WO2025235689A2

WO2025235689A2 - Peptides targeting alpl for blood-brain barrier crossing

Info

Publication number: WO2025235689A2
Application number: PCT/US2025/028263
Authority: WO
Inventors: David S. OJALA; Matthew R. TIFFANY
Original assignee: Sangamo Therapeutics Inc
Current assignee: Sangamo Therapeutics Inc
Priority date: 2024-05-07
Filing date: 2025-05-07
Publication date: 2025-11-13
Anticipated expiration: 2026-11-07

Abstract

This application relates to targeting peptides and engineering AAV capsids. In some embodiments, the targeting peptides and engineered AAV capsids are capable of interacting with ALPL (Tissue Non-Specific Alkaline Phosphatase) to mediate delivery to a cell or tissue.

Description

PEPTIDES TARGETING ALPL FOR BLOOD-BRAIN BARRIER CROSSING

FIELD

This application relates to peptides and engineered AAV (adeno-associated virus) capsids that mediate blood-brain barrier crossing by interacting with ALPL (Tissue Non-Specific Alkaline Phosphatase).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 63/643,805, filed on May 7, 2024 and entitled “PEPTIDES TARGETING ALPL FOR BLOOD-BRAIN BARRIER CROSSING,” and U.S. Provisional Patent Application No. 63/643,847, filed on May 7, 2024 and entitled “VARIANTS OF STAC-BBB THAT INTERACT WITH ALPL FOR FURTHER ENHANCEMENT OF BBB CROSSING,” the entire contents of which are incorporated by reference herein.

BACKGROUND

The clinical translation of genomic medicines has been limited by inefficient gene delivery through viral vectors like AAV capsids.

Attempts at engineering AAV capsids with improved properties, e.g., improved tropism to a target cell or tissue upon systemic administration, have met with limited success due to the unpredictable nature of how AAV capsid modifications influence targeting of cellular receptors. As such, there is a need for improved methods of engineering AAV capsids for delivery of genetic material of interest to a target cell or tissue, e.g., a CNS cell or tissue, including delivery across the blood-brain barrier (BBB). One approach to achieving this goal is to engineer capsids that interact with receptors that are highly expressed on the human bloodbrain barrier.

There remains a need to engineer AAV capsids having enhanced tropism to a target cell or tissue through engineering novel receptor interactions.

SUMMARY

In an aspect, targeting molecules, i.e., targeting peptides, are provided to enable targeting of a cell or a tissue, for example, the CNS. In some embodiments, a CNS-targeting molecule interacts with (e.g., binds to) ALPL, thereby enabling the CNS-targeting molecule to cross the BBB. In some embodiments, the CNS-targeting molecule comprises a peptide amino acid motif as indicated below in a single row:

In some embodiments, the CNS-targeting molecule comprises a peptide amino acid motif as indicated below in a single row:

In some embodiments, the CNS-targeting molecule comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11,

12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1, 2, 3, or 4. In some embodiments, the amino acid sequence is fused or conjugated to a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein. In some embodiments, a method for identifying a CNS-targeting molecule that crosses the BBB is provided, comprising selecting for variant AAV capsids that interact with ALPL.

In some embodiments, an adeno-associated virus (AAV) capsid protein is provided that interacts with (e.g., binds to) ALPL, thereby enabling the AAV capsid protein to cross the BBB.

In some embodiments, the AAV capsid protein comprises a peptide amino acid motif as indicated in a single row in Table 5 or Table 6, optionally wherein the peptide amino acid motif is located within a surface-exposed loop of the AAV capsid protein. In some embodiemnts, the capsid protein is AAV9 (SEQ ID NO: 7006) and optionally the peptide insertion site is between amino acids 454 and 455, as shown in a single row in Table 5. In some embodiments, the capsid protein is AAV6 (SEQ ID NO: 7007) and optionally the peptide insertion site is between amino acids 453 and 454, as shown in a single row in Table 6.

In some embodiments, the AAV capsid protein comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,

13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4. In some embodiments, the amino acid sequence is inserted into a parent capsid ("Parent Capsid”) at an insertion site (“Peptide Insertion Site”). In some embodiments, the amino acid sequence comprises a peptide sequence as indicated in a single row in Tables 1 to 4, and optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row.

In some embodiments, the amino acid sequence comprises a peptide sequence as indicated in a single row as shown below, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row Tables 7-9. In some embodiments, the amino acid sequence is inserted into any of the parental capsids AAV1, AAV2, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, AAVrhlO, AAVrh39, AAVrh74, or STAC-BBB (i.e., CNSRCV300 in US Application No.63/606,012).

In some embodiments, an engineered AAV capsid protein is provided, wherein the engineered AAV capsid protein is at least 80%, 85%, 90%, 95%, or 99% identical to or comprises a sequence set forth in SEQ ID NOs: 7008-7087 and 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403, CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409, CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415, CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461, CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467, CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473, CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479, CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505, CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511, CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517, CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523, CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529, CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535, CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315, CNSRCV316, CNSRCV317, CNSRCV319, and CNSRCV318.

In some embodiments, a nucleic acid molecule encoding an engineered AAV capsid protein described herein is provided. In some embodiment, a host cell comprising such a nucleic acid molecule is provided. In some embodiments, a composition is provided comprising: 1) an adeno-associated virus (AAV) capsid protein as described herein; and 2) an expression construct comprising a coding sequence for a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload. In some embodiments, the payload of interest is a therapeutic payload, and the therapeutic payload comprises a DNA binding domain, optionally wherein the therapeutic payload comprises a fusion protein. In some embodiments, the payload of interest comprises a therapeutic protein, a zinc finger protein, a CRISPR-associated DNA binding protein, a TALE protein, an antibody, an enzyme, a regulatory RNA, a Bxbl serine recombinase, or a DNA recombinase protein.

In some embodiments, a method of delivering a payload of interest to a cell or a tissue is provided, wherein a coding sequence for the therapeutic payload is encapsidated in an AAV capsid protein as described herein, and wherein the AAV capsid protein interacts with ALPL. In some embodiments, delivering the payload of interest to the cell or the tissue comprises crossing a BBB.

In some embodiments, a method of activating, expressing, repressing, or modulating the expression of a therapeutically relevant gene of interest in a cell, comprising contacting the cell with the composition as described herein.

In some embodiments, a method of treating a disease in a subject is provided, comprising administering to the subject the composition as described herein.

In some embodiments, use of an AAV capsid protein, a nucleic acid construct, or a host cell as described herein is provided for the manufacture of a medicament in a method as described herein.

