGG ATTGGCAGGA 2460 AGTACAAGAA GGTCAGGTTC ATGGCCTACA CTGATGAAAC CTTCAAGACC AGGGAGGCCA 2520 TCCAGCATGA GTCTGGCATC CTGGGCCCCC TGCTGTATGG GGAGGTGGGG GACACCCTGC 2580 TGATCATCTT CAAGAACCAG GCCAGCAGGC CCTACAACAT CTACCCCCAT GGCATCACTG 2640 ATGTGAGGCC CCTGTACAGC AGGAGGCTGC CCAAGGGGGT GAAGCACCTG AAGGACTTCC 2700 CCATCCTGCC TGGGGAGATC TTCAAGTACA AGTGGACTGT GACTGTGGAG GATGGCCCCA 2760 CCAAGTCTGA CCCCAGGTGC CTGACCAGAT ACTACAGCAG CTTTGTGAAC ATGGAGAGGG 2820 ACCTGGCCTC TGGCCTGATT GGCCCCCTGC TGATCTGCTA CAAGGAGTCT GTGGACCAGA 2880 GGGGCAACCA GATCATGTCT GACAAGAGGA ATGTGATCCT GTTCTCTGTG TTTGATGAGA 2940 ACAGGAGCTG GTACCTGACT GAGAACATCC AGAGGTTCCT GCCCAACCCT GCTGGGGTGC 3000 AGCTGGAGGA CCCTGAGTTC CAGGCCAGCA ACATCATGCA CAGCATCAAT GGCTATGTGT 3060 TTGACAGCCT GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC CTACTGGTAC ATCCTGAGCA 3120 TTGGGGCCCA GACTGACTTC CTGTCTGTGT TCTTCTCTGG CTACACCTTC AAGCACAAGA 3180 TGGTGTATGA GGACACCCTG ACCCTGTTCC CCTTCTCTGG GGAGACTGTG TTCATGAGCA 3240 TGGAGAACCC TGGCCTGTGG ATTCTGGGCT GCCACAACTC TGACTTCAGG AACAGGGGCA 3300 TGACTGCCCT GCTGAAAGTC TCCAGCTGTG ACAAGAACAC TGGGGACTAC TATGAGGACA 3360 GCTATGAGGA CATCTCTGCC TACCTGCTGA GCAAGAACAA TGCCATTGAG CCCAGGAGCT 3420 TCAGCCAGAA CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA GATCACCAGG ACCACCCTGC 3480 AGTCTGACCA GGAGGAGATT GACTATGATG ACACCATCTC TGTGGAGATG AAGAAGGAGG 3540 ACTTTGACAT CTACGACGAG GACGAGAACC AGAGCCCCAG GAGCTTCCAG AAGAAGACCA 3600 GGCACTACTT CATTGCTGCT GTGGAGAGGC TGTGGGACTA TGGCATGAGC AGCAGCCCCC 3660 ATGTGCTGAG GAACAGGGCC CAGTCTGGCT CTGTGCCCCA GTTCAAGAAG GTGGTGTTCC 3720 AGGAGTTCAC TGATGGCAGC TTCACCCAGC CCCTGTACAG AGGGGAGCTG AATGAGCACC 3780 TGGGCCTGCT GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA CAACATCATG GTGACCTTCA 3840 GGAACCAGGC CAGCAGGCCC TACAGCTTCT ACAGCAGCCT GATCAGCTAT GAGGAGGACC 3900 AGAGGCAGGG GGCTGAGCCC AGGAAGAACT TTGTGAAGCC CAATGAAACC AAGACCTACT 3960 TCTGGAAGGT GCAGCACCAC ATGGCCCCCA CCAAGGATGA GTTTGACTGC AAGGCCTGGG 4020 CCTACTTCTC TGATGTGGAC CTGGAGAAGG ATGTGCACTC TGGCCTGATT GGCCCCCTGC 4080 TGGTGTGCCA CACCAACACC CTGAACCCTG CCCATGGCAG GCAGGTGACT GTGCAGGAGT 4140 TTGCCCTGTT CTTCACCATC TTTGATGAAA CCAAGAGCTG GTACTTCACT GAGAACATGG 4200 AGAGGAACTG CAGGGCCCCC TGCAACATCC AGATGGAGGA CCCCACCTTC AAGGAGAACT 4260 ACAGGTTCCA TGCCATCAAT GGCTACATCA TGGACACCCT GCCTGGCCTG GTGATGGCCC 4320 AGGACCAGAG GATCAGGTGG TACCTGCTGA GCATGGGCAG CAATGAGAAC ATCCACAGCA 4380 TCCACTTCTC TGGCCATGTG TTCACTGTGA GGAAGAAGGA GGAGTACAAG ATGGCCCTGT 4440 ACAACCTGTA CCCTGGGGTG TTTGAGACTG TGGAGATGCT GCCCAGCAAG GCTGGCATCT 4500 GGAGGGTGGA GTGCCTGATT GGGGAGCACC TGCATGCTGG CATGAGCACC CTGTTCCTGG 4560 TGTACAGCAA CAAGTGCCAG ACCCCCCTGG GCATGGCCTC TGGCCACATC AGGGACTTCC 4620 AGATCACTGC CTCTGGCCAG TATGGCCAGT GGGCCCCCAA GCTGGCCAGG CTGCACTACT 4680 CTGGCAGCAT CAATGCCTGG AGCACCAAGG AGCCCTTCAG CTGGATCAAG GTGGACCTGC 4740 TGGCCCCCAT GATCATCCAT GGCATCAAGA CCCAGGGGGC CAGGCAGAAG TTCAGCAGCC 4800 TGTACATCAG CCAGTTCATC ATCATGTACA GCCTGGATGG CAAGAAGTGG CAGACCTACA 4860 GGGGCAACAG CACTGGCACC CTGATGGTGT TCTTTGGCAA TGTGGACAGC TCTGGCATCA 4920 AGCACAACAT CTTCAACCCC CCCATCATTG CCAGATACAT CAGGCTGCAC CCCACCCACT 4980 ACAGCATCAG GAGCACCCTG AGGATGGAGC TGATGGGCTG TGACCTGAAC AGCTGCAGCA 5040 TGCCCCTGGG CATGGAGAGC AAGGCCATCT CTGATGCCCA GATCACTGCC AGCAGCTACT 5100 TCACCAACAT GTTTGCCACC TGGAGCCCCA GCAAGGCCAG GCTGCACCTG CAGGGCAGGA 5160 GCAATGCCTG GAGGCCCCAG GTCAACAACC CCAAGGAGTG GCTGCAGGTG GACTTCCAGA 5220 AGACCATGAA GGTGACTGGG GTGACCACCC AGGGGGTGAA GAGCCTGCTG ACCAGCATGT 5280 ATGTGAAGGA GTTCCTGATC AGCAGCAGCC AGGATGGCCA CCAGTGGACC CTGTTCTTCC 5340 AGAATGGCAA GGTGAAGGTG TTCCAGGGCA ACCAGGACAG CTTCACCCCT GTGGTGAACA 5400 GCCTGGACCC CCCCCTGCTG ACCAGATACC TGAGGATTCA CCCCCAGAGC TGGGTGCACC 5460 AGATTGCCCT GAGGATGGAG GTGCTGGGCT GTGAGGCCCA GGACCTGTAC TGACCTCGAG 5520 GTGTGCCTTC TAGTTGCCAG CCATCTGTTG TTTGCCCCTC CCCCGTGCCT TCCTTGACCC 5580 TGGAAGGTGC CACTCCCACT GTCCTTTCCT AATAAAATGA GGAAATTGCA TCGCATTGTC 5640 TGAGTAGGTG TCATTCTATT CTGGGGGGTG GGGTGGGGCA GGACAGCAAG GGGGAGGATT 5700 GGGAAGACAA TAGCAGGCAT GCTGGGGATG CGGTGGGCTC TATGGGCACG TGGCGGCCGC 5760 AGGAACCCCT AGTGATGGAG TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG 5820 CCGGGCGACC AAAGGTCGCC CGACGCCCGG GCTTTGCCCG GGCGGCCTCA GTGAGCGAGC 5880 GAGCGCGCAG AGAGGGAGTG GCCAA 5905 SEQ ID NO: 41 <211> 5355 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 41 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACTG TTTGCTGTTT 180 GCTGCTTGCA ATGTTTGCCC ATTTTAGGGA CATGTTTGCT GTTTGCTGCT TGCAATGTTT 240 GCCCATTTTA GGGACATGTT TGCTGTTTGC TGCTTGCAAT GTTTGCCCAT TTTAGGGACA 300 TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG GACAACGCGA AACGTCGACT 360 GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC AGATCCCAGC CAGTGGACTT 420 AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT TAATATTCAC CAGCAGCCTC 480 CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA GGACAGGGCC CTGTCTCCTC 540 AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGCG ATCGCCACCA TGCAGATTGA 600 GCTGAGCACC TGCTTCTTCC TGTGCCTGCT GAGGTTCTGC TTCTCTGCCA CCAGGAGATA 660 CTACCTGGGG GCTGTGGAGC TGAGCTGGGA CTACATGCAG TCTGACCTGG GGGAGCTGCC 720 TGTGGATGCC AGGTTCCCCC CCAGAGTGCC CAAGAGCTTC CCCTTCAACA CCTCTGTGGT 780 GTACAAGAAG ACCCTGTTTG TGGAGTTCAC TGACCACCTG TTCAACATTG CCAAGCCCAG 840 GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC CATCCAGGCT GAGGTGTATG ACACTGTGGT 900 GATCACCCTG AAGAACATGG CCAGCCACCC TGTGAGCCTG CATGCTGTGG GGGTGAGCTA 960 CTGGAAGGCC TCTGAGGGGG CTGAGTATGA TGACCAGACC AGCCAGAGGG AGAAGGAGGA 1020 TGACAAGGTG TTCCCTGGGG GCAGCCACAC CTATGTGTGG CAGGTGCTGA AGGAGAATGG 1080 CCCCATGGCC TCTGACCCCC TGTGCCTGAC CTACAGCTAC CTGAGCCATG TGGACCTGGT 1140 GAAGGACCTG AACTCTGGCC TGATTGGGGC CCTGCTGGTG TGCAGGGAGG GCAGCCTGGC 1200 CAAGGAGAAG ACCCAGACCC TGCACAAGTT CATCCTGCTG TTTGCTGTGT TTGATGAGGG 1260 CAAGAGCTGG CACTCTGAAA CCAAGAACAG CCTGATGCAG GACAGGGATG CTGCCTCTGC 1320 CAGGGCCTGG CCCAAGATGC ACACTGTGAA TGGCTATGTG AACAGGAGCC TGCCTGGCCT 1380 GATTGGCTGC CACAGGAAGT CTGTGTACTG GCATGTGATT GGCATGGGCA CCACCCCTGA 1440 GGTGCACAGC ATCTTCCTGG AGGGCCACAC CTTCCTGGTC AGGAACCACA GGCAGGCCAG 1500 CCTGGAGATC AGCCCCATCA CCTTCCTGAC TGCCCAGACC CTGCTGATGG ACCTGGGCCA 1560 GTTCCTGCTG TTCTGCCACA TCAGCAGCCA CCAGCATGAT GGCATGGAGG CCTATGTGAA 1620 GGTGGACAGC TGCCCTGAGG AGCCCCAGCT GAGGATGAAG AACAATGAGG AGGCTGAGGA 1680 CTATGATGAT GACCTGACTG ACTCTGAGAT GGATGTGGTG AGGTTTGATG ATGACAACAG 1740 CCCCAGCTTC ATCCAGATCA GGTCTGTGGC CAAGAAGCAC CCCAAGACCT GGGTGCACTA 1800 CATTGCTGCT GAGGAGGAGG ACTGGGACTA TGCCCCCCTG GTGCTGGCCC CTGATGACAG 1860 GAGCTACAAG AGCCAGTACC TGAACAATGG CCCCCAGAGG ATTGGCAGGA AGTACAAGAA 1920 GGTCAGGTTC ATGGCCTACA CTGATGAAAC CTTCAAGACC AGGGAGGCCA TCCAGCATGA 1980 GTCTGGCATC CTGGGCCCCC TGCTGTATGG GGAGGTGGGG GACACCCTGC TGATCATCTT 2040 CAAGAACCAG GCCAGCAGGC CCTACAACAT CTACCCCCAT GGCATCACTG ATGTGAGGCC 2100 CCTGTACAGC AGGAGGCTGC CCAAGGGGGT GAAGCACCTG AAGGACTTCC CCATCCTGCC 2160 TGGGGAGATC TTCAAGTACA AGTGGACTGT GACTGTGGAG GATGGCCCCA CCAAGTCTGA 2220 CCCCAGGTGC CTGACCAGAT ACTACAGCAG CTTTGTGAAC ATGGAGAGGG ACCTGGCCTC 2280 TGGCCTGATT GGCCCCCTGC TGATCTGCTA CAAGGAGTCT GTGGACCAGA GGGGCAACCA 2340 GATCATGTCT GACAAGAGGA ATGTGATCCT GTTCTCTGTG TTTGATGAGA ACAGGAGCTG 2400 GTACCTGACT GAGAACATCC AGAGGTTCCT GCCCAACCCT GCTGGGGTGC AGCTGGAGGA 2460 CCCTGAGTTC CAGGCCAGCA ACATCATGCA CAGCATCAAT GGCTATGTGT TTGACAGCCT 2520 GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC CTACTGGTAC ATCCTGAGCA TTGGGGCCCA 2580 GACTGACTTC CTGTCTGTGT TCTTCTCTGG CTACACCTTC AAGCACAAGA TGGTGTATGA 2640 GGACACCCTG ACCCTGTTCC CCTTCTCTGG GGAGACTGTG TTCATGAGCA TGGAGAACCC 2700 TGGCCTGTGG ATTCTGGGCT GCCACAACTC TGACTTCAGG AACAGGGGCA TGACTGCCCT 2760 GCTGAAAGTC TCCAGCTGTG ACAAGAACAC TGGGGACTAC TATGAGGACA GCTATGAGGA 2820 CATCTCTGCC TACCTGCTGA GCAAGAACAA TGCCATTGAG CCCAGGAGCT TCAGCCAGAA 2880 CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA GATCACCAGG ACCACCCTGC AGTCTGACCA 2940 GGAGGAGATT GACTATGATG ACACCATCTC TGTGGAGATG AAGAAGGAGG ACTTTGACAT 3000 CTACGACGAG GACGAGAACC AGAGCCCCAG GAGCTTCCAG AAGAAGACCA GGCACTACTT 3060 CATTGCTGCT GTGGAGAGGC TGTGGGACTA TGGCATGAGC AGCAGCCCCC ATGTGCTGAG 3120 GAACAGGGCC CAGTCTGGCT CTGTGCCCCA GTTCAAGAAG GTGGTGTTCC AGGAGTTCAC 3180 TGATGGCAGC TTCACCCAGC CCCTGTACAG AGGGGAGCTG AATGAGCACC TGGGCCTGCT 3240 GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA CAACATCATG GTGACCTTCA GGAACCAGGC 3300 CAGCAGGCCC TACAGCTTCT ACAGCAGCCT GATCAGCTAT GAGGAGGACC AGAGGCAGGG 3360 GGCTGAGCCC AGGAAGAACT TTGTGAAGCC CAATGAAACC AAGACCTACT TCTGGAAGGT 3420 GCAGCACCAC ATGGCCCCCA