In some embodiments, a method for identifying an AAV capsid variant that crosses a BBB is provided, comprising selecting for variant AAV capsids that interact with ALPL.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic of the approach used to pan AAV capsid libraries against an immobilized receptor. The receptor, in this case human ALPL, is biotinylated and then immobilized on a streptavidin coated bead. The AAV capsid libraries are then panned in parallel against the immobilized receptor or a streptavidin bead control without a receptor. AAV library genomes are extracted from each sample, amplified via PCR, and subjected to next-generation sequencing to quantify the enrichment of capsid variants. Capsids that specifically interact with the receptor are identified by comparing enrichment in the immobilized receptor condition relative to the bead only control.

FIG. 2 illustrates a schematic of the approach used to assess AAV library transduction in cells overexpressing a receptor, in this case human ALPL, relative to AAV library transduction in cells expressing a fluorescent protein transfection control. Cells are transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells are transduced with the AAV capsid libraries. Cells are incubated for 72 hours to allow for AAV-mediated expression of transgene mRNA. RNAis extracted from cells, reverse transcribed to cDNA, and then PCR is used to amplify the AAV cDNA. Next-generation sequencing analysis is used to quantify enrichment of capsid variants. Capsids that specifically interact with the receptor are identified by comparing enrichment in the receptor expression condition relative to the fluorescent protein transfection control.

FIG. 3 illustrates a schematic of the approach used to assess AAV library binding in cells overexpressing a receptor, in this case human ALPL, relative to AAV library binding in cells expressing a fluorescent protein transfection control. Cells are transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells are transduced with the AAV capsid libraries. Cells are incubated for 1 hour to allow for AAV binding to cells. DNA is extracted from cells and then PCR is used to amplify the AAV genome. Next-generation sequencing analysis is used to quantify enrichment of capsid variants. Capsids that specifically interact with the receptor are identified by comparing enrichment in the receptor expression condition relative to the fluorescent protein transfection control.

FIG. 4 The figure shows that AAV library screens can identify capsid variants that specifically target human or cynomolgus macaque ALPL. The top panel shows that biological replicates are highly correlated in library screens targeting ALPL. Each point on the plot represents a unique capsid that was detected. Spearman correlation coefficients are calculated between biological replicates 1 and 2. The bottom panel shows three representative examples of capsid library screens that were conducted for ALPL: 1) Immobilized human receptor versus a bead only control. Data shown are for the round 1 library of peptides inserted into the parent capsid AAV6.

2) Transduction of cells overexpressing human ALPL versus a transfection control. Data shown are for the round 1 library of peptides inserted into the parent capsid AAV9.

3) Transduction of cells overexpressing cynomolgus macaque ALPL versus a transfection control. Data shown are for the round 1 library of peptides inserted into the parent capsid AAV9.

A subset of capsids that exhibited specific enrichment for human or cynomolgus macaque ALPL orthologs are colored in green. The marginal axis histograms represent capsids that were identified in only the receptor condition (y-axis) or the negative control (x-axis).

FIG. 5 illustrates a schematic of the approach used to assess transduction mediated by individual AAV capsids in cells overexpressing a receptor, in this case human ALPL, relative to transduction in cells expressing a fluorescent protein transfection control. Cells are transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells are transduced with the AAV capsid libraries. Cells are incubated for 72 hours to allow for AAV-mediated expression of transgene mRNA. RNAis extracted from cells, and RT-qPCR is used to quantify mRNA transgene expression. Microscopy images are acquired to visualize the expression of a fluorescent protein.

FIG. 6 shows the transgene expression mediated by individual engineered capsids in cells overexpressing human, cynomolgus macaque, or mouse ALPL, relative to the transgene expression in cells expressing a fluorescent protein transfection control. HEK293 cells were transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells were transduced with the AAV capsid at a multiplicity of infection of 1E3, 3E3, 1E4, or 3E4 vector genomes per cell. Cells were incubated for 72 hours to allow for AAV-mediated expression of transgene mRNA. RNA was extracted from cells and RT-qPCR was conducted to quantify mRNA transgene expression. Data were normalized to expression of the housekeeping gene GAPDH. Engineered capsids CNSRCV400, CNSRCV401, and CNSRCV402 exhibit higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV9 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. The asterisk symbol indicates a single sample that was lost during processing for the 3E4 MOI of CNSRCV401 evaluated in cells overexpressing cynomolgus macaque ALPL.

FIG. 7 shows the fold change improvement in AAV mediated transgene expression for cells expressing ALPL relative to cells expressing the transfection control. Capsids CNSRCV400, CNSRCV401, and CNSRCV402 exhibit significantly higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV9 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control.

FIG. 8 shows the fold change improvement in transgene expression for capsids CNSRCV400, CNSRCV401, and CNSRCV402 relative to AAV9. The transduction mediated by receptor- targeted capsids is significantly enhanced relative to AAV9 in cells expressing human, cynomolgus macaque, and mouse ALPL.

FIG. 9 shows detection of mCherry fluorescent protein expression in cells overexpressing human ALPL. An increase in mCherry fluorescence is observed for receptor-targeted capsids CNSRCV400, CNSRCV401, and CNSRCV402 relative to the parental capsid AAV9.

FIG. 10 shows the impact of introducing the capsid mutation W503A in CNSRCV402 and AAV9. Capsid mutation W503A is known to abolish the ability of AAV9 to bind galactose, leading to a reduction in cell transduction (see Bell et al (2012) Journal of Virology 86(13):7326-7333). As expected, introduction of the W503A mutation in AAV9 resulted in a reduction in transduction relative to wild type AAV9. Potency is also reduced for the ALPL- targeted capsid CNSRCV402, however, a gain of transduction phenotype is still observed in cells overexpressing human, cynomolgus macaque, or mouse ALPL. These results suggest that capsid CNSRCV402 can utilize both galactose and ALPL for cell transduction.

FIG. 11(A)-(D) shows Tables 1, 2, 3, and 4. FIG. 12 shows the transgene expression mediated by additional individual engineered capsids based on the parent capsid AAV9 in cells overexpressing human, cynomolgus macaque, or mouse ALPL, relative to the transgene expression in cells expressing a fluorescent protein transfection control. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. HEK293 cells were transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells were transduced with the AAV capsid at a multiplicity of infection of 3E3. Cells were incubated for 72 hours to allow for AAV-mediated expression of transgene mRNA. RNA was extracted from cells and RT- qPCR was conducted to quantify mRNA transgene expression. Data were normalized to expression of the housekeeping gene GAPDH. Capsids engineered to target ALPL exhibit higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV9 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control.

FIG. 13 shows the fold change improvement in AAV mediated transgene expression for cells expressing ALPL relative to cells expressing the transfection control. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. Capsids engineered to target ALPL exhibit significantly higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV9 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control.

FIG. 14 shows the fold change improvement in transgene expression for capsids engineered to target ALPL relative to AAV9. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. The transduction mediated by the capsids engineered to target ALPL is significantly enhanced relative to AAV9 in cells expressing human, cynomolgus macaque, and mouse ALPL. FIG. 15 shows the transgene expression mediated by additional individual engineered capsids based on the parent capsid AAV6 in cells overexpressing human, cynomolgus macaque, or mouse ALPL, relative to the transgene expression in cells expressing a fluorescent protein transfection control. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. HEK293 cells were transfected with a plasmid encoding a strong ubiquitous promoter that drives the expression of the receptor or a negative control fluorescent protein. Forty-eight hours after transfection, the cells were transduced with the AAV capsid at a multiplicity of infection of 1E3. Cells were incubated for 72 hours to allow for AAV-mediated expression of transgene mRNA. RNA was extracted from cells and RT- qPCR was conducted to quantify mRNA transgene expression. Data were normalized to expression of the housekeeping gene GAPDH. Capsids engineered to target ALPL exhibit higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV6 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control.

FIG. 16 shows the fold change improvement in AAV mediated transgene expression for cells expressing ALPL relative to cells expressing the transfection control. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. Capsids engineered to target ALPL exhibit significantly higher transduction in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control. In contrast, the parent capsid AAV6 shows no significant increase in transgene expression in cells overexpressing human, cynomolgus macaque, or mouse ALPL relative to cells overexpressing a fluorescent protein transfection control.

FIG. 17 shows the fold change improvement in transgene expression for capsids engineered to target ALPL relative to AAV6. Representative engineered capsids, designed to target ALPL and described herein, are presented as illustrative examples. The transduction mediated by capsids engineered to target ALPL is significantly enhanced relative to AAV6 in cells expressing human, cynomolgus macaque, and mouse ALPL. FIG. 18 shows representative examples of the binding kinetics of capsids engineered to target ALPL. Bio-layer interferometry experiments were performed to assess the binding of capsids to human ALPL. Human ALPL protein was immobilized on Octet BLI sensors and binding to each capsid analyte was measured across a range of capsid concentrations from 6.25E10 to 1E12 vg/mL. Each plot represents a single capsid that was evaluated for binding to human ALPL. Capsids engineered to target ALPL exhibit robust binding responses while the parent capsid AAV9 exhibits no binding.

FIG. 19 shows the relative transgene expression mediated by a barcoded pool of AAV capsids in cells overexpressing ALPL relative to cells expressing the transfection control. AAV capsids were each manufactured individually with a unique barcoded transgene expression cassette and then pooled to create a barcoded pool of AAV capsids. The pool included the parent capsid STAC-BBB and variants of STAC-BBB that contain an ALPL targeting peptide (CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV3 15, CNSRCV316, CNSRCV317, and CNSRCV319). HEK293 cells were seeded in a 6-well plate and then transfected 24 hours later with an ALPL overexpression construct or a fluorescent protein transfection control using Lipofectamine 3000. The media was changed 24 hours post transfection. 48 hours post transfection, the cells were transduced with the barcoded pool of capsids in reduced serum media (0.5% FBS) at a multiplicity of infection of 1E5 viral genomes per cell. Cells were incubated for 72 hours to allow for AAV-mediated expression of the barcoded transgene mRNA. RNA was extracted from cells, reverse transcribed to cDNA, and then PCR was used to amplify the barcoded AAV cDNA. Next-generation sequencing analysis was conducted to quantify enrichment of capsid variants in the pool relative to the input abundance of each capsid in the barcoded pool. These fold change enrichment values were then normalized relative to STAC-BBB. The figure shows that insertion of ALPL targeting peptides into the STAC-BBB parent capsid endows STAC-BBB with enhanced transduction in cells overexpressing the human, cynomolgus macaque, or mouse ortholog of ALPL relative to a transfection control expressing a fluorescent protein. The size of each circle is proportional to the absolute value of the log2FC. The log2FC value is annotated above each circle. The coefficient of variation (CoV) percentile is represented by the circle opacity as shown in the legend, wherein a higher percentile score indicates a lower coefficient of variation.

DETAILED DESCRIPTION In an aspect, targeting molecules, i.e., targeting peptides, are provided for interacting with a specific cellular receptor, preferably where in the receptor is expressed on the blood brain barrier. In embodiments, the receptor is the tissue non-specific alkaline phosphatase, ALPL. In an aspect, delivery to and/or targeting of a cell or a tissue, preferably wherein the molecules are CNS (central nervous system)-targeting. In embodiments, CNS-targeting molecules comprising a targeting peptide sequence indicated in Tables 1-4 are provided. In another aspect, engineered AAV capsid proteins are provided. In embodiments, a targeting peptide is inserted into a parental AAV capsid, for example an AAV6 capsid protein (SEQ ID NO: 7007), an AAV9 capsid protein (SEQ ID NO: 7006), or a STAC-BBB capsid protein (SEQ ID NO: 7088). In embodiments, the targeting peptide is any of the targeting peptides disclosed in Tables 1-4. In embodiments, the peptide sequence is inserted into the parental capsid at any of the peptide insertion sites disclosed in Tables 1-4. In embodiments, the peptide sequence that is inserted into the parental capsid contains a peptide amino acid motif disclosed in Tables 5 and 6. In some embodiments, the targeting peptide functions to target the CNS-targeting molecule to a specific target tissue (e.g., CNS tissue).

Generation of an Engineered AAV Capsid Library

In one embodiment, disclosed herein is the development of libraries encoding engineered AAV capsid proteins, wherein members of the library encode engineered AAV capsid proteins having different sequences, and wherein some members of the library encode an AAV capsid protein having a desired characteristic compared to a natural/wild-type AAV serotype. In one embodiment, disclosed herein is the development of libraries encoding engineered AAV capsid proteins with a desired characteristic compared to a parent capsid. Thus, described herein are libraries of AAV capsid proteins with a desired characteristic compared to a parent capsid. In some embodiments, the desired characteristic is enhanced cell or tissue tropism as compared to the parent capsid, for example, enhanced cell or tissue tropism to the central nervous system (CNS) as compared to the parent capsid. In some embodiments, the desired characteristic is increased penetrance through the blood brain barrier following administration to a subject. In some embodiments, the desired characteristic is wider distribution throughout the multiple brain regions, e.g., frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate, and/or hippocampus. In some embodiments, the desired characteristic is elevated genetic material expression in multiple brain regions. In some embodiments, the desired characteristic is delivery of genetic material of interest to a desired tissue, cell, or organelle.