CCAAGGATGA GTTTGACTGC AAGGCCTGGG CCTACTTCTC 3480 TGATGTGGAC CTGGAGAAGG ATGTGCACTC TGGCCTGATT GGCCCCCTGC TGGTGTGCCA 3540 CACCAACACC CTGAACCCTG CCCATGGCAG GCAGGTGACT GTGCAGGAGT TTGCCCTGTT 3600 CTTCACCATC TTTGATGAAA CCAAGAGCTG GTACTTCACT GAGAACATGG AGAGGAACTG 3660 CAGGGCCCCC TGCAACATCC AGATGGAGGA CCCCACCTTC AAGGAGAACT ACAGGTTCCA 3720 TGCCATCAAT GGCTACATCA TGGACACCCT GCCTGGCCTG GTGATGGCCC AGGACCAGAG 3780 GATCAGGTGG TACCTGCTGA GCATGGGCAG CAATGAGAAC ATCCACAGCA TCCACTTCTC 3840 TGGCCATGTG TTCACTGTGA GGAAGAAGGA GGAGTACAAG ATGGCCCTGT ACAACCTGTA 3900 CCCTGGGGTG TTTGAGACTG TGGAGATGCT GCCCAGCAAG GCTGGCATCT GGAGGGTGGA 3960 GTGCCTGATT GGGGAGCACC TGCATGCTGG CATGAGCACC CTGTTCCTGG TGTACAGCAA 4020 CAAGTGCCAG ACCCCCCTGG GCATGGCCTC TGGCCACATC AGGGACTTCC AGATCACTGC 4080 CTCTGGCCAG TATGGCCAGT GGGCCCCCAA GCTGGCCAGG CTGCACTACT CTGGCAGCAT 4140 CAATGCCTGG AGCACCAAGG AGCCCTTCAG CTGGATCAAG GTGGACCTGC TGGCCCCCAT 4200 GATCATCCAT GGCATCAAGA CCCAGGGGGC CAGGCAGAAG TTCAGCAGCC TGTACATCAG 4260 CCAGTTCATC ATCATGTACA GCCTGGATGG CAAGAAGTGG CAGACCTACA GGGGCAACAG 4320 CACTGGCACC CTGATGGTGT TCTTTGGCAA TGTGGACAGC TCTGGCATCA AGCACAACAT 4380 CTTCAACCCC CCCATCATTG CCAGATACAT CAGGCTGCAC CCCACCCACT ACAGCATCAG 4440 GAGCACCCTG AGGATGGAGC TGATGGGCTG TGACCTGAAC AGCTGCAGCA TGCCCCTGGG 4500 CATGGAGAGC AAGGCCATCT CTGATGCCCA GATCACTGCC AGCAGCTACT TCACCAACAT 4560 GTTTGCCACC TGGAGCCCCA GCAAGGCCAG GCTGCACCTG CAGGGCAGGA GCAATGCCTG 4620 GAGGCCCCAG GTCAACAACC CCAAGGAGTG GCTGCAGGTG GACTTCCAGA AGACCATGAA 4680 GGTGACTGGG GTGACCACCC AGGGGGTGAA GAGCCTGCTG ACCAGCATGT ATGTGAAGGA 4740 GTTCCTGATC AGCAGCAGCC AGGATGGCCA CCAGTGGACC CTGTTCTTCC AGAATGGCAA 4800 GGTGAAGGTG TTCCAGGGCA ACCAGGACAG CTTCACCCCT GTGGTGAACA GCCTGGACCC 4860 CCCCCTGCTG ACCAGATACC TGAGGATTCA CCCCCAGAGC TGGGTGCACC AGATTGCCCT 4920 GAGGATGGAG GTGCTGGGCT GTGAGGCCCA GGACCTGTAC TGACCTCGAG GTGTGCCTTC 4980 TAGTTGCCAG CCATCTGTTG TTTGCCCCTC CCCCGTGCCT TCCTTGACCC TGGAAGGTGC 5040 CACTCCCACT GTCCTTTCCT AATAAAATGA GGAAATTGCA TCGCATTGTC TGAGTAGGTG 5100 TCATTCTATT CTGGGGGGTG GGGTGGGGCA GGACAGCAAG GGGGAGGATT GGGAAGACAA 5160 TAGCAGGCAT GCTGGGGATG CGGTGGGCTC TATGGGCACG TGGCGGCCGC AGGAACCCCT 5220 AGTGATGGAG TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGGGCGACC 5280 AAAGGTCGCC CGACGCCCGG GCTTTGCCCG GGCGGCCTCA GTGAGCGAGC GAGCGCGCAG 5340 AGAGGGAGTG GCCAA 5355 SEQ ID NO: 42 <211> 5618 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 42 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTTCGACCA GAGAGGTCTC 180 TGACCTCTGC CCCAGCTCCA AGGTCAGCAG GCAGGGAGGG CTGTGTGTTT GCTGTTTGCT 240 GCTTGCAATG TTTGCCCATT TTAGGGACAT GAGTAGGCTG AAGTTTGTTC AGTGTGGACT 300 TCAGAGGCAG CACACAAACA GCCAGAGAGG TCTCTGACCT CTGCCCCAGC TCCAAGGTCA 360 GCAGGCAGGG AGGGCTGTGT GTTTGCTGTT TGCTGCTTGC AATGTTTGCC CATTTTAGGG 420 ACATGAGTAG GCTGAAGTTT GTTCAGTGTG GACTTCAGAG GCAGCACACA AACAGCCAGA 480 GAGGTCTCTG ACCTCTGCCC CAGCTCCAAG GTCAGCAGGC AGGGAGGGCT GTGTGTTTGC 540 TGTTTGCTGC TTGCAATGTT TGCCCATTTT AGGGACATGA GTAGGCTGAA GTTTGTTCAG 600 TGTGGACTTC AGAGGCAGCA CACAAACAGC CAGAGAGGTC TCTGACCTCT GCCCCAGCTC 660 CAAGGTCAGC AGGCAGGGAG GGCTGTGTGT TTGCTGTTTG CTGCTTGCAA TGTTTGCCCA 720 TTTTAGGGAC ATGAGTAGGC TGAAGTTTGT TCAGTGTGGA CTTCAGAGGC AGCACACAAA 780 CAGCACGCGA AACGTCGACT GGACACAGGA CGCTGTGGTT TCTGAGCCAG GGGGCGACTC 840 AGATCCCAGC CAGTGGACTT AGCCCCTGTT TGCTCCTCCG ATAACTGGGG TGACCTTGGT 900 TAATATTCAC CAGCAGCCTC CCCCGTTGCC CCTCTGGATC CACTGCTTAA ATACGGACGA 960 GGACAGGGCC CTGTCTCCTC AGCTTCAGGC ACCACCACTG ACCTGGGACA GTGAATCGCG 1020 ATCGCCACCA TGCAGATTGA GCTGAGCACC TGCTTCTTCC TGTGCCTGCT GAGGTTCTGC 1080 TTCTCTGCCA CCAGGAGATA CTACCTGGGG GCTGTGGAGC TGAGCTGGGA CTACATGCAG 1140 TCTGACCTGG GGGAGCTGCC TGTGGATGCC AGGTTCCCCC CCAGAGTGCC CAAGAGCTTC 1200 CCCTTCAACA CCTCTGTGGT GTACAAGAAG ACCCTGTTTG TGGAGTTCAC TGACCACCTG 1260 TTCAACATTG CCAAGCCCAG GCCCCCCTGG ATGGGCCTGC TGGGCCCCAC CATCCAGGCT 1320 GAGGTGTATG ACACTGTGGT GATCACCCTG AAGAACATGG CCAGCCACCC TGTGAGCCTG 1380 CATGCTGTGG GGGTGAGCTA CTGGAAGGCC TCTGAGGGGG CTGAGTATGA TGACCAGACC 1440 AGCCAGAGGG AGAAGGAGGA TGACAAGGTG TTCCCTGGGG GCAGCCACAC CTATGTGTGG 1500 CAGGTGCTGA AGGAGAATGG CCCCATGGCC TCTGACCCCC TGTGCCTGAC CTACAGCTAC 1560 CTGAGCCATG TGGACCTGGT GAAGGACCTG AACTCTGGCC TGATTGGGGC CCTGCTGGTG 1620 TGCAGGGAGG GCAGCCTGGC CAAGGAGAAG ACCCAGACCC TGCACAAGTT CATCCTGCTG 1680 TTTGCTGTGT TTGATGAGGG CAAGAGCTGG CACTCTGAAA CCAAGAACAG CCTGATGCAG 1740 GACAGGGATG CTGCCTCTGC CAGGGCCTGG CCCAAGATGC ACACTGTGAA TGGCTATGTG 1800 AACAGGAGCC TGCCTGGCCT GATTGGCTGC CACAGGAAGT CTGTGTACTG GCATGTGATT 1860 GGCATGGGCA CCACCCCTGA GGTGCACAGC ATCTTCCTGG AGGGCCACAC CTTCCTGGTC 1920 AGGAACCACA GGCAGGCCAG CCTGGAGATC AGCCCCATCA CCTTCCTGAC TGCCCAGACC 1980 CTGCTGATGG ACCTGGGCCA GTTCCTGCTG TTCTGCCACA TCAGCAGCCA CCAGCATGAT 2040 GGCATGGAGG CCTATGTGAA GGTGGACAGC TGCCCTGAGG AGCCCCAGCT GAGGATGAAG 2100 AACAATGAGG AGGCTGAGGA CTATGATGAT GACCTGACTG ACTCTGAGAT GGATGTGGTG 2160 AGGTTTGATG ATGACAACAG CCCCAGCTTC ATCCAGATCA GGTCTGTGGC CAAGAAGCAC 2220 CCCAAGACCT GGGTGCACTA CATTGCTGCT GAGGAGGAGG ACTGGGACTA TGCCCCCCTG 2280 GTGCTGGCCC CTGATGACAG GAGCTACAAG AGCCAGTACC TGAACAATGG CCCCCAGAGG 2340 ATTGGCAGGA AGTACAAGAA GGTCAGGTTC ATGGCCTACA CTGATGAAAC CTTCAAGACC 2400 AGGGAGGCCA TCCAGCATGA GTCTGGCATC CTGGGCCCCC TGCTGTATGG GGAGGTGGGG 2460 GACACCCTGC TGATCATCTT CAAGAACCAG GCCAGCAGGC CCTACAACAT CTACCCCCAT 2520 GGCATCACTG ATGTGAGGCC CCTGTACAGC AGGAGGCTGC CCAAGGGGGT GAAGCACCTG 2580 AAGGACTTCC CCATCCTGCC TGGGGAGATC TTCAAGTACA AGTGGACTGT GACTGTGGAG 2640 GATGGCCCCA CCAAGTCTGA CCCCAGGTGC CTGACCAGAT ACTACAGCAG CTTTGTGAAC 2700 ATGGAGAGGG ACCTGGCCTC TGGCCTGATT GGCCCCCTGC TGATCTGCTA CAAGGAGTCT 2760 GTGGACCAGA GGGGCAACCA GATCATGTCT GACAAGAGGA ATGTGATCCT GTTCTCTGTG 2820 TTTGATGAGA ACAGGAGCTG GTACCTGACT GAGAACATCC AGAGGTTCCT GCCCAACCCT 2880 GCTGGGGTGC AGCTGGAGGA CCCTGAGTTC CAGGCCAGCA ACATCATGCA CAGCATCAAT 2940 GGCTATGTGT TTGACAGCCT GCAGCTGTCT GTGTGCCTGC ATGAGGTGGC CTACTGGTAC 3000 ATCCTGAGCA TTGGGGCCCA GACTGACTTC CTGTCTGTGT TCTTCTCTGG CTACACCTTC 3060 AAGCACAAGA TGGTGTATGA GGACACCCTG ACCCTGTTCC CCTTCTCTGG GGAGACTGTG 3120 TTCATGAGCA TGGAGAACCC TGGCCTGTGG ATTCTGGGCT GCCACAACTC TGACTTCAGG 3180 AACAGGGGCA TGACTGCCCT GCTGAAAGTC TCCAGCTGTG ACAAGAACAC TGGGGACTAC 3240 TATGAGGACA GCTATGAGGA CATCTCTGCC TACCTGCTGA GCAAGAACAA TGCCATTGAG 3300 CCCAGGAGCT TCAGCCAGAA CCCCCCAGTG CTGAAGAGGC ACCAGAGGGA GATCACCAGG 3360 ACCACCCTGC AGTCTGACCA GGAGGAGATT GACTATGATG ACACCATCTC TGTGGAGATG 3420 AAGAAGGAGG ACTTTGACAT CTACGACGAG GACGAGAACC AGAGCCCCAG GAGCTTCCAG 3480 AAGAAGACCA GGCACTACTT CATTGCTGCT GTGGAGAGGC TGTGGGACTA TGGCATGAGC 3540 AGCAGCCCCC ATGTGCTGAG GAACAGGGCC CAGTCTGGCT CTGTGCCCCA GTTCAAGAAG 3600 GTGGTGTTCC AGGAGTTCAC TGATGGCAGC TTCACCCAGC CCCTGTACAG AGGGGAGCTG 3660 AATGAGCACC TGGGCCTGCT GGGCCCCTAC ATCAGGGCTG AGGTGGAGGA CAACATCATG 3720 GTGACCTTCA GGAACCAGGC CAGCAGGCCC TACAGCTTCT ACAGCAGCCT GATCAGCTAT 3780 GAGGAGGACC AGAGGCAGGG GGCTGAGCCC AGGAAGAACT TTGTGAAGCC CAATGAAACC 3840 AAGACCTACT TCTGGAAGGT GCAGCACCAC ATGGCCCCCA CCAAGGATGA GTTTGACTGC 3900 AAGGCCTGGG CCTACTTCTC TGATGTGGAC CTGGAGAAGG ATGTGCACTC TGGCCTGATT 3960 GGCCCCCTGC TGGTGTGCCA CACCAACACC CTGAACCCTG CCCATGGCAG GCAGGTGACT 4020 GTGCAGGAGT TTGCCCTGTT CTTCACCATC TTTGATGAAA CCAAGAGCTG GTACTTCACT 4080 GAGAACATGG AGAGGAACTG CAGGGCCCCC TGCAACATCC AGATGGAGGA CCCCACCTTC 4140 AAGGAGAACT ACAGGTTCCA TGCCATCAAT GGCTACATCA TGGACACCCT GCCTGGCCTG 4200 GTGATGGCCC AGGACCAGAG GATCAGGTGG TACCTGCTGA GCATGGGCAG CAATGAGAAC 4260 ATCCACAGCA TCCACTTCTC TGGCCATGTG TTCACTGTGA GGAAGAAGGA GGAGTACAAG 4320 ATGGCCCTGT ACAACCTGTA CCCTGGGGTG TTTGAGACTG TGGAGATGCT GCCCAGCAAG 4380 GCTGGCATCT GGAGGGTGGA GTGCCTGATT GGGGAGCACC TGCATGCTGG CATGAGCACC 4440 CTGTTCCTGG TGTACAGCAA CAAGTGCCAG ACCCCCCTGG GCATGGCCTC TGGCCACATC 4500 AGGGACTTCC AGATCACTGC CTCTGGCCAG TATGGCCAGT GGGCCCCCAA GCTGGCCAGG 4560 CTGCACTACT CTGGCAGCAT CAATGCCTGG AGCACCAAGG AGCCCTTCAG CTGGATCAAG 4620 GTGGACCTGC TGGCCCCCAT GATCATCCAT GGCATCAAGA CCCAGGGGGC CAGGCAGAAG 4680 TTCAGCAGCC TGTACATCAG CCAGTTCATC ATCATGTACA GCCTGGATGG CAAGAAGTGG 4740 CAGACCTACA GGGGCAACAG CACTGGCACC CTGATGGTGT TCTTTGGCAA TGTGGACAGC 4800 TCTGGCATCA AGCACAACAT CTTCAACCCC CCCATCATTG CCAGATACAT CAGGCTGCAC 4860 CCCACCCACT ACAGCATCAG GAGCACCCTG AGGATGGAGC TGATGGGCTG TGACCTGAAC 4920 AGCTGCAGCA TGCCCCTGGG CATGGAGAGC AAGGCCATCT CTGATGCCCA GATCACTGCC 4980 AGCAGCTACT TCACCAACAT GTTTGCCACC TGGAGCCCCA GCAAGGCCAG GCTGCACCTG 5040 CAGGGCAGGA GCAATGCCTG GAGGCCCCAG GTCAACAACC CCAAGGAGTG GCTGCAGGTG 5100 GACTTCCAGA AGACCATGAA GGTGACTGGG GTGACCACCC AGGGGGTGAA GAGCCTGCTG 5160 ACCAGCATGT