In some embodiments, each member of a library comprises one or more of a) a nucleic acid sequence encoding an AAV capsid protein comprising an engineered variant AAV sequence; b) a nucleic acid sequence encoding barcode; c) nucleic acid sequence(s) encoding a promoter(s); d) a nucleic acid sequence encoding a unique molecular identifier (UMI); and combinations thereof. In some embodiments, each member of the library also includes genetic material to be delivered to and expressed in a cell or tissue of interest. In some embodiments, each member of the library also includes a polyA sequence.

In some embodiments, each engineered AAV capsid protein was synthesized as an oligo pool. In some embodiments, each member of a library comprises one or more (such as 1-10) of a nucleic acid sequence encoding an AAV capsid protein comprising a) nucleic acid sequences encoding one or more (such as 1-10) barcodes: b) nucleic acid sequences encoding one or more (such as 1-10) promoters; c) nucleic acid sequences encoding one or more (such as 1-10,000) unique molecular identifiers (UMIs); or combinations thereof. In some embodiments, each member of the library also includes genetic material to be delivered to a cell or tissue of interest. In some embodiments, each member of the library also includes a polyA sequence. In some embodiments, each of the one or more (such as 1-10) barcodes is linked to the identity of a single engineered AAV capsid protein. In some embodiments, each of the barcodes is linked to one or more (such as 1-10,000) UMIs.

In some embodiments, a nucleic acid comprising a barcode is added to the genome of each AAV capsid in a library. In some embodiments, a unique barcode is bioinformatically linked to each different variant sequence that is represented within the library, for example, each different variant AAV sequence. In some embodiments, the DNA sequences encoding an AAV variant sequence are synthesized to further comprise a random or specified barcode. The barcode may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more nucleotides. In some embodiments, each AAV variant sequence is linked to at least 2 distinct barcodes. In some embodiments, each barcode is linked to one or more (such as 1-10,000) UMIs.

In some embodiments, each member of the library comprises a nucleic acid comprising more than one barcode sequences (such as 1-10). In some embodiments, each member of the library comprises two or more nucleic acids (such as 1-10) each comprising a barcode sequence. In some embodiments, each member of the library comprises a first nucleic acid comprising a first barcode and a second nucleic acid comprising a second barcode. In some embodiments, the first nucleic acid comprising the first barcode and the second nucleic acid comprising the second barcode are different. In some embodiments, each of the first nucleic acid comprising the first barcode and the second nucleic acid comprising the second barcode is independently operatively linked to a promoter. In some embodiments, each capsid is linked to at least one unique barcode. In some embodiments, each capsid is linked to at least two unique barcodes using a bioinformatic look-up table. In some embodiments, capsid performance is evaluated based on barcoded mRNA expression from the neuron specific promoter. In some embodiments, capsid performance is evaluated based on barcoded mRNA expression from the neuron specific human Synapsin 1 promoter. In some embodiments, capsid performance is evaluated based on barcoded mRNA expression from the ubiquitous CMV promoter.

In some embodiments, libraries are created encoding engineered AAV capsid proteins that comprise at least one mutation relative to a parent capsid, for example, the parent capsid AAV6, AAV9, or STAC-BBB (SEQ ID NOs: 7007, 7006, or 7088). In some embodiments, the engineered AAV capsid proteins contain a peptide sequence inserted within a parent capsid protein, for example, the parent capsid AAV6, AAV9, or STAC-BBB (SEQ ID NOs: 7007, 7006, or 7088). In some embodiments, the engineered AAV capsid proteins contain a peptide sequence inserted within a surface exposed loop of a parent capsid protein, for example, the parent capsid AAV6, AAV9, or STAC-BBB (SEQ ID NOs: 7007, 7006, or 7088).

In some embodiments, the libraries are packaged in HEK293 cells where the helper functions (e.g. E2A, E4, VA, El A and E1B) are supplied in trans. In some embodiments, the AAV rep function comprises rep78, rep 68, rep 52, and rep40 genes. In some embodiments, the rep genes are supplied in trans. In some embodiments, the start codon of the rep78 and/or the rep68 gene is altered from ACG to ATG to increase replication of the capsid library construct containing inverted terminal repeats (ITRs), thereby improving AAV library manufacturing yield. In some embodiments, the cap genes are supplied as genetic material that is packaged into the manufactured AAVs. In some embodiments, the capsid gene is controlled by the p40 promoter such that it is only expressed during manufacturing in HEK293 cells in the presence of helper virus functions. Methods of Screening Libraries of Engineered AAV Capsid Proteins

In some embodiments, a method of identifying an engineered AAV capsid protein with a desired characteristic compared to a natural/wild-type AAV serotype is provided comprising: (i) contacting an immobilized receptor protein, a cell, a cell line, or tissue in vitro or in vivo with any one of the libraries of engineered AAV capsid proteins, (ii) allowing the engineered AAV capsid proteins in said library to transduce the cell, cell line, or tissue; (iii) recovering from the immobilized receptor protein, cell, cell line, or tissue the AAV variant; and (iv) identifying the engineered AAV capsid protein with the desired characteristic.

In another embodiment, disclosed herein are methods for directed evolution of engineered AAV capsid proteins and identification of an engineered AAV capsid protein with a desired characteristic compared to a natural/wild-type AAV serotype. In some embodiments, the steps for directed evolution of engineered AAV capsid proteins to identify engineered AAV capsid proteins with a desired characteristic compared to a natural/wild-type AAV serotype comprise (i) modifying the natural/wild-type AAV serotype to create variant capsids; (ii) packaging of the variant AAVs in producer cells wherein adenovirus helper and AAV rep functions are supplied in trans; (iii) purification of viral capsid library pools; (iv) administration of the pools in vitro or in vivo; (v) recovery of engineered AAV capsid proteins from target tissues or cell lines; (vi) next-generation sequencing to determine the identity of the engineered variant capsid sequences; (vii) repeated rounds of in vitro or in vivo selection where variants are isolated from a target tissue or cell line; and (viii) full evaluation of enriched variants. In some embodiments, the desired characteristic includes enhanced tissue tropism as compared to the natural/wild- type AAV serotype. In some embodiments, the desired characteristic includes enhanced tissue tropism fortissues of the peripheral nervous system as compared to the natural/wild-type AAV serotype. In some embodiments, the desired characteristic includes enhanced tissue tropism of the central nervous system as compared to the natural/wild-type AAV serotype.

Engineered AAV Capsid Proteins

In one embodiment, described herein are compositions comprising engineered AAV capsid proteins and methods of making and using the same. In some embodiments, the engineered AAV capsid proteins interact with a receptor, e.g. ALPL. In some embodiments, the engineered AAV capsid proteins demonstrate binding to a receptor, e.g. ALPL. The engineered AAV capsid proteins may be delivered to one or more of target cells, tissues, organs, or organisms. In some embodiments, the engineered AAV capsid protein has enhanced tropism for a cell or tissue, e.g., for the delivery of genetic material to a specific cell or tissue, for example a CNS tissue or a CNS cell, or cells and tissues of a muscle. The engineered AAV capsid proteins may, in addition, or alternatively, have decreased tropism for an undesired target cell-type, tissue or organ. As a non-limiting example, the engineered AAV capsid proteins that are desired to have tropism for CNS cells may have enhanced tropism for neurons, astrocytes, oligodendrocytes, microglia, endothelial cells, Schwann cells, and reduced tropism for liver and dorsal root ganglion.

In some embodiments, an engineered AAV capsid protein is provided comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all contiguous amino acids of a peptide sequence inserted within a parent capsid protein. In some embodiments, the peptide sequence is inserted within or near a surface-exposed loop of the parent capsid protein. In a preferred embodiment, the parent capsid is AAV6, AAV9, or STAC-BBB (SEQ ID NOs: 7007, 7006, or 7088). In some embodiments, the peptide sequence is inserted within or near amino acids 453 through 454 corresponding to the sequence of AAV6 (SEQ ID NO: 7007). In some embodiments the peptide sequence is inserted within or near amino acids 454 through 455 corresponding to the sequence of AAV9 (SEQ ID NO: 7006). In some embodiments the peptide sequence is inserted within or near amino acids 454 through 455 corresponding to the sequence of STAC-BBB (SEQ ID NO: 7088).

In some embodiments, an amino acid sequence is inserted into a parent capsid ("Parent Capsid”) at an insertion site (“Peptide Insertion Site”). In some embodiments, the inserted amino acid sequence comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4. In some embodiments, an engineered AAV capsid protein is provided comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4. In some embodiments, the amino acid sequence comprises a peptide sequence as indicated in a single row in Tables 1 to 4, and optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row. In some embodiments, an engineered AAV capsid protein sequence is provided comprising a peptide motif as indicated in a single row of Table 5 of 6, optionally wherein the peptide motif is located within an insertion between amino acids 453 through 454 corresponding to the sequence of AAV6 (SEQ ID NO: 7007), or amino acids 454 through 455 corresponding to the sequence of AAV9 (SEQ ID NO: 7006).

In some embodiments, an amino acid sequence is inserted into a parental capsid, optionally wherein the parental capsid is selected from any one of AAV1, AAV2, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, AAVrhlO, AAVrh39, AAVrh74, or STAC- BBB. In some embodiments, the inserted amino acid sequence comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4.

In some embodiments, the engineered AAV capsid protein is at least 80%, 85%, 90%, 95%, or 99% identical to or comprises any one of the sequences corresponding to SEQ ID NOs: 7008- 7087 and 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403,

CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409

CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415

CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461.

CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467

CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473

CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479

CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505

CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511

CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517

CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523

CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529

CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535

CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307

CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315

CNSRCV316, CNSRCV317, CNSRCV319, and CNSRCV318.

In some embodiments, the engineered AAV capsid proteins have advantages over wild-type AAV capsid proteins. In some embodiments, these advantages including (i) enhanced cell or tissue tropism as compared to the natural/wild-type AAV serotype, for example, enhanced cell or tissue tropism to the central nervous system (CNS) as compared to the natural/wild-type AAV serotype (ii) increased penetrance through the blood brain barrier following administration to a subject, (iii) wider distribution throughout the multiple brain regions, for example, the frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate, and/or hippocampus, (iv) elevated expression of genetic material in multiple brain regions. In some embodiments, the engineered AAV capsids enhance the delivery of genetic material to multiple regions of the brain including for example, the frontal cortex, sensory cortex, motor cortex, putamen, thalamus, cerebellar cortex, dentate nucleus, caudate, and/or hippocampus, (v) is delivery of genetic material of interest to a desired tissue, cell, or organelle.

In embodiments, the engineered AAV capsid proteins and genetic material described herein may be delivered to one or more (such as 1-10) target cells, tissues, organs, or organisms. In some embodiments, the engineered AAV capsid proteins have enhanced tropism for a specific target cell type, tissue or organ. As a non-limiting example, the engineered AAV capsid protein has enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively). In some embodiments, engineered AAV capsid proteins are produced recombinantly and are an adeno-associated virus (AAV) serotype such as AAV1, AAV2, AAV3B, AAV5, AAV6, AAV8, AAV9, AAV3, AAV4, AAV7, AAV11, AAVrhlO, AAVrh39, AAVrh74, or STAC-BBB, or a combination thereof. In some embodiments, engineered AAV capsid proteins are produced recombinantly and are based on any one or more (such as 1-15) AAV serotypes known in the art.

Adeno-associated virus (AAV)

AAV are capable of infecting a wide range of cells including quiescent cells and dividing cells. In some embodiments, AAV can be modified so that it contains the components necessary for the assembly of a functional recombinant virus or viral particle. In some embodiments, the AAV is engineered to interact with a specific receptor, e.g. ALPL. In some embodiments, the AAV is engineered to target a specific tissue and/or cell, for example, CNS tissue and/or cell. In some embodiments, the AAV is engineered to deliver specific genetic material to a tissue and/or cell. In some embodiments, the AAV is engineered to target a blood brain barrier receptor, for example, ALPL.

Modified AAV Serotypes

In some embodiments, an engineered AAV may be based on any natural or recombinant AAV serotype. Different AAV serotypes have different characteristics such as different packaging, tropism, and transduction profiles. In some embodiments, the engineered AAV capsid proteins are based on a wild-type AAV serotype. In some embodiments, the AAV serotype comprises AAV1, AAV2, AAV3B, AAV5, AAV6, AAV8, or AAV9. In some embodiments, the AAV serotype comprises less well-characterized AAV serotypes such as AAV3, AAV4, AAV7, AAV11, AAVrhlO, AAVrh39, or AAVrh74. In some embodiments, the AAV serotype is an engineered AAV serotype such as STAC-BBB. In some embodiments, the engineered AAV capsid protein is derived from multiple AAV serotypes, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more AAV serotypes. In some embodiments, AAV variant capsid proteins derived from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more AAV serotypes are combined to create chimeric capsids. In some embodiments, combinatorial libraries are generated by modifying nucleic acids encoding AAV capsid proteins from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more serotypes in the same pool.

In some embodiments, different AAV serotypes are different in their ability to direct or modulate an AAV particle to a particular cell or tissue. In some embodiments, the AAV serotype can be modified to interact with a receptor, e.g. ALPL. In some embodiments, the AAV serotype modified to interact with a receptor has an altered tropism. In some embodiments, the AAV serotype can be modified to increase the tropism of the AAV particle to cells or tissues of the central nervous system (CNS). In some embodiments, the AAV serotype can be modified to increase tropism of the AAV particle to cells or tissues of the peripheral nervous system (PNS).