ATGTGAAGGA GTTCCTGATC AGCAGCAGCC AGGATGGCCA CCAGTGGACC 5220 CTGTTCTTCC AGAATGGCAA GGTGAAGGTG TTCCAGGGCA ACCAGGACAG CTTCACCCCT 5280 GTGGTGAACA GCCTGGACCC CCCCCTGCTG ACCAGATACC TGAGGATTCA CCCCCAGAGC 5340 TGGGTGCACC AGATTGCCCT GAGGATGGAG GTGCTGGGCT GTGAGGCCCA GGACCTGTAC 5400 TGACCTCGAG GAATAAAGGA AATTTATTTT CATTGCAATA GTGTGTTGGT TTTTTGTGTC 5460 ACGTGGCGGC CGCAGGAACC CCTAGTGATG GAGTTGGCCA CTCCCTCTCT GCGCGCTCGC 5520 TCGCTCACTG AGGCCGGGCG ACCAAAGGTC GCCCGACGCC CGGGCTTTGC CCGGGCGGCC 5580 TCAGTGAGCG AGCGAGCGCG CAGAGAGGGA GTGGCCAA 5618 SEQ ID NO: 43 <211> 5993 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 43 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTAAACGTC GACAGGTTAA 180 TTTTTAAAAA GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC 240 TCTGGTTAAT AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC 300 TGGACTTATC CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTCAGGTTAA TTTTTAAAAA 360 GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC TCTGGTTAAT 420 AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC TGGACTTATC 480 CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTGTCGACTG GACACAGGAC GCTGTGGTTT 540 CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA 600 TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC 660 ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA 720 CCTGGGACAG TGAATCGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT 780 GTGCCTGCTG AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT 840 GAGCTGGGAC TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC 900 CAGAGTGCCC AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT 960 GGAGTTCACT GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT 1020 GGGCCCCACC ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC 1080 CAGCCACCCT GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC 1140 TGAGTATGAT GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG 1200 CAGCCACACC TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT 1260 GTGCCTGACC TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT 1320 GATTGGGGCC CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT 1380 GCACAAGTTC ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC 1440 CAAGAACAGC CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA 1500 CACTGTGAAT GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC 1560 TGTGTACTGG CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA 1620 GGGCCACACC TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC 1680 CTTCCTGACT GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT 1740 CAGCAGCCAC CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA 1800 GCCCCAGCTG AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA 1860 CTCTGAGATG GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG 1920 GTCTGTGGCC AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA 1980 CTGGGACTAT GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT 2040 GAACAATGGC CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC 2100 TGATGAAACC TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT 2160 GCTGTATGGG GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC 2220 CTACAACATC TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC 2280 CAAGGGGGTG AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA 2340 GTGGACTGTG ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA 2400 CTACAGCAGC TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT 2460 GATCTGCTAC AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA 2520 TGTGATCCTG TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA 2580 GAGGTTCCTG CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA 2640 CATCATGCAC AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA 2700 TGAGGTGGCC TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT 2760 CTTCTCTGGC TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC 2820 CTTCTCTGGG GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG 2880 CCACAACTCT GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA 2940 CAAGAACACT GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG 3000 CAAGAACAAT GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA 3060 CCAGAGGGAG ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA 3120 CACCATCTCT GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA 3180 GAGCCCCAGG AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT 3240 GTGGGACTAT GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC 3300 TGTGCCCCAG TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC 3360 CCTGTACAGA GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA 3420 GGTGGAGGAC AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA 3480 CAGCAGCCTG ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT 3540 TGTGAAGCCC AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC 3600 CAAGGATGAG TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA 3660 TGTGCACTCT GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC 3720 CCATGGCAGG CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC 3780 CAAGAGCTGG TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA 3840 GATGGAGGAC CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT 3900 GGACACCCTG CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG 3960 CATGGGCAGC AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG 4020 GAAGAAGGAG GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT 4080 GGAGATGCTG CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT 4140 GCATGCTGGC ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG 4200 CATGGCCTCT GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG 4260 GGCCCCCAAG CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA 4320 GCCCTTCAGC TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC 4380 CCAGGGGGCC AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG 4440 CCTGGATGGC AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT 4500 CTTTGGCAAT GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC 4560 CAGATACATC AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT 4620 GATGGGCTGT GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC 4680 TGATGCCCAG ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG 4740 CAAGGCCAGG CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC 4800 CAAGGAGTGG CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA 4860 GGGGGTGAAG AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA 4920 GGATGGCCAC CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA 4980 CCAGGACAGC TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT 5040 GAGGATTCAC CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG 5100 TGAGGCCCAG GACCTGTACT GACCTCGAGG AATAAAGGAA ATTTATTTTC ATTGCAATAG 5160 TGTGTTGGTT TTTTGTGTCA CGTGCCCTCT CACACTACCT AAACCACGCC AGGACAACCT 5220 CTGCTCCTCT CCACCGAAAT TCCAAGGGGT CGAGTGGATG TTGGAGGTGG CATGGGCCCA 5280 GAGAGGTCTC TGACCTCTGC CCCAGCTCCA AGGTCAGCAG GCAGGGAGGG CTGTGTGTTT 5340 GCTGTTTGCT GCTTGCAATG TTTGCCCATT TTAGGGACAT GAGTAGGCTG AAGTTTGTTC 5400 AGTGTGGACT TCAGAGGCAG CACACAAACA GCTGCTGGAG GATGGGAACT GAGGGGTTGG 5460 AAGGGGGCAG GGTGAGCCCA GAAACTCCTG TGTGCCTCTG AGCCTGCAGC CCTCTCACAC 5520 TACCTAAACC ACGCCAGGAC AACCTCTGCT CCTCTCCACC GAAATTCCAA GGGGTCGAGT 5580 GGATGTTGGA GGTGGCATGG GCCCAGAGAG GTCTCTGACC TCTGCCCCAG CTCCAAGGTC 5640 AGCAGGCAGG GAGGGCTGTG TGTTTGCTGT TTGCTGCTTG CAATGTTTGC CCATTTTAGG 5700 GACATGAGTA GGCTGAAGTT TGTTCAGTGT GGACTTCAGA GGCAGCACAC AAACAGCTGC 5760 TGGAGGATGG GAACTGAGGG GTTGGAAGGG GGCAGGGTGA GCCCAGAAAC TCCTGTGTGC 5820 CTCTGAGCCT GCAGCACGTG GCGGCCGCAG GAACCCCTAG TGATGGAGTT GGCCACTCCC 5880 TCTCTGCGCG CTCGCTCGCT CACTGAGGCC GGGCGACCAA AGGTCGCCCG ACGCCCGGGC 5940 TTTGCCCGGG CGGCCTCAGT GAGCGAGCGA GCGCGCAGAG AGGGAGTGGC CAA 5993 SEQ ID NO: 44 <211> 5337 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 44 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTAAACGTC GACAGGTTAA 180 TTTTTAAAAA GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC 240 TCTGGTTAAT AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC 300 TGGACTTATC CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTCAGGTTAA TTTTTAAAAA 360 GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC TCTGGTTAAT 420 AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC TGGACTTATC 480 CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTGTCGACTG GACACAGGAC GCTGTGGTTT 540 CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA 600 TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC 660 ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA 720 CCTGGGACAG TGAATCGCGA TCGCCACCAT GCAGATTGAG CTGAGCACCT GCTTCTTCCT 780 GTGCCTGCTG AGGTTCTGCT TCTCTGCCAC CAGGAGATAC TACCTGGGGG CTGTGGAGCT 840 GAGCTGGGAC TACATGCAGT CTGACCTGGG GGAGCTGCCT GTGGATGCCA GGTTCCCCCC 900 CAGAGTGCCC AAGAGCTTCC CCTTCAACAC CTCTGTGGTG TACAAGAAGA CCCTGTTTGT 960 GGAGTTCACT GACCACCTGT TCAACATTGC CAAGCCCAGG CCCCCCTGGA TGGGCCTGCT 1020 GGGCCCCACC ATCCAGGCTG AGGTGTATGA CACTGTGGTG ATCACCCTGA AGAACATGGC 1080 CAGCCACCCT GTGAGCCTGC ATGCTGTGGG GGTGAGCTAC TGGAAGGCCT CTGAGGGGGC 1140 TGAGTATGAT GACCAGACCA GCCAGAGGGA GAAGGAGGAT GACAAGGTGT TCCCTGGGGG 1200 CAGCCACACC TATGTGTGGC AGGTGCTGAA GGAGAATGGC CCCATGGCCT CTGACCCCCT 1260 GTGCCTGACC TACAGCTACC TGAGCCATGT GGACCTGGTG AAGGACCTGA ACTCTGGCCT 1320 GATTGGGGCC CTGCTGGTGT GCAGGGAGGG CAGCCTGGCC AAGGAGAAGA CCCAGACCCT 1380 GCACAAGTTC ATCCTGCTGT TTGCTGTGTT TGATGAGGGC AAGAGCTGGC ACTCTGAAAC 1440 CAAGAACAGC CTGATGCAGG ACAGGGATGC TGCCTCTGCC AGGGCCTGGC CCAAGATGCA 1500 CACTGTGAAT GGCTATGTGA ACAGGAGCCT GCCTGGCCTG ATTGGCTGCC ACAGGAAGTC 1560 TGTGTACTGG CATGTGATTG GCATGGGCAC CACCCCTGAG GTGCACAGCA TCTTCCTGGA 1620 GGGCCACACC TTCCTGGTCA GGAACCACAG GCAGGCCAGC CTGGAGATCA GCCCCATCAC 1680 CTTCCTGACT GCCCAGACCC TGCTGATGGA CCTGGGCCAG TTCCTGCTGT TCTGCCACAT 1740 CAGCAGCCAC CAGCATGATG GCATGGAGGC CTATGTGAAG GTGGACAGCT GCCCTGAGGA 1800 GCCCCAGCTG AGGATGAAGA ACAATGAGGA GGCTGAGGAC TATGATGATG ACCTGACTGA 1860 CTCTGAGATG GATGTGGTGA GGTTTGATGA TGACAACAGC CCCAGCTTCA TCCAGATCAG 1920 GTCTGTGGCC AAGAAGCACC CCAAGACCTG GGTGCACTAC ATTGCTGCTG AGGAGGAGGA 1980 CTGGGACTAT GCCCCCCTGG TGCTGGCCCC TGATGACAGG AGCTACAAGA GCCAGTACCT 2040 GAACAATGGC CCCCAGAGGA TTGGCAGGAA GTACAAGAAG GTCAGGTTCA TGGCCTACAC 2100 TGATGAAACC TTCAAGACCA GGGAGGCCAT CCAGCATGAG TCTGGCATCC TGGGCCCCCT 2160 GCTGTATGGG GAGGTGGGGG ACACCCTGCT GATCATCTTC AAGAACCAGG CCAGCAGGCC 2220 CTACAACATC TACCCCCATG GCATCACTGA TGTGAGGCCC CTGTACAGCA GGAGGCTGCC 2280 CAAGGGGGTG AAGCACCTGA AGGACTTCCC CATCCTGCCT GGGGAGATCT TCAAGTACAA 2340 GTGGACTGTG ACTGTGGAGG ATGGCCCCAC CAAGTCTGAC CCCAGGTGCC TGACCAGATA 2400 CTACAGCAGC TTTGTGAACA TGGAGAGGGA CCTGGCCTCT GGCCTGATTG GCCCCCTGCT 2460 GATCTGCTAC AAGGAGTCTG TGGACCAGAG GGGCAACCAG ATCATGTCTG ACAAGAGGAA 2520 TGTGATCCTG TTCTCTGTGT TTGATGAGAA CAGGAGCTGG TACCTGACTG AGAACATCCA 2580 GAGGTTCCTG CCCAACCCTG CTGGGGTGCA GCTGGAGGAC CCTGAGTTCC AGGCCAGCAA 2640 CATCATGCAC AGCATCAATG GCTATGTGTT TGACAGCCTG CAGCTGTCTG TGTGCCTGCA 2700 TGAGGTGGCC TACTGGTACA TCCTGAGCAT TGGGGCCCAG ACTGACTTCC TGTCTGTGTT 2760 CTTCTCTGGC TACACCTTCA AGCACAAGAT GGTGTATGAG GACACCCTGA CCCTGTTCCC 2820 CTTCTCTGGG GAGACTGTGT TCATGAGCAT GGAGAACCCT GGCCTGTGGA TTCTGGGCTG 2880 CCACAACTCT GACTTCAGGA ACAGGGGCAT GACTGCCCTG CTGAAAGTCT CCAGCTGTGA 2940 CAAGAACACT GGGGACTACT ATGAGGACAG CTATGAGGAC ATCTCTGCCT ACCTGCTGAG 3000 CAAGAACAAT GCCATTGAGC CCAGGAGCTT CAGCCAGAAC CCCCCAGTGC TGAAGAGGCA 3060 CCAGAGGGAG ATCACCAGGA CCACCCTGCA GTCTGACCAG GAGGAGATTG ACTATGATGA 3120 CACCATCTCT GTGGAGATGA AGAAGGAGGA CTTTGACATC TACGACGAGG ACGAGAACCA 3180 GAGCCCCAGG AGCTTCCAGA AGAAGACCAG GCACTACTTC ATTGCTGCTG TGGAGAGGCT 3240 GTGGGACTAT GGCATGAGCA GCAGCCCCCA TGTGCTGAGG AACAGGGCCC AGTCTGGCTC 3300 TGTGCCCCAG TTCAAGAAGG TGGTGTTCCA GGAGTTCACT GATGGCAGCT TCACCCAGCC 3360 CCTGTACAGA GGGGAGCTGA ATGAGCACCT GGGCCTGCTG GGCCCCTACA TCAGGGCTGA 3420 GGTGGAGGAC AACATCATGG TGACCTTCAG GAACCAGGCC AGCAGGCCCT ACAGCTTCTA 3480 CAGCAGCCTG ATCAGCTATG AGGAGGACCA GAGGCAGGGG GCTGAGCCCA GGAAGAACTT 3540 TGTGAAGCCC AATGAAACCA AGACCTACTT CTGGAAGGTG CAGCACCACA TGGCCCCCAC 3600 CAAGGATGAG TTTGACTGCA AGGCCTGGGC CTACTTCTCT GATGTGGACC TGGAGAAGGA 3660 TGTGCACTCT GGCCTGATTG GCCCCCTGCT GGTGTGCCAC ACCAACACCC TGAACCCTGC 3720 CCATGGCAGG CAGGTGACTG TGCAGGAGTT TGCCCTGTTC TTCACCATCT TTGATGAAAC 3780 CAAGAGCTGG TACTTCACTG AGAACATGGA GAGGAACTGC AGGGCCCCCT GCAACATCCA 3840 GATGGAGGAC CCCACCTTCA AGGAGAACTA CAGGTTCCAT GCCATCAATG GCTACATCAT 3900 GGACACCCTG CCTGGCCTGG TGATGGCCCA GGACCAGAGG ATCAGGTGGT ACCTGCTGAG 3960 CATGGGCAGC AATGAGAACA TCCACAGCAT CCACTTCTCT GGCCATGTGT TCACTGTGAG 4020 GAAGAAGGAG GAGTACAAGA TGGCCCTGTA CAACCTGTAC CCTGGGGTGT TTGAGACTGT 4080 GGAGATGCTG CCCAGCAAGG CTGGCATCTG GAGGGTGGAG TGCCTGATTG GGGAGCACCT 4140 GCATGCTGGC ATGAGCACCC TGTTCCTGGT GTACAGCAAC AAGTGCCAGA CCCCCCTGGG 4200 CATGGCCTCT GGCCACATCA GGGACTTCCA GATCACTGCC TCTGGCCAGT ATGGCCAGTG 4260 GGCCCCCAAG CTGGCCAGGC TGCACTACTC TGGCAGCATC AATGCCTGGA GCACCAAGGA 4320 GCCCTTCAGC TGGATCAAGG TGGACCTGCT GGCCCCCATG ATCATCCATG GCATCAAGAC 4380 CCAGGGGGCC AGGCAGAAGT TCAGCAGCCT GTACATCAGC CAGTTCATCA TCATGTACAG 4440 CCTGGATGGC AAGAAGTGGC AGACCTACAG GGGCAACAGC ACTGGCACCC TGATGGTGTT 4500 CTTTGGCAAT GTGGACAGCT CTGGCATCAA GCACAACATC TTCAACCCCC CCATCATTGC 4560 CAGATACATC AGGCTGCACC CCACCCACTA CAGCATCAGG AGCACCCTGA GGATGGAGCT 4620 GATGGGCTGT GACCTGAACA GCTGCAGCAT GCCCCTGGGC ATGGAGAGCA AGGCCATCTC 4680 TGATGCCCAG ATCACTGCCA GCAGCTACTT CACCAACATG TTTGCCACCT GGAGCCCCAG 4740 CAAGGCCAGG CTGCACCTGC AGGGCAGGAG CAATGCCTGG AGGCCCCAGG TCAACAACCC 4800 CAAGGAGTGG CTGCAGGTGG ACTTCCAGAA GACCATGAAG GTGACTGGGG TGACCACCCA 4860 GGGGGTGAAG AGCCTGCTGA CCAGCATGTA TGTGAAGGAG TTCCTGATCA GCAGCAGCCA 4920 GGATGGCCAC CAGTGGACCC TGTTCTTCCA GAATGGCAAG GTGAAGGTGT TCCAGGGCAA 4980 CCAGGACAGC TTCACCCCTG TGGTGAACAG CCTGGACCCC CCCCTGCTGA CCAGATACCT 5040 GAGGATTCAC CCCCAGAGCT GGGTGCACCA GATTGCCCTG AGGATGGAGG TGCTGGGCTG 5100 TGAGGCCCAG GACCTGTACT GACCTCGAGG AATAAAGGAA ATTTATTTTC ATTGCAATAG 5160 TGTGTTGGTT TTTTGTGTCA CGTGGCGGCC GCAGGAACCC CTAGTGATGG AGTTGGCCAC 5220 TCCCTCTCTG CGCGCTCGCT CGCTCACTGA GGCCGGGCGA CCAAAGGTCG CCCGACGCCC 5280 GGGCTTTGCC CGGGCGGCCT CAGTGAGCGA GCGAGCGCGC AGAGAGGGAG TGGCCAA 5337 SEQ ID NO: 45 <211> 5542 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 45 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60 CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG TTTAAACGTC GACAGGTTAA 180 TTTTTAAAAA GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC 240 TCTGGTTAAT AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC 300 TGGACTTATC CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTCAGGTTAA TTTTTAAAAA 360 GCAGTCAAAA GTCCAAGTGG CCCTTGGCAG CATTTACTCT CTCTGTTTGC TCTGGTTAAT 420 AATCTCAGGA GCACAAACAT TCCTGGAGGC AGGAGAAGAA ATCAACATCC TGGACTTATC 480 CTCTGGGCCT CTCCCCACCC CCAGGAGAGG CTGTCGACTG GACACAGGAC GCTGTGGTTT 540 CTGAGCCAGG GGGCGACTCA GATCCCAGCC AGTGGACTTA GCCCCTGTTT GCTCCTCCGA 600 TAACTGGGGT GACCTTGGTT AATATTCACC AGCAGCCTCC CCCGTTGCCC CTCTGGATCC 660 ACTGCTTAAA TACGGACGAG GACAGGGCCC TGTCTCCTCA GCTTCAGGCA CCACCACTGA 720 CCTGGGACAG TGAATCGTAA GTATGCCTTT CACTGCGAGA GGTTCTGGAG AGGCTTCTGA 780 GCTCCCCATG GCCCAGGCAG GCAGCAGGTC TGGGGCAGGA GGGGGGTTGT GGAGTGCCTT 840 GACTCGGGGC CTGGCCCCCC CATCTCTGTC TTGCAGGACA ATTGCCGTCT TCTGTCTCGT 900 GGGGCATCCT CCTGCTGGCA GGCCTGTGCT GCCTGGTCCC TGCGATCGCC ACCATGCAGA 960 TTGAGCTGAG CACCTGCTTC TTCCTGTGCC TGCTGAGGTT CTGCTTCTCT GCCACCAGGA 1020 GATACTACCT GGGGGCTGTG GAGCTGAGCT GGGACTACAT GCAGTCTGAC CTGGGGGAGC 1080 TGCCTGTGGA TGCCAGGTTC CCCCCCAGAG TGCCCAAGAG CTTCCCCTTC AACACCTCTG 1140 TGGTGTACAA GAAGACCCTG TTTGTGGAGT TCACTGACCA CCTGTTCAAC ATTGCCAAGC 1200 CCAGGCCCCC CTGGATGGGC CTGCTGGGCC CCACCATCCA GGCTGAGGTG TATGACACTG 1260 TGGTGATCAC CCTGAAGAAC ATGGCCAGCC ACCCTGTGAG CCTGCATGCT GTGGGGGTGA 1320 GCTACTGGAA GGCCTCTGAG GGGGCTGAGT ATGATGACCA GACCAGCCAG AGGGAGAAGG 1380 AGGATGACAA GGTGTTCCCT GGGGGCAGCC ACACCTATGT GTGGCAGGTG CTGAAGGAGA 1440 ATGGCCCCAT GGCCTCTGAC CCCCTGTGCC TGACCTACAG CTACCTGAGC CATGTGGACC 1500 TGGTGAAGGA CCTGAACTCT GGCCTGATTG GGGCCCTGCT GGTGTGCAGG GAGGGCAGCC 1560 TGGCCAAGGA GAAGACCCAG ACCCTGCACA AGTTCATCCT GCTGTTTGCT GTGTTTGATG 1620 AGGGCAAGAG CTGGCACTCT GAAACCAAGA ACAGCCTGAT GCAGGACAGG GATGCTGCCT 1680 CTGCCAGGGC CTGGCCCAAG ATGCACACTG TGAATGGCTA TGTGAACAGG AGCCTGCCTG 1740 GCCTGATTGG CTGCCACAGG AAGTCTGTGT ACTGGCATGT GATTGGCATG GGCACCACCC 1800 CTGAGGTGCA CAGCATCTTC CTGGAGGGCC ACACCTTCCT GGTCAGGAAC CACAGGCAGG 1860 CCAGCCTGGA GATCAGCCCC ATCACCTTCC TGACTGCCCA GACCCTGCTG ATGGACCTGG 1920 GCCAGTTCCT GCTGTTCTGC CACATCAGCA GCCACCAGCA TGATGGCATG GAGGCCTATG 1980 TGAAGGTGGA CAGCTGCCCT GAGGAGCCCC AGCTGAGGAT GAAGAACAAT GAGGAGGCTG 2040 AGGACTATGA TGATGACCTG ACTGACTCTG AGATGGATGT GGTGAGGTTT GATGATGACA 2100 ACAGCCCCAG CTTCATCCAG ATCAGGTCTG TGGCCAAGAA GCACCCCAAG ACCTGGGTGC 2160 ACTACATTGC TGCTGAGGAG GAGGACTGGG ACTATGCCCC CCTGGTGCTG GCCCCTGATG 2220 ACAGGAGCTA CAAGAGCCAG TACCTGAACA ATGGCCCCCA GAGGATTGGC AGGAAGTACA 2280 AGAAGGTCAG GTTCATGGCC TACACTGATG