In some embodiments, the modified AAV serotype has a desired characteristic compared to a parental AAV serotype. In some embodiments, the modified AAV serotype allows for increased penetration of the blood brain barrier following administration to a subject. In some embodiments, the modified AAV serotype causes increased biodistribution to a brain region. In some embodiments, the brain region comprises the frontal cortex, the sensory cortex, the motor cortex, the cerebellar cortex, the hippocampus, the thalamus, or the putamen. In some embodiments, the brain comprises any brain region known in the art. In some embodiments, the modified AAV serotype causes increased biodistribution to more than one brain regions, for example, 2 brain regions, 3 brain regions, 4 brain regions, 5 brain regions, 6 brain regions, 7 brain regions, 8 brain regions, 9 brain regions, or 10 brain regions. In some embodiments, the modified AAV serotype causes increased biodistribution to 1- 10 brain regions. In some embodiments, the modified AAV serotype are useful in elevating genetic material expression in multiple brain regions. In some embodiments, the modified AAV serotype are used to deliver genetic material of interest to a desired tissue, cell, or organelle. In some embodiments, the modified AAV serotype causes increased biodistribution to regions of the spinal cord. In some embodiments, the region of the spinal cord comprises any of the thoracic spinal cord region, the lumbar spinal cord region, and/or the cervical spinal cord region. In some embodiments, the region of the spinal cord includes any region of the spinal cord known in the art.

In some embodiments, the modified AAV serotype comprises a peptide motif described herein (e.g., as shown in Tables 5 and 6). In some embodiments, the modified AAV serotype comprises an inserted sequence having at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of a Peptide Sequence shown in Tables 1-4. In some embodiments, the inserted sequence is inserted into a parent capsid serotype as shown in Tables 1-4. In some embodiments, the inserted sequence is inserted into a parent capsid sequence at or near the Peptide Insertion Site as shown in Tables 1-4. In some embodiments, the modified AAV serotype comprises an inserted peptide sequence described herein (e.g., a Peptide Sequence shown in Tables 1-4) and/or a peptide motif described herein (e.g., as shown in Tables 5 and 6). In some embodiments, the modified AAV serotype comprises a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the sequences corresponding to a sequence set forth in set forth in SEQ ID NOs: 7008-7087, and 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403, CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409, CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415, CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461, CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467, CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473, CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479, CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505, CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511, CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517, CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523, CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529, CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535, CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313,

CNSRCV3 14, CNSRCV315, CNSRCV316, CNSRCV317, CNSRCV319, or CNSRCV318. In some embodiments, the modified AAV sequence comprises any one of the sequences corresponding to a sequence set forth in set forth in SEQ ID NOs: 7008-7087, and 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403, CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409, CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415, CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461, CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467, CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473, CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479, CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505, CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511, CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517, CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523, CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529, CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535, CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315, CNSRCV316,

CNSRCV317, CNSRCV319, or CNSRCV318.

Structure of AAV

In some embodiments, the genome of the AAV comprises a single-strand DNA (ssDNA) molecule that is approximately between about 2.5 kb and about 5.0 kb in length. In some embodiments, the genome of the AAV comprises a self-complementary DNA (scDNA) molecule that is approximately between about 0.5 kb and about 2.5 kb in length. In some embodiments, the AAV genome contains inverted terminal repeats (ITRs) that flank the 5’ and 3’ ends of the AAV molecule. In some embodiments, the ITRs contain origins of replication for the viral genome. In some embodiments, the length of the ITRs is about 145 bp in length, for example, between about 130 bp in length and 160 bp in length.

In some embodiments, the AAV genome comprises the rep and cap genes. In some embodiments, the AAV genome nucleotide includes nucleotide sequences that encode four non- structural Rep proteins (Rep 78, Rep68, Rep52, Rep40, encoded by Rep genes). In some embodiments, the AAV viral genome includes nucleotide sequences that encode the three capsid, or structural, proteins (i.e., VP1, VP2, VP3, encoded by the cap gene). In some embodiments, the rep proteins are used for replication and packaging. In some embodiments, the capsid proteins are assembled to create the protein shell of the AAV.

AAV particles

In some embodiments, the engineered AAV capsid proteins assemble to form AAV particles. In some embodiments, the engineered AAV capsid proteins interact with a receptor expressed at the blood brain barrier, for example, ALPL. In some embodiments, the AAV particles that have enhanced tropism for a target tissue (e.g., CNS and PNS) are provided. In some embodiments, the AAV particles include engineered AAV variant sequences that alter tropism to a particular cell-type, tissue, organ or organism, in vivo, ex vivo or in vitro. In some embodiments, the AAV particles are capable of penetrating the blood brain barrier.

Delivery of AAV particles

The AAV particles may be delivered to one or more target cells, tissues, organs, or organisms. In some embodiments, the AAV particles demonstrate enhanced tropism for a target cell type, tissue or organ. As a non-limiting example, the AAV particle may have enhanced tropism for cells and tissues of the central or peripheral nervous systems (CNS and PNS, respectively), or cells and tissues of a muscle. The AAV particles may, in addition, or alternatively, have decreased tropism for an undesired target cell-type, tissue or organ.

In some embodiments, the AAV particles can be used to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating. In some embodiments, the AAV particles are used to deliver any cargoes of interest, or example, therapeutic cargoes.

AAV viral genomes

In some embodiments, the AAV particles are used to deliver a viral genome (i.e., a genetic payload) to a tissue or cells such as CNS or PNS cell or tissue.

The delivered viral genome may include genetic material of interest, such as, for example, genetic material that encodes an engineered DNA recombinase protein, a fusion protein comprising a DNA-binding domain (e.g., a zinc finger or a TALE protein) fused to a functional domain (e.g., to modulate DNA function or to cleave DNA), an antibody, an enzyme, regulatory RNA, a CRISPR protein, or a cDNA, amongst others. In some embodiments, the viral genome includes 2 ITR sequences. In some embodiments, the ITR sequences flank the genetic material of interest. In some embodiments, the ITR sequences are complementary to each other. In some embodiments, the ITR sequences are not complementary to each other. In some embodiments, one ITR sequence is a self-complementary ITR. In some embodiments, the ITR regions are derived from the same serotype as the capsid protein. In some embodiments, the ITR regions are derived from AAV2 serotype. In some embodiments, the ITR regions are derived from a serotype known to the art. ITR regions may be between 100 and 150 nucleotides in length.