AAACCTTCAA GACCAGGGAG GCCATCCAGC 2340 ATGAGTCTGG CATCCTGGGC CCCCTGCTGT ATGGGGAGGT GGGGGACACC CTGCTGATCA 2400 TCTTCAAGAA CCAGGCCAGC AGGCCCTACA ACATCTACCC CCATGGCATC ACTGATGTGA 2460 GGCCCCTGTA CAGCAGGAGG CTGCCCAAGG GGGTGAAGCA CCTGAAGGAC TTCCCCATCC 2520 TGCCTGGGGA GATCTTCAAG TACAAGTGGA CTGTGACTGT GGAGGATGGC CCCACCAAGT 2580 CTGACCCCAG GTGCCTGACC AGATACTACA GCAGCTTTGT GAACATGGAG AGGGACCTGG 2640 CCTCTGGCCT GATTGGCCCC CTGCTGATCT GCTACAAGGA GTCTGTGGAC CAGAGGGGCA 2700 ACCAGATCAT GTCTGACAAG AGGAATGTGA TCCTGTTCTC TGTGTTTGAT GAGAACAGGA 2760 GCTGGTACCT GACTGAGAAC ATCCAGAGGT TCCTGCCCAA CCCTGCTGGG GTGCAGCTGG 2820 AGGACCCTGA GTTCCAGGCC AGCAACATCA TGCACAGCAT CAATGGCTAT GTGTTTGACA 2880 GCCTGCAGCT GTCTGTGTGC CTGCATGAGG TGGCCTACTG GTACATCCTG AGCATTGGGG 2940 CCCAGACTGA CTTCCTGTCT GTGTTCTTCT CTGGCTACAC CTTCAAGCAC AAGATGGTGT 3000 ATGAGGACAC CCTGACCCTG TTCCCCTTCT CTGGGGAGAC TGTGTTCATG AGCATGGAGA 3060 ACCCTGGCCT GTGGATTCTG GGCTGCCACA ACTCTGACTT CAGGAACAGG GGCATGACTG 3120 CCCTGCTGAA AGTCTCCAGC TGTGACAAGA ACACTGGGGA CTACTATGAG GACAGCTATG 3180 AGGACATCTC TGCCTACCTG CTGAGCAAGA ACAATGCCAT TGAGCCCAGG AGCTTCAGCC 3240 AGAACCCCCC AGTGCTGAAG AGGCACCAGA GGGAGATCAC CAGGACCACC CTGCAGTCTG 3300 ACCAGGAGGA GATTGACTAT GATGACACCA TCTCTGTGGA GATGAAGAAG GAGGACTTTG 3360 ACATCTACGA CGAGGACGAG AACCAGAGCC CCAGGAGCTT CCAGAAGAAG ACCAGGCACT 3420 ACTTCATTGC TGCTGTGGAG AGGCTGTGGG ACTATGGCAT GAGCAGCAGC CCCCATGTGC 3480 TGAGGAACAG GGCCCAGTCT GGCTCTGTGC CCCAGTTCAA GAAGGTGGTG TTCCAGGAGT 3540 TCACTGATGG CAGCTTCACC CAGCCCCTGT ACAGAGGGGA GCTGAATGAG CACCTGGGCC 3600 TGCTGGGCCC CTACATCAGG GCTGAGGTGG AGGACAACAT CATGGTGACC TTCAGGAACC 3660 AGGCCAGCAG GCCCTACAGC TTCTACAGCA GCCTGATCAG CTATGAGGAG GACCAGAGGC 3720 AGGGGGCTGA GCCCAGGAAG AACTTTGTGA AGCCCAATGA AACCAAGACC TACTTCTGGA 3780 AGGTGCAGCA CCACATGGCC CCCACCAAGG ATGAGTTTGA CTGCAAGGCC TGGGCCTACT 3840 TCTCTGATGT GGACCTGGAG AAGGATGTGC ACTCTGGCCT GATTGGCCCC CTGCTGGTGT 3900 GCCACACCAA CACCCTGAAC CCTGCCCATG GCAGGCAGGT GACTGTGCAG GAGTTTGCCC 3960 TGTTCTTCAC CATCTTTGAT GAAACCAAGA GCTGGTACTT CACTGAGAAC ATGGAGAGGA 4020 ACTGCAGGGC CCCCTGCAAC ATCCAGATGG AGGACCCCAC CTTCAAGGAG AACTACAGGT 4080 TCCATGCCAT CAATGGCTAC ATCATGGACA CCCTGCCTGG CCTGGTGATG GCCCAGGACC 4140 AGAGGATCAG GTGGTACCTG CTGAGCATGG GCAGCAATGA GAACATCCAC AGCATCCACT 4200 TCTCTGGCCA TGTGTTCACT GTGAGGAAGA AGGAGGAGTA CAAGATGGCC CTGTACAACC 4260 TGTACCCTGG GGTGTTTGAG ACTGTGGAGA TGCTGCCCAG CAAGGCTGGC ATCTGGAGGG 4320 TGGAGTGCCT GATTGGGGAG CACCTGCATG CTGGCATGAG CACCCTGTTC CTGGTGTACA 4380 GCAACAAGTG CCAGACCCCC CTGGGCATGG CCTCTGGCCA CATCAGGGAC TTCCAGATCA 4440 CTGCCTCTGG CCAGTATGGC CAGTGGGCCC CCAAGCTGGC CAGGCTGCAC TACTCTGGCA 4500 GCATCAATGC CTGGAGCACC AAGGAGCCCT TCAGCTGGAT CAAGGTGGAC CTGCTGGCCC 4560 CCATGATCAT CCATGGCATC AAGACCCAGG GGGCCAGGCA GAAGTTCAGC AGCCTGTACA 4620 TCAGCCAGTT CATCATCATG TACAGCCTGG ATGGCAAGAA GTGGCAGACC TACAGGGGCA 4680 ACAGCACTGG CACCCTGATG GTGTTCTTTG GCAATGTGGA CAGCTCTGGC ATCAAGCACA 4740 ACATCTTCAA CCCCCCCATC ATTGCCAGAT ACATCAGGCT GCACCCCACC CACTACAGCA 4800 TCAGGAGCAC CCTGAGGATG GAGCTGATGG GCTGTGACCT GAACAGCTGC AGCATGCCCC 4860 TGGGCATGGA GAGCAAGGCC ATCTCTGATG CCCAGATCAC TGCCAGCAGC TACTTCACCA 4920 ACATGTTTGC CACCTGGAGC CCCAGCAAGG CCAGGCTGCA CCTGCAGGGC AGGAGCAATG 4980 CCTGGAGGCC CCAGGTCAAC AACCCCAAGG AGTGGCTGCA GGTGGACTTC CAGAAGACCA 5040 TGAAGGTGAC TGGGGTGACC ACCCAGGGGG TGAAGAGCCT GCTGACCAGC ATGTATGTGA 5100 AGGAGTTCCT GATCAGCAGC AGCCAGGATG GCCACCAGTG GACCCTGTTC TTCCAGAATG 5160 GCAAGGTGAA GGTGTTCCAG GGCAACCAGG ACAGCTTCAC CCCTGTGGTG AACAGCCTGG 5220 ACCCCCCCCT GCTGACCAGA TACCTGAGGA TTCACCCCCA GAGCTGGGTG CACCAGATTG 5280 CCCTGAGGAT GGAGGTGCTG GGCTGTGAGG CCCAGGACCT GTACTGACCT CGAGGAATAA 5340 AGGAAATTTA TTTTCATTGC AATAGTGTGT TGGTTTTTTG TGTCACGTGG CGGCCGCAGG 5400 AACCCCTAGT GATGGAGTTG GCCACTCCCT CTCTGCGCGC TCGCTCGCTC ACTGAGGCCG 5460 GGCGACCAAA GGTCGCCCGA CGCCCGGGCT TTGCCCGGGC GGCCTCAGTG AGCGAGCGAG 5520 CGCGCAGAGA GGGAGTGGCC AA 5542 SEQ ID NO: 46 <211> 5126 <212> DNA <213> ADENO-ASSOCIATED VIRUS 2 <400> 46 TTGGCCACTC CCTCTCTGCG CGCTCGCTCG CTCACTGAGG CCGCCCGGGC AAAGCCCGGG 60
Figure imgf000258_0001
CGTCGGGCGA CCTTTGGTCG CCCGGCCTCA GTGAGCGAGC GAGCGCGCAG AGAGGGAGTG 120 GCCAACTCCA TCACTAGGGG TTCCTGCGGC CGCACGCGTG GGAGGCTGCT GGTGAATATT 180 AACCAAGGTC ACCCCAGTTA TCGGAGGAGC AAACAGGGGC TAAGTCCACG GGGAGGCTGC 240 TGGTGAATAT TAACCAAGGT CACCCCAGTT ATCGGAGGAG CAAACAGGGG CTAAGTCCAC 300 GGTCGACTGG ACACAGGACG CTGTGGTTTC TGAGCCAGGG GGCGACTCAG ATCCCAGCCA 360 GTGGACTTAG CCCCTGTTTG CTCCTCCGAT AACTGGGGTG ACCTTGGTTA ATATTCACCA 420 GCAGCCTCCC CCGTTGCCCC TCTGGATCCA CTGCTTAAAT ACGGACGAGG ACAGGGCCCT 480 GTCTCCTCAG CTTCAGGCAC CACCACTGAC CTGGGACAGT GAATCGCGAT CGCCACCATG 540 CAGATTGAGC TGAGCACCTG CTTCTTCCTG TGCCTGCTGA GGTTCTGCTT CTCTGCCACC 600 AGGAGATACT ACCTGGGGGC TGTGGAGCTG AGCTGGGACT ACATGCAGTC TGACCTGGGG 660 GAGCTGCCTG TGGATGCCAG GTTCCCCCCC AGAGTGCCCA AGAGCTTCCC CTTCAACACC 720 TCTGTGGTGT ACAAGAAGAC CCTGTTTGTG GAGTTCACTG ACCACCTGTT CAACATTGCC 780 AAGCCCAGGC CCCCCTGGAT GGGCCTGCTG GGCCCCACCA TCCAGGCTGA GGTGTATGAC 840 ACTGTGGTGA TCACCCTGAA GAACATGGCC AGCCACCCTG TGAGCCTGCA TGCTGTGGGG 900 GTGAGCTACT GGAAGGCCTC TGAGGGGGCT GAGTATGATG ACCAGACCAG CCAGAGGGAG 960 AAGGAGGATG ACAAGGTGTT CCCTGGGGGC AGCCACACCT ATGTGTGGCA GGTGCTGAAG 1020 GAGAATGGCC CCATGGCCTC TGACCCCCTG TGCCTGACCT ACAGCTACCT GAGCCATGTG 1080 GACCTGGTGA AGGACCTGAA CTCTGGCCTG ATTGGGGCCC TGCTGGTGTG CAGGGAGGGC 1140 AGCCTGGCCA AGGAGAAGAC CCAGACCCTG CACAAGTTCA TCCTGCTGTT TGCTGTGTTT 1200 GATGAGGGCA AGAGCTGGCA CTCTGAAACC AAGAACAGCC TGATGCAGGA CAGGGATGCT 1260 GCCTCTGCCA GGGCCTGGCC CAAGATGCAC ACTGTGAATG GCTATGTGAA CAGGAGCCTG 1320 CCTGGCCTGA TTGGCTGCCA CAGGAAGTCT GTGTACTGGC ATGTGATTGG CATGGGCACC 1380 ACCCCTGAGG TGCACAGCAT CTTCCTGGAG GGCCACACCT TCCTGGTCAG GAACCACAGG 1440 CAGGCCAGCC TGGAGATCAG CCCCATCACC TTCCTGACTG CCCAGACCCT GCTGATGGAC 1500 CTGGGCCAGT TCCTGCTGTT CTGCCACATC AGCAGCCACC AGCATGATGG CATGGAGGCC 1560 TATGTGAAGG TGGACAGCTG CCCTGAGGAG CCCCAGCTGA GGATGAAGAA CAATGAGGAG 1620 GCTGAGGACT ATGATGATGA CCTGACTGAC TCTGAGATGG ATGTGGTGAG GTTTGATGAT 1680 GACAACAGCC CCAGCTTCAT CCAGATCAGG TCTGTGGCCA AGAAGCACCC CAAGACCTGG 1740 GTGCACTACA TTGCTGCTGA GGAGGAGGAC TGGGACTATG CCCCCCTGGT GCTGGCCCCT 1800 GATGACAGGA GCTACAAGAG CCAGTACCTG AACAATGGCC CCCAGAGGAT TGGCAGGAAG 1860 TACAAGAAGG TCAGGTTCAT GGCCTACACT GATGAAACCT TCAAGACCAG GGAGGCCATC 1920 CAGCATGAGT CTGGCATCCT GGGCCCCCTG CTGTATGGGG AGGTGGGGGA CACCCTGCTG 1980 ATCATCTTCA AGAACCAGGC CAGCAGGCCC TACAACATCT ACCCCCATGG CATCACTGAT 2040 GTGAGGCCCC TGTACAGCAG GAGGCTGCCC AAGGGGGTGA AGCACCTGAA GGACTTCCCC 2100 ATCCTGCCTG GGGAGATCTT CAAGTACAAG TGGACTGTGA CTGTGGAGGA TGGCCCCACC 2160 AAGTCTGACC CCAGGTGCCT GACCAGATAC TACAGCAGCT TTGTGAACAT GGAGAGGGAC 2220 CTGGCCTCTG GCCTGATTGG CCCCCTGCTG ATCTGCTACA AGGAGTCTGT GGACCAGAGG 2280 GGCAACCAGA TCATGTCTGA CAAGAGGAAT GTGATCCTGT TCTCTGTGTT TGATGAGAAC 2340 AGGAGCTGGT ACCTGACTGA GAACATCCAG AGGTTCCTGC CCAACCCTGC TGGGGTGCAG 2400 CTGGAGGACC CTGAGTTCCA GGCCAGCAAC ATCATGCACA GCATCAATGG CTATGTGTTT 2460 GACAGCCTGC AGCTGTCTGT GTGCCTGCAT GAGGTGGCCT ACTGGTACAT CCTGAGCATT 2520 GGGGCCCAGA CTGACTTCCT GTCTGTGTTC TTCTCTGGCT ACACCTTCAA GCACAAGATG 2580 GTGTATGAGG ACACCCTGAC CCTGTTCCCC TTCTCTGGGG AGACTGTGTT CATGAGCATG 2640 GAGAACCCTG GCCTGTGGAT TCTGGGCTGC CACAACTCTG ACTTCAGGAA CAGGGGCATG 2700 ACTGCCCTGC TGAAAGTCTC CAGCTGTGAC AAGAACACTG GGGACTACTA TGAGGACAGC 2760 TATGAGGACA TCTCTGCCTA CCTGCTGAGC AAGAACAATG CCATTGAGCC CAGGAGCTTC 2820 AGCCAGAACC CCCCAGTGCT GAAGAGGCAC CAGAGGGAGA TCACCAGGAC CACCCTGCAG 2880 TCTGACCAGG AGGAGATTGA CTATGATGAC ACCATCTCTG TGGAGATGAA GAAGGAGGAC 2940 TTTGACATCT ACGACGAGGA CGAGAACCAG AGCCCCAGGA GCTTCCAGAA GAAGACCAGG 3000 CACTACTTCA TTGCTGCTGT GGAGAGGCTG TGGGACTATG GCATGAGCAG CAGCCCCCAT 3060 GTGCTGAGGA ACAGGGCCCA GTCTGGCTCT GTGCCCCAGT TCAAGAAGGT GGTGTTCCAG 3120 GAGTTCACTG ATGGCAGCTT CACCCAGCCC CTGTACAGAG GGGAGCTGAA TGAGCACCTG 3180 GGCCTGCTGG GCCCCTACAT CAGGGCTGAG GTGGAGGACA ACATCATGGT GACCTTCAGG 3240 AACCAGGCCA GCAGGCCCTA CAGCTTCTAC AGCAGCCTGA TCAGCTATGA GGAGGACCAG 3300 AGGCAGGGGG CTGAGCCCAG GAAGAACTTT GTGAAGCCCA ATGAAACCAA GACCTACTTC 3360 TGGAAGGTGC AGCACCACAT GGCCCCCACC AAGGATGAGT TTGACTGCAA GGCCTGGGCC 3420 TACTTCTCTG ATGTGGACCT GGAGAAGGAT GTGCACTCTG GCCTGATTGG CCCCCTGCTG 3480 GTGTGCCACA CCAACACCCT GAACCCTGCC CATGGCAGGC AGGTGACTGT GCAGGAGTTT 3540 GCCCTGTTCT TCACCATCTT TGATGAAACC AAGAGCTGGT ACTTCACTGA GAACATGGAG 3600 AGGAACTGCA GGGCCCCCTG CAACATCCAG ATGGAGGACC CCACCTTCAA GGAGAACTAC 3660 AGGTTCCATG CCATCAATGG CTACATCATG GACACCCTGC CTGGCCTGGT GATGGCCCAG 3720 GACCAGAGGA TCAGGTGGTA CCTGCTGAGC ATGGGCAGCA ATGAGAACAT CCACAGCATC 3780 CACTTCTCTG GCCATGTGTT CACTGTGAGG AAGAAGGAGG AGTACAAGAT GGCCCTGTAC 3840 AACCTGTACC CTGGGGTGTT TGAGACTGTG GAGATGCTGC CCAGCAAGGC TGGCATCTGG 3900 AGGGTGGAGT GCCTGATTGG GGAGCACCTG CATGCTGGCA TGAGCACCCT GTTCCTGGTG 3960 TACAGCAACA AGTGCCAGAC CCCCCTGGGC ATGGCCTCTG GCCACATCAG GGACTTCCAG 4020 ATCACTGCCT CTGGCCAGTA TGGCCAGTGG GCCCCCAAGC TGGCCAGGCT GCACTACTCT 4080 GGCAGCATCA ATGCCTGGAG CACCAAGGAG CCCTTCAGCT GGATCAAGGT GGACCTGCTG 4140 GCCCCCATGA TCATCCATGG CATCAAGACC CAGGGGGCCA GGCAGAAGTT CAGCAGCCTG 4200 TACATCAGCC AGTTCATCAT CATGTACAGC CTGGATGGCA AGAAGTGGCA GACCTACAGG 4260 GGCAACAGCA CTGGCACCCT GATGGTGTTC TTTGGCAATG TGGACAGCTC TGGCATCAAG 4320 CACAACATCT TCAACCCCCC CATCATTGCC AGATACATCA GGCTGCACCC CACCCACTAC 4380 AGCATCAGGA GCACCCTGAG GATGGAGCTG ATGGGCTGTG ACCTGAACAG CTGCAGCATG 4440 CCCCTGGGCA TGGAGAGCAA GGCCATCTCT GATGCCCAGA TCACTGCCAG CAGCTACTTC 4500 ACCAACATGT TTGCCACCTG GAGCCCCAGC AAGGCCAGGC TGCACCTGCA GGGCAGGAGC 4560 AATGCCTGGA GGCCCCAGGT CAACAACCCC AAGGAGTGGC TGCAGGTGGA CTTCCAGAAG 4620 ACCATGAAGG TGACTGGGGT GACCACCCAG GGGGTGAAGA GCCTGCTGAC CAGCATGTAT 4680 GTGAAGGAGT TCCTGATCAG CAGCAGCCAG GATGGCCACC AGTGGACCCT GTTCTTCCAG 4740 AATGGCAAGG TGAAGGTGTT CCAGGGCAAC CAGGACAGCT TCACCCCTGT GGTGAACAGC 4800 CTGGACCCCC CCCTGCTGAC CAGATACCTG AGGATTCACC CCCAGAGCTG GGTGCACCAG 4860 ATTGCCCTGA GGATGGAGGT GCTGGGCTGT GAGGCCCAGG ACCTGTACTG ACCTCGAGGA 4920 ATAAAGGAAA TTTATTTTCA TTGCAATAGT GTGTTGGTTT TTTGTGTCAC GTGGCGGCCG 4980 CAGGAACCCC TAGTGATGGA GTTGGCCACT CCCTCTCTGC GCGCTCGCTC GCTCACTGAG 5040 GCCGGGCGAC CAAAGGTCGC CCGACGCCCG GGCTTTGCCC GGGCGGCCTC AGTGAGCGAG 5100 CGAGCGCGCA GAGAGGGAGT GGCCAA 5126 SEQ ID NO: 47 <211> 51 <212> DNA <213> ARTIFICIAL SEQUENCE <220> <223> PORTION OF MODIFIED FACTOR VIII B DOMAIN SEQUENCE <400> 47 GCCACTAATG TGTCTAACAA CAGCAACACC AGCAATGACA GCAATGTGTC T SEQ ID NO: 48 <211> 4425 <212> DNA <213> ARTIFICIAL SEQUENCE <220> <223> MODIFIED FACTOR VIII SEQUENCE <400> 48 ATGCAGATTG AGCTGAGCAC CTGCTTCTTC CTGTGCCTGC TGAGGTTCTG CTTCTCTGCC 60 ACCAGGAGAT ACTACCTGGG GGCTGTGGAG CTGAGCTGGG ACTACATGCA GTCTGACCTG 120 GGGGAGCTGC CTGTGGATGC CAGGTTCCCC CCCAGAGTGC CCAAGAGCTT CCCCTTCAAC 180 ACCTCTGTGG TGTACAAGAA GACCCTGTTT GTGGAGTTCA CTGACCACCT GTTCAACATT 240 GCCAAGCCCA GGCCCCCCTG GATGGGCCTG CTGGGCCCCA CCATCCAGGC TGAGGTGTAT 300 GACACTGTGG TGATCACCCT GAAGAACATG GCCAGCCACC CTGTGAGCCT GCATGCTGTG 360 GGGGTGAGCT ACTGGAAGGC CTCTGAGGGG GCTGAGTATG ATGACCAGAC CAGCCAGAGG 420 GAGAAGGAGG ATGACAAGGT GTTCCCTGGG GGCAGCCACA CCTATGTGTG GCAGGTGCTG 480 AAGGAGAATG GCCCCATGGC CTCTGACCCC CTGTGCCTGA CCTACAGCTA CCTGAGCCAT 540 GTGGACCTGG TGAAGGACCT GAACTCTGGC CTGATTGGGG CCCTGCTGGT GTGCAGGGAG 600 GGCAGCCTGG CCAAGGAGAA GACCCAGACC CTGCACAAGT TCATCCTGCT GTTTGCTGTG 660 TTTGATGAGG GCAAGAGCTG GCACTCTGAA ACCAAGAACA GCCTGATGCA GGACAGGGAT 720 GCTGCCTCTG CCAGGGCCTG GCCCAAGATG CACACTGTGA ATGGCTATGT GAACAGGAGC 780 CTGCCTGGCC TGATTGGCTG CCACAGGAAG TCTGTGTACT GGCATGTGAT TGGCATGGGC 840 ACCACCCCTG AGGTGCACAG CATCTTCCTG GAGGGCCACA CCTTCCTGGT CAGGAACCAC 900 AGGCAGGCCA GCCTGGAGAT CAGCCCCATC ACCTTCCTGA CTGCCCAGAC CCTGCTGATG 960 GACCTGGGCC AGTTCCTGCT GTTCTGCCAC ATCAGCAGCC ACCAGCATGA TGGCATGGAG 1020 GCCTATGTGA AGGTGGACAG CTGCCCTGAG GAGCCCCAGC TGAGGATGAA GAACAATGAG 1080 GAGGCTGAGG ACTATGATGA TGACCTGACT GACTCTGAGA TGGATGTGGT GAGGTTTGAT 1140 GATGACAACA GCCCCAGCTT CATCCAGATC AGGTCTGTGG CCAAGAAGCA CCCCAAGACC 1200 TGGGTGCACT ACATTGCTGC TGAGGAGGAG GACTGGGACT ATGCCCCCCT GGTGCTGGCC 1260 CCTGATGACA GGAGCTACAA GAGCCAGTAC CTGAACAATG GCCCCCAGAG GATTGGCAGG 1320 AAGTACAAGA AGGTCAGGTT CATGGCCTAC ACTGATGAAA CCTTCAAGAC CAGGGAGGCC 1380 ATCCAGCATG AGTCTGGCAT CCTGGGCCCC CTGCTGTATG GGGAGGTGGG GGACACCCTG 1440 CTGATCATCT TCAAGAACCA GGCCAGCAGG CCCTACAACA TCTACCCCCA TGGCATCACT 1500 GATGTGAGGC CCCTGTACAG CAGGAGGCTG CCCAAGGGGG TGAAGCACCT GAAGGACTTC 1560 CCCATCCTGC CTGGGGAGAT CTTCAAGTAC AAGTGGACTG TGACTGTGGA GGATGGCCCC 1620 ACCAAGTCTG ACCCCAGGTG CCTGACCAGA TACTACAGCA GCTTTGTGAA CATGGAGAGG 1680 GACCTGGCCT CTGGCCTGAT TGGCCCCCTG CTGATCTGCT ACAAGGAGTC TGTGGACCAG 1740 AGGGGCAACC AGATCATGTC TGACAAGAGG AATGTGATCC TGTTCTCTGT GTTTGATGAG 1800 AACAGGAGCT GGTACCTGAC TGAGAACATC CAGAGGTTCC TGCCCAACCC TGCTGGGGTG 1860 CAGCTGGAGG ACCCTGAGTT CCAGGCCAGC AACATCATGC ACAGCATCAA TGGCTATGTG 1920 TTTGACAGCC TGCAGCTGTC TGTGTGCCTG CATGAGGTGG CCTACTGGTA CATCCTGAGC 1980 ATTGGGGCCC AGACTGACTT CCTGTCTGTG TTCTTCTCTG GCTACACCTT CAAGCACAAG 2040 ATGGTGTATG AGGACACCCT GACCCTGTTC CCCTTCTCTG GGGAGACTGT GTTCATGAGC 2100 ATGGAGAACC CTGGCCTGTG GATTCTGGGC TGCCACAACT CTGACTTCAG GAACAGGGGC 2160 ATGACTGCCC TGCTGAAAGT CTCCAGCTGT GACAAGAACA CTGGGGACTA CTATGAGGAC 2220 AGCTATGAGG ACATCTCTGC CTACCTGCTG AGCAAGAACA ATGCCATTGA GCCCAGGAGC 2280 TTCAGCCAGA ATGCCACTAA TGTGTCTAAC AACAGCAACA CCAGCAATGA CAGCAATGTG 2340 TCTCCCCCAG TGCTGAAGAG GCACCAGAGG GAGATCACCA GGACCACCCT GCAGTCTGAC 2400 CAGGAGGAGA TTGACTATGA TGACACCATC TCTGTGGAGA TGAAGAAGGA GGACTTTGAC 2460 ATCTACGACG AGGACGAGAA CCAGAGCCCC AGGAGCTTCC AGAAGAAGAC CAGGCACTAC 2520 TTCATTGCTG CTGTGGAGAG GCTGTGGGAC TATGGCATGA GCAGCAGCCC CCATGTGCTG 2580 AGGAACAGGG CCCAGTCTGG CTCTGTGCCC CAGTTCAAGA AGGTGGTGTT CCAGGAGTTC 2640 ACTGATGGCA GCTTCACCCA GCCCCTGTAC AGAGGGGAGC TGAATGAGCA CCTGGGCCTG 2700 CTGGGCCCCT ACATCAGGGC TGAGGTGGAG GACAACATCA TGGTGACCTT CAGGAACCAG 2760 GCCAGCAGGC CCTACAGCTT CTACAGCAGC CTGATCAGCT ATGAGGAGGA CCAGAGGCAG 2820 GGGGCTGAGC CCAGGAAGAA CTTTGTGAAG CCCAATGAAA CCAAGACCTA CTTCTGGAAG 2880 GTGCAGCACC ACATGGCCCC CACCAAGGAT GAGTTTGACT GCAAGGCCTG GGCCTACTTC 2940 TCTGATGTGG ACCTGGAGAA GGATGTGCAC TCTGGCCTGA TTGGCCCCCT GCTGGTGTGC 3000 CACACCAACA CCCTGAACCC TGCCCATGGC AGGCAGGTGA CTGTGCAGGA GTTTGCCCTG 3060 TTCTTCACCA TCTTTGATGA AACCAAGAGC TGGTACTTCA CTGAGAACAT GGAGAGGAAC 3120 TGCAGGGCCC CCTGCAACAT CCAGATGGAG GACCCCACCT TCAAGGAGAA CTACAGGTTC 3180 CATGCCATCA ATGGCTACAT CATGGACACC CTGCCTGGCC TGGTGATGGC CCAGGACCAG 3240 AGGATCAGGT GGTACCTGCT GAGCATGGGC AGCAATGAGA ACATCCACAG CATCCACTTC 3300 TCTGGCCATG TGTTCACTGT GAGGAAGAAG GAGGAGTACA AGATGGCCCT GTACAACCTG 3360 TACCCTGGGG TGTTTGAGAC TGTGGAGATG CTGCCCAGCA AGGCTGGCAT CTGGAGGGTG 3420 GAGTGCCTGA TTGGGGAGCA CCTGCATGCT GGCATGAGCA CCCTGTTCCT GGTGTACAGC 3480 AACAAGTGCC AGACCCCCCT GGGCATGGCC TCTGGCCACA TCAGGGACTT CCAGATCACT 3540 GCCTCTGGCC AGTATGGCCA GTGGGCCCCC AAGCTGGCCA GGCTGCACTA CTCTGGCAGC 3600 ATCAATGCCT GGAGCACCAA GGAGCCCTTC AGCTGGATCA AGGTGGACCT GCTGGCCCCC 3660 ATGATCATCC ATGGCATCAA GACCCAGGGG GCCAGGCAGA AGTTCAGCAG CCTGTACATC 3720 AGCCAGTTCA TCATCATGTA CAGCCTGGAT GGCAAGAAGT GGCAGACCTA CAGGGGCAAC 3780 AGCACTGGCA CCCTGATGGT GTTCTTTGGC AATGTGGACA GCTCTGGCAT CAAGCACAAC 3840 ATCTTCAACC CCCCCATCAT TGCCAGATAC ATCAGGCTGC ACCCCACCCA CTACAGCATC 3900 AGGAGCACCC TGAGGATGGA GCTGATGGGC TGTGACCTGA ACAGCTGCAG CATGCCCCTG 3960 GGCATGGAGA GCAAGGCCAT CTCTGATGCC CAGATCACTG CCAGCAGCTA CTTCACCAAC 4020 ATGTTTGCCA CCTGGAGCCC CAGCAAGGCC AGGCTGCACC TGCAGGGCAG GAGCAATGCC 4080 TGGAGGCCCC AGGTCAACAA CCCCAAGGAG TGGCTGCAGG TGGACTTCCA GAAGACCATG 4140 AAGGTGACTG GGGTGACCAC CCAGGGGGTG AAGAGCCTGC TGACCAGCAT GTATGTGAAG 4200 GAGTTCCTGA TCAGCAGCAG CCAGGATGGC CACCAGTGGA CCCTGTTCTT CCAGAATGGC 4260 AAGGTGAAGG TGTTCCAGGG CAACCAGGAC AGCTTCACCC CTGTGGTGAA CAGCCTGGAC 4320 CCCCCCCTGC TGACCAGATA CCTGAGGATT CACCCCCAGA GCTGGGTGCA CCAGATTGCC 4380 CTGAGGATGG AGGTGCTGGG CTGTGAGGCC CAGGACCTGT ACTGA 4425

Claims

What is claimed: 1. A method of treating hemophilia in a subject comprising administering an adeno-associated virus (AAV) vector to a subject wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
2. The method of claim 1 wherein the subject has antibodies resulting from pre-existing natural immunity to an AAV.
3. The method of claim 1 or 2 wherein the subject has antibodies resulting from prior exposure to an AAV-based gene therapy vector.
4. The method of any one of claims 1-3 wherein the subject has antibodies specific for a capsid protein from AAV5, AAV6 or AAV8.
5. A method of treating hemophilia in a subject comprising administering a second dose of an AAV vector to a subject wherein the subject has received a dose of the AAV vector prior to administration of the second dose of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
6. A method of treating hemophilia in a subject comprising administering an IgG degrading enzyme prior to administration of an AAV vector to a subject wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
7. , The method of claim 6 where in the antibodies specific for an AAV capsid protein are AAV5 capsid specific antibodies.