Targeting Peptide Sequences

In embodiments, targeting peptide sequences (e.g., targeting molecules or sequences) are disclosed herein. In some embodiments, the sequences enhance or enable interaction with ALPL. In some embodiments, the sequences can function to target a cell or a tissue, for example, as a general CNS-targeting molecule or sequence.

In embodiments, the targeting sequences function as a general CNS-targeting molecule sequence. In some embodiments, the CNS-targeting sequence is fused or conjugated to a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein. In some embodiments, any one of the targeting sequences or sequence motifs described herein may be fused or conjugated to a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein. In some embodiments, CNS-targeting sequences may be utilized to enable a small molecule, an antibody, zinc finger protein, scFV, ASO (antisense oligonucleotide), siRNA, lipid, polymer or recombinant protein to cross the blood brain barrier.

In some embodiments, the targeting sequences are part of an engineered AAV capsid protein. In some embodiments, the engineered AAV capsid protein is any engineered AAV capsid protein disclosed herein.

In some embodiments, the targeting sequences enable the binding of an AAV capsid protein to a specific receptor, e.g. ALPL. In some embodiments, the targeting sequences enable the binding of an AAV capsid protein to a specific receptor expressed at the blood brain barrier, e.g. ALPL. In some embodiments, the targeting sequences modulate the binding affinity of an AAV capsid protein to a specific receptor, e.g. ALPL.

In some embodiments, the sequences may increase tropism of an AAV capsid protein to a cell or tissue of the CNS. In some embodiments, the cell of the CNS is a neuron (e.g., excitatory, inhibitory, motor, sensory, autonomic, sympathetic, parasympathetic, Purkinje, Betz, etc.), a glial cells (e.g., microglia, astrocytes, oligodendrocytes) and/or a supporting cells of the brain such as immune cells (e.g., T cells). In some embodiments, the CNS tissue is the cortex (e.g., frontal, parietal, occipital, temporal), thalamus, hypothalamus, striatum, caudate nucleus, hippocampus, putamen, basal ganglia, entorhinal cortex, cerebellum, or spinal cord.

In some embodiments, the sequences increase tropism of an AAV capsid protein to a cell, region, or tissue of the PNS. In some embodiments, the cell or tissue of the PNS is dorsal root ganglion (DRG).

In some embodiments, the sequences decrease tropism of an AAV capsid protein to a cell, region, or tissue of the PNS. In some embodiments, the cell or tissue of the PNS is dorsal root ganglion (DRG).

In some embodiments, the targeting sequence comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4. In some embodiments, the sequence comprises a motif sequence as shown in Tables 5 and 6. In some embodiments, the sequence comprises the amino acid sequence (“Peptide Sequence”) as shown in a single row in the first column of Tables 1 to 4.

In some embodiments, the targeting peptide sequence is inserted within a parent AAV capsid sequence. In some embodiments, the inserted sequence is inserted into a parent capsid serotype as shown in Tables 1-4. In some embodiments, the inserted sequence is inserted into a parent capsid sequence at or near the Peptide Insertion Site as shown in Tables 1-4. In some embodiments, the targeting peptide sequence is inserted within or near a surface-exposed loop of a parent AAV capsid sequence. In some embodiments, the parent capsid sequence is any of the serotypes AAV1, AAV2, AAV3B, AAV5, AAV6, AAV8, AAV9, or STAC-BBB.

In some embodiments the peptide sequence is inserted within or near amino acids 453 through 454 corresponding to the sequence of AAV6 (SEQ ID NO: 7007). In some embodiments the peptide sequence is inserted within or near amino acids 454 through 455 corresponding to the sequence of AAV9 (SEQ ID NO: 7006).

Administering Engineered AAV Capsid Proteins to Subjects

In some embodiments, when administered to subjects, AAV capsid proteins containing the targeting peptides described herein mediate enhanced delivery to cells and tissues relative to AAV capsid proteins that lack the targeting peptides. In some embodiments, the AAV capsid protein administered to subjects comprises an engineered AAV sequence described herein.

Genetic Material

In some embodiments, the engineered AAV capsid proteins described herein encapsidate genetic material of interest to be delivered to a cell of interest. In some embodiment, the genetic material of interest may be a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload. As such, in embodiments the engineered AAV capsid proteins described herein enable delivery of genetic material to a cell of interest. In embodiments, the genetic material may encode a research, diagnostic, and/or therapeutic payload. In embodiments, the genetic material encodes a zinc finger protein, a TALE protein, a recombinase protein, and/or a CRISPR protein, or fragments thereof. In embodiments, the genetic material encodes one or more antibodies or an antibody fragments. In some embodiments the genetic material encodes one or more regulatory RNA, such as RNAi agents or microRNAs.

In some embodiments, the genetic material can include sequences that are coding sequences. In some embodiments, the genetic material can include sequences that are non-coding sequences. In some embodiments, the genetic material can include sequences that are both coding sequences and non-coding sequences. In some embodiments, the expression of the genetic material is capable of being regulated. In some embodiments, the genetic material comprises elements that are regulatable.

In some embodiments, mRNA is encoded in the genetic material. In some embodiments, the mRNA is codon optimized.

In some embodiments, the genetic material encodes a gene therapy product. A gene therapy product can include a peptide, a polypeptide, or an RNA molecule that when expressed carries out a desired therapeutic effect. In some embodiments, the therapeutic effect is treating any one or more diseases or disorders described herein.

In some embodiments, a promoter is operably linked to the genetic material to be delivered to the cell. In some embodiments, the promoter comprises a tissue and/or cell specific promoter. In some embodiments, the one more promoters comprise a ubiquitous promoter. Examples of ubiquitous promoters include cytomegalovirus (CMV), chicken P-actin (CBA), ubiquitin C (UBC), and elongation factor la-subunit (EFl -a), amongst others. In some embodiments, the promoter comprises a cell type and/or tissue specific type promoter. Exemplary cell type and/or tissue specific promoters include the human synapsin promoter (hSynl), only expressed in neurons, or the transthyretin promoter (TTR), expressed in hepatocytes. Other non-limiting cell type and/or tissue specific promoters for use in the methods and compositions of the invention include cytokeratin 18 and 19 (epithelial cell specific, Other cell-specific promoters include GFAP promoter (astrocytes), TBG promoter (liver), MHCK promoter (skeletal muscle), MYH6 promoter (cardiomyocytes). In embodiments, tissue specific or cell specific promoters can restrict expression to tissues or cells of the CNS or PNS. In embodiments, tissue specific or cell specific promoters can be used to restrict expression to neurons of the sympathetic system, the parasympathetic system, astrocytes, microglia, oligodendrocytes, and/or Schwann cells.