8. The method of claim 6 or 7 wherein the subject had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy.
9. The method of any one of claims 6-8 wherein the IgG degrading enzyme is Imlifidase (IdeS), IdeZ, IgdE (family) or IdeP.
10. A method of treating hemophilia in a subject comprising administering to a subject i) a corticosteroid and ii) an AAV comprising a functionally active FVIII coding region, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV.
11. The method of claim 10 wherein the corticosteroid is administered on the day of AAV administration, or at least about 2 hours prior to administration of the AAV, or at least about 4 hours prior to administration of the AAV, or at least about 6 hours prior to administration of the AAV, or at least 12 hours prior to administration of the AAV, or at least 24 hours prior to administration of the AAV.
12. The method of claim 10 or 11 wherein the method further comprises the step of continuing administration of a corticosteroid once a day for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 8 weeks, or at least 16 weeks, or at least 19 weeks after administration of the AAV.
13. A method of treating hemophilia in a subject comprising administering an AAV vector to the subject wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
14. The method of claim 13 wherein the subject has a high titer FVIII inhibitors.
15. The method of claim 13 wherein the subject has a moderate titer FVIII inhibitors.
16. The method of claim 13 wherein the subject has a low titer FVIII inhibitors.
17. A method of treating hemophilia in a subject comprising administering an AAV vector to the subject wherein the subject received FVIII replacement therapy and has developed FVIII inhibitors prior to administration of the AAV vector, and wherein the subject does not have active FVIII inhibitors at the time of administration of the AAV vector.
18. The method of claim 17 wherein the subject has a FVIII inhibitor titer of less than 6.0 BU after administration of FVIII replacement therapy.
19. The method of claim 17 or 18 wherein the subject has a FVIII inhibitor titer of less than a 0.6 BU at the time of administration of the AAV vector.
20. The method of any one of claims 17-19 wherein the subject has a history of having a FVIII inhibitor titer of greater than 0.6 BU but has a titer of less than 0.6 BU at the time of administration of the AAV vector.
21. The method of any one of claims 17-20 wherein the subject has received a FVIII replacement therapy for at least 12 months prior to administration of the AAV vector.
22. The method of any one of claims 1-21, further comprising subjecting the subject to therapeutic plasma exchange or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
23. The method of claim 22 wherein the subject is subjected to at least two sessions of therapeutic aphesis or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
24. The method of any one of claims 1-23, further comprising the step of prophylactically administering corticosteroids after administration of the AAV vector.
25. The method of any one of claims 1-24, further comprising the step of prophylactically administering corticosteroids before or at the same time as administration of the AAV vector.
26. The method of any one of claims 1-24, further comprising the step of prophylactically administering corticosteroids at least about 3 hours prior to administration of the AAV vector.
27. The method of any one of claims 1-26, further comprising the step of prophylactically administering a corticosteroid once a day for at least 7 days after administration of the AAV vector .
28. The method of any one of claims 24-27 wherein the corticosteroid is administered orally at a dose of 40 mg.
29. The method of any one of claims 1-28 further comprising the step of therapeutically administering a corticosteroid or a non-steroidal immunosuppressive agent after administration of the AAV vector.
30. The method of claim 29 wherein the therapeutic corticosteroid is administered at a dose of 60 mg/day.
31. The method of claim 29 or 30 wherein the therapeutic corticosteroid is administered for 21 days, and the dose of therapeutic corticosteroid is gradually tapered off at day 22.
32. The method of claim 31, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at a dose of 30 mg/day for 28 days.
33. The method of any one of claims 24-32, wherein the corticosteroid is presnisone or prednisolone.
34. The method of claim 29 wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
35. The method of 29 or 34, wherein the non-steroidal systemic immunosuppressive agent is administered systemically.
36. The method of any one of claims 29-35, wherein the subject has elevated ALT level or an elevated level of FVIII inhibitors after administration of an AAV vector comprising a functionally active FVIII coding region as compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
37. The method of claim 36, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
38. A method of treating hemophilia in a subject comprising administering a corticosteroid and an AAV vector comprising a functionally active FVIII coding region, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV vector.
39. The method of claim 38 wherein the corticosteroid is administered at least about 3 hours prior to administration of the AAV vector.
40. The method of any one of claims 38 or 39, wherein the corticosteroid is administered once a day for at least 7 days after administration of the AAV vector.
41. The method of any one of claims 38-40 wherein corticosteroid is administered orally at a dose of 40 mg.
42. The method of any one of claims 38-40 further comprising the step of administering a corticosteroid or a non-steroidal immunosuppressive agent therapeutically after administration of the AAV vector.
43. The method of claim 42, wherein the therapeutic corticosteroid is administered at a dose of 60 mg/day.
44. The method of claim 42 or 43, wherein the therapeutic corticosteroid is administered for 21 days, and the dose gradually tapered off at day 22.
45. The method of claim 44, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at 30 mg/day for 28 days.
46. The method of any one of claims 38-45, wherein the corticosteroid is presnisone or prednisolone.
47. The method of claim 42 wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
48. The method of 42 or 47 wherein the non-steroidal systemic immunosuppressive agent is administered systemically.
49. The method of any one of claims 38-48, comprising administering corticosteroids or a non-steroidal systemic immunosuppressive agent to a subject having elevated ALT level or elevated FVIII inhibitor level compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
50. The method of claim 49, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
51. The method of any of the preceding claims wherein the AAV vector is administered intravenously.
52. Use of an adeno-associated virus (AAV) vector for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
53. The use of claim 52 wherein the subject has antibodies resulting from pre-existing natural immunity to an AAV.
54. The use of claims 52 and 53 wherein the subject has antibodies resulting from prior exposure to an AAV-based gene therapy vector.
55. The use of any one of claims 52-54 wherein the subject has antibodies specific for a capsid protein from AAV5, AAV6 or AAV8.
56. Use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject has received a dose of the AAV vector prior to administration of the medicament, and wherein the AAV vector comprises a functionally active FVIII coding region.
57. Use of an IgG degrading enzyme for the preparation of a medicament for treating hemophilia in a subject, wherein the IgG degrading enzyme is administered prior to administration of an AAV vector to a subject, and wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
58. The use of claim 57 where in the antibodies specific for an AAV capsid protein are AAV5 capsid specific antibodies.
59. The use of claims 57 or 58, wherein the subject had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy.
60. The method of any one of claims 6-8 wherein the IgG degrading enzyme is Imlifidase (IdeS), IdeZ, IgdE (family) or IdeP.
61. Use of a corticosteroid and an AAV for the preparation of a medicament for treating hemophilia in a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV, and wherein the AAV comprises a functionally active FVIII coding region.
62. The use of claim 61 wherein the corticosteroid is administered on the day of AAV administration, or at least about 2 hours prior to administration of the AAV, or at least about 4 hours prior to administration of the AAV, or at least about 6 hours prior to administration of the AAV, or at least 12 hours prior to administration of the AAV, or at least 24 hours prior to administration of the AAV.
63. The use of claim 61 or 62 wherein the corticosteroid is administered once a day for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 8 weeks, or at least 16 weeks, or at least 19 weeks after administration of the AAV.
64. Use of an AAV vector for the preparation of a medicament for treating hemophilia in a subject, wherein the subject has active FVIII inhibitors prior to or at the time of administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
65. The use of claim 64 wherein the subject has a high titer FVIII inhibitors.
66. The use of claim 64 wherein the subject has a moderate titer FVIII inhibitors.
67. The use of claim 64 wherein the subject has a low titer FVIII inhibitors.
68. Use of AAV vector for the preparation of a medicament for treating hemophilia in a subject wherein the subject received FVIII replacement therapy and has developed FVIII inhibitors prior to administration of the AAV vector, and wherein the subject does not have active FVIII inhibitors at the time of administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
69. The use of claim 68 wherein the subject has a FVIII inhibitor titer of less than 6.0 BU after administration of FVIII replacement therapy.
70. The use of claim 68 or 69 wherein the subject has a FVIII inhibitor titer of less than a 0.6 BU at the time of administration of the AAV vector.
71. The use of any one of claims 68-70 wherein the subject has a history of having a FVIII inhibitor titer of greater than 0.6 BU but has a titer of less than 0.6 BU at the time of administration of the AAV vector.
72. The use of any one of claims 68-71 wherein the subject has received a FVIII replacement therapy for at least 12 months prior to administration of the AAV vector.
73. The use of any one of claims 68-72 wherein the subject has a history of having a FVIII inhibitor titer of greater than 0.6 BU but has a titer of less than 0.6 BU at the time of administration of the AAV vector.
74. The use of any one of claims 68-73 wherein the subject has received a FVIII replacement therapy for at least 12 months prior to administration of the AAV vector.
75. The use of any one of claims 52-74, wherein the subject is subjected to therapeutic plasma exchange or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
76. The use of claim 75, wherein the subject is subjected to at least two sessions of therapeutic aphesis or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
77. The use of any one of claims 52-76, wherein the subject is prophylactically administered corticosteroids after administration of the AAV vector.
78. The use of any one of claims 52-77, wherein the subject was prophylactically administered corticosteroids before or at the same time as administration of the AAV vector.
79. The use of any one of claims 52-77, wherein the subject was prophylactically administered corticosteroids at least about 3 hours prior to administration of the AAV vector.
80. The use of any one of claims 52-79, wherein the subject was prophylactically administered a corticosteroid once a day for at least 7 days after administration of the AAV vector .
81. The use of any one of claims 77-80, wherein the corticosteroid is formulated for oral administration at a dose of 40 mg.
82. The use of any one of claims 52-81, wherein a corticosteroid or a non-steroidal immunosuppressive agent is therapeutically administered after administration of the AAV vector.
83. The use of claim 82 wherein the therapeutic corticosteroid is administered at a dose of 60 mg/day.
84. The use of claim 82 or 83 wherein the therapeutic corticosteroid is administered for 21 days, and the dose of therapeutic corticosteroid is gradually tapered off at day 22.
85. The use of claim 84, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at a dose of 30 mg/day for 28 days.
86. The use of any one of claims 77-85, wherein the corticosteroid is presnisone or prednisolone.
87. The use of claim 82 wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
88. The use of 82 or 87, wherein the non-steroidal systemic immunosuppressive agent is administered systemically. The method of any one of claims 29-35, wherein the subject has elevated ALT level or an elevated level of FVIII inhibitors after administration of an AAV vector comprising a functionally active FVIII coding region as compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
89. The use of claim 36, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
90. Use of a corticosteroid and an AAV vector for the preparation of a medicament for treating hemophilia in a subject, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV vector, and wherein the AAV vector comprises a functionally active FVIII coding region.
91. The use of claim 90 wherein the corticosteroid is administered at least about 3 hours prior to administration of the AAV vector.
92. The use of any one of claims 90 or 91, wherein the corticosteroid is administered once a day for at least 7 days after administration of the AAV vector.
93. The use of any one of claims 90-92, wherein corticosteroid is formulated for oral administration at a dose of 40 mg.
94. The use of any one of claims 90-93, wherein a corticosteroid or a non-steroidal immunosuppressive agent is administered therapeutically after administration of the AAV vector.
95. The use of claim 94, wherein the therapeutic corticosteroid is administered at a dose of 60 mg/day.
96. The use of claim 94 or 95, wherein the therapeutic corticosteroid is administered for 21 days, and the dose gradually tapered off at day 22.
97. The use of claim 96, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at 30 mg/day for 28 days.
98. The use of any one of claims 90-97, wherein the corticosteroid is presnisone or prednisolone.
99. The use of claim 94 wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
100. The use of 94 or 99 wherein the non-steroidal systemic immunosuppressive agent is administered systemically.
101. The use of any one of claims 90-100, wherein the subject has elevated ALT level or elevated FVIII inhibitor level compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
102. The use of claim 101, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
103. The use of any one of claims -52-101, wherein the AAV vector is formulated for intravenous administration.
104. A composition for use in treating hemophilia in a subject, wherein the composition comprises an adeno-associated virus (AAV) vector comprising a functionally active FVIII coding region and wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector.
105. The composition of claim 104 wherein the subject has antibodies resulting from pre- existing natural immunity to an AAV.
106. The composition of claim 104 or 105 wherein the subject has antibodies resulting from prior exposure to an AAV-based gene therapy vector.
107. The composition of any one of claims 1014-106 wherein the subject has antibodies specific for a capsid protein from AAV5, AAV6 or AAV8.
108. A composition for use in treating hemophilia in a subject, wherein the composition comprises an AAV vector comprises a functionally active FVIII coding region and the subject has received a dose of the AAV vector prior to administration of the composition.
109. A composition for use in treating hemophilia in a subject, wherein the composition comprises an IgG degrading enzyme, wherein the composition is administered to the subject prior to administration of an AAV vector comprising a functionally active FVIII coding region, wherein the subject has antibodies specific for an AAV capsid protein prior to administration of the AAV vector.
110. , The composition of claim 109, wherein the antibodies specific for an AAV capsid protein are AAV5 capsid specific antibodies.
111. The composition of claim 109 or 110, wherein the subject had prior exposure to natural AAV or had undergone prior treatment with AAV gene therapy.
112. The composition of any one of claims 109-111, wherein the IgG degrading enzyme is Imlifidase (IdeS), IdeZ, IgdE (family) or IdeP.
113. A composition for use in treating hemophilia in a subject, wherein the composition comprises i) a corticosteroid and ii) an AAV comprising a functionally active FVIII coding region, wherein the corticosteroid is administered prophylactically before or at the same time as administration of the AAV.
114. The composition of claim 113, wherein the corticosteroid is administered on the day of AAV administration, or at least about 2 hours prior to administration of the AAV, or at least about 4 hours prior to administration of the AAV, or at least about 6 hours prior to administration of the AAV, or at least 12 hours prior to administration of the AAV, or at least 24 hours prior to administration of the AAV.
115. The composition of claims 112 or 113, wherein the corticosteroid is administered once a day for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 8 weeks, or at least 16 weeks, or at least 19 weeks after administration of the AAV.
116. A composition for use in of treating hemophilia in a subject comprising an AAV vector comprising a functionally active FVIII coding region, and the subject has active FVIII inhibitors prior to or at the time of administration of the AAV vector.
117. The composition of claim 116, wherein the subject has a high titer FVIII inhibitors.
118. The of composition of claim 116, wherein the subject has a moderate titer FVIII inhibitors.
119. The composition of claim 116, wherein the subject has a low titer FVIII inhibitors.
120. A composition for use in treating hemophilia in a subject, wherein the composition comprises an AAV vector comprises a functionally active FVIII coding region, and wherein the subject received FVIII replacement therapy and has developed FVIII inhibitors prior to administration of the AAV vector, and wherein the subject does not have active FVIII inhibitors at the time of administration of the AAV vector.
121. The composition of claim 120, wherein the subject has a FVIII inhibitor titer of less than 6.0 BU after administration of FVIII replacement therapy.
122. The composition of claim 120 or 121, wherein the subject has a FVIII inhibitor titer of less than a 0.6 BU at the time of administration of the AAV vector.
123. The composition of any one of claims 120-122, wherein the subject has a history of having a FVIII inhibitor titer of greater than 0.6 BU but has a titer of less than 0.6 BU at the time of administration of the AAV vector.
124. The composition of any one of claims 120-123, wherein the subject has received a FVIII replacement therapy for at least 12 months prior to administration of the AAV vector.
125. The composition of any one of claims 124, wherein the subject is subjected to therapeutic plasma exchange or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
126. The composition of claim 125, wherein the subject is subjected to at least two sessions of therapeutic aphesis or immunoadsorption plasmapheresis prior to the administration of the AAV vector.
127. The composition of any one of claims 104-126, wherein the subject is prophylactically administered corticosteroids after administration of the AAV vector.
128. The composition of any one of claims 104-127, wherein the subject is prophylactically administered corticosteroids before or at the same time as administration of the AAV vector.
129. The composition of any one of claims 104-127, wherein the subject is prophylactically administered corticosteroids at least about 3 hours prior to administration of the AAV vector.
130. The composition of any one of claims 104-129, wherein the subject is prophylactically administered a corticosteroid once a day for at least 7 days after administration of the AAV vector.
131. The composition of any one of claims 127-130, wherein the corticosteroid is formulated for oral administration at a dose of 40 mg.
132. The composition of any one of claims 104-131, wherein the subject is therapeutically administering a corticosteroid or a non-steroidal immunosuppressive agent after administration of the AAV vector.
133. The composition of claim 132 wherein the therapeutic corticosteroid is administered at a dose of 60 mg/day.
134. The composition of claim 132 or 133, wherein the therapeutic corticosteroid is administered for 21 days, and the dose of therapeutic corticosteroid is gradually tapered off at day 22.
135. The composition of claim 135, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at a dose of 30 mg/day for 28 days.
136. The composition of any one of claims 127-135, wherein the corticosteroid is presnisone or prednisolone.
137. The composition of claim 132, wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
138. The composition of claim 132 or 137, wherein the non-steroidal systemic immunosuppressive agent is administered systemically.
139. The composition of any one of claims 132-138, wherein the subject has elevated ALT level or an elevated level of FVIII inhibitors after administration of an AAV vector comprising a functionally active FVIII coding region as compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
140. The composition of claim 139, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
141. A composition for use in treating hemophilia in a subject, wherein the composition comprises a corticosteroid and an AAV vector comprising a functionally active FVIII coding region, wherein the corticosteroid is formulated for prophylactic administration before or at the same time as administration of the AAV vector.
142. The composition of claim 141 wherein the corticosteroid is administered at least about 3 hours prior to administration of the AAV vector.
143. The composition of claim 141 or 142, wherein the corticosteroid is administered once a day for at least 7 days after administration of the AAV vector.
144. The composition of any one of claims 141-143, wherein corticosteroid is formulated for oral administration at a dose of 40 mg.
145. The composition of any one of claims 141-143, wherein the subject is administered a corticosteroid or a non-steroidal immunosuppressive agent therapeutically after administration of the AAV vector.
146. The composition of claim 145, wherein the therapeutic corticosteroid is formulated for administration at a dose of 60 mg/day.
147. The composition of claim 145 or 146, wherein the therapeutic corticosteroid is administered for 21 days, and the dose gradually tapered off at day 22.
148. The composition of claim 147, wherein at day 22 the corticosteroid is administered at a dose of 40 mg/day for 28 days, and at day 29 the corticosteroid is administered at 30 mg/day for 28 days.
149. The composition of any one of claims 141-148, wherein the corticosteroid is presnisone or prednisolone.
150. The composition of claim 145, wherein the non-steroidal systemic immunosuppressive agent is cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab.
151. The composition of 141 or 150, wherein the non-steroidal systemic immunosuppressive agent is administered systemically.
152. The composition of any one of claims 141-151, wherein the subject has elevated ALT level or elevated FVIII inhibitor level compared to ALT levels or FVIII inhibitor levels before administration of the AAV vector.
153. The composition of claim 152, wherein the ALT level is at least 1.5x of the ALT level prior to administration of the AAV vector.
154. The composition of any one of claims 104-153, wherein the AAV vector is formulated for intravenous administration.
155. The method, use or composition of any of the preceding claims wherein the AAV vector comprising the functionally active FVIII coding region of SEQ ID NO: 1.
156. The method, use or composition of any of the preceding claims wherein the AAV vector comprises the nucleotide sequence of SEQ ID NO: 2.
157. The method, use or composition of any of the preceding claims wherein the AAV vector is administered at a dose of 6E13 vg/kg.
158. The method, use or composition of any of the preceding claims wherein subject has a with residual FVIII activity ^ 1 IU/dL prior to administration of the AAV vector.
159. The method, use or composition of any of the preceding claims wherein subject has a with residual FVIII activity > 1 IU/dL prior to administration of the AAV vector.
160. The method, use or composition of any of the preceding claims wherein administration of the AAV vector results in > 5 IU/dL FVIII activity.
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