In some embodiments, the promoters are naturally occurring promoters. In some embodiments, the promoter is synthetic. In some embodiments, the promoter is derived from mammals, humans, viruses, or plants. In some embodiments, the promoters are truncated. In some embodiments, the promoter is mutated.

Gene Editing System

In some embodiments, the genetic material of interest comprises a gene editing system or portions of a gene editing system. In some embodiments, the gene editing system is capable of inducing single or double-stranded breaks into nucleic acid sequences at one or more site of interest. In some embodiments, the gene editing system is capable of inserting, substituting, or deleting a base or a sequence of bases into nucleic acid sequences at one or more site of interest. In some embodiments, the gene editing system includes a CRISPR-Cas system. In some embodiments, the gene editing system includes a TALEN. In some embodiments, the gene editing system includes a zinc finger nuclease. In some embodiments, the gene editing system includes a modified recombinase protein. Epigenetic Regulation System

In some embodiments, the genetic material of interest comprises an epigenetic regulation system or components of an epigenetic regulation system for general or targeted gene regulation. In some embodiments, the epigenetic regulation system is capable of modifying chromatin structure or altering epigenetic marks on nucleic acid sequences. In some embodiments, the epigenetic regulation system is capable of promoting or repressing gene expression without altering the underlying DNA sequence. In some embodiments, the epigenetic regulation system includes a CRISPR-dCas system fused to epigenetic effector domains. In some embodiments, the epigenetic regulation system includes a transcription activator or repressor domain tethered to a programmable DNA-binding protein. In some embodiments, the epigenetic regulation system includes hi stone-modifying enzymes or DNA methyltransferases targeted to a specific genomic locus. In some embodiments, the epigenetic regulation system includes a TALEN. In some embodiments, the epigenetic regulation system includes a zinc finger protein fused to an epigenetic effector domain, for example, a zinc finger repressor or a zinc finger activator.

Active Agents

In some embodiments, engineered AAV sequences described herein are fused or coupled to an active agent. In some embodiments, a sequence is fused or coupled to an active agent through conjugation. In some embodiments, the active agent comprises a therapeutic agent. In some embodiments, the therapeutic agent comprises an antibody or a portion of an antibody (e.g., Fc region). In some embodiments, the sequence is fused to a Fc region of an antibody. In some embodiments, the sequence is fused to the C-terminus of the Fc region. In some embodiments, the sequence is fused to the N-terminus of the Fc region. In some embodiments, the therapeutic agent comprises an RNAi agent (e.g., siRNA, shRNA, IncRNA, piRNA, snoRNA, or miRNA). In some embodiments, the sequence is fused or coupled directly to at least on strand of the RNAi. In some embodiments, the sequence is fused or coupled to at least one strand of RNAi using a linker. In some embodiments, the sequence is fused or coupled to the sense strand of RNAi. In some embodiments, the sequence is fused or coupled to the antisense strand of RNAi.

In some embodiments the active agent comprises a diagnostic agent. In some embodiments, the diagnostic agent comprises a detectable moiety such as a fluorophore. In some embodiments, the active agent is a small molecule. Pharmaceutical Compositions and Dosage Forms

Compositions herein (e.g., engineered AAV capsid sequences, AAV particles, and engineered AAV capsid proteins) can be included in pharmaceutical compositions. In some embodiments, the pharmaceutical compositions can include one or more excipients or diluents to (1) increase stability; (2) increase cell transfection or transduction; (3) permit the sustained or delayed release of the genetic material; (4) alter the biodistribution (e.g., target the composition to specific tissues or cell types); (5) increase the translation of encoded protein; (6) alter the release profile of encoded protein and/or (7) allow for regulatable expression of the genetic material.

The pharmaceutical compositions described herein can be administered periodically, such as once or twice a day, or any other suitable time period. For example, pharmaceutical compositions may be administered to a subject in need once a week, once every other week, once every three weeks, once a month, every other month, every three months, every six months, every nine months, once a year, every eighteen months, every two years, every thirty months, or every three years.

In some embodiments, the compositions described herein (e.g., engineered AAV capsid sequences, AAV particles, and engineered AAV capsid proteins) can be formulated in a wide variety of dosage forms, including but not limited to nasal, pulmonary, oral, topical, or parenteral dosage forms for clinical. Each of the dosage forms can comprise various solubilizing agents, disintegrating agents, surfactants, fillers, thickeners, binders, diluents such as wetting agents or other pharmaceutically acceptable excipients. The compositions described herein can also be formulated for injection, insufflation, infusion, or intradermal exposure. For instance, an injectable formulation may comprise the disclosed compositions in an aqueous or non-aqueous solution at a suitable pH and tonicity. The compositions can be included liquid dosage form for oral administration, such as suspensions, emulsions, or syrups.

In some embodiments, the pharmaceutical compositions described herein function to increase the stability, increase transduction or transfection efficiency, impact biodistribution, increase expression of the protein, and/or alter the release profile.

Methods of Delivery and Treatment

In some embodiments, methods for introducing the compositions described herein (e.g., engineered AAV capsid sequences, AAV particles, and engineered AAV capsid proteins) into cells and/or tissues are provided. In some embodiments, the methods comprise introducing into cells and/or tissues any of the compositions described herein in an amount sufficient to modulate, e.g., increase, the production of a target mRNA and/or protein in the cells and/or tissues.

In some embodiments, the compositions described herein are delivered via a localized delivery route. In some embodiments, the localized delivery route includes any one or more of intramuscular administration, intraparenchymal administration, and intracerebral administration, amongst others. In some embodiments, the compositions described herein are administered via a localized delivery route through a bolus infusion.

In some embodiments, the compositions described herein are administered through systemic administration. In some embodiments, systemic administration includes intravenous administration.

In some embodiments, the compositions described herein are administered to the central nervous system of via intraventricular administration and/or intrathecal administration. In some embodiments, the compositions described herein are administered to the central nervous system via systemic administration. In some embodiments, the systemic administration is intravenous (IV) injection. In some embodiments, the compositions described herein are administered to the central nervous system via administration into the cerebrospinal fluid.

In some embodiments the compositions can be delivered to target cells or target tissue including, but not limited to, the CNS, heart, lung, trachea, esophagus, muscle, bone, cartilage, stomach, pancreas, intestine, liver, bladder, kidney, ureter, urethra, uterus, fallopian tube, ovary, testes, prostate, eye, blood, lymph, or oral mucosa. In some embodiments, the target cell or tissue includes, but is not limited to CNS, heart, lung, trachea, esophagus, muscle, bone, cartilage, stomach, pancreas, intestine, liver, bladder, kidney, ureter, urethra, uterus, fallopian tube, ovary, testes, prostate, eye, blood, lymph, or oral mucosa. In some embodiments, the target cell or target tissue is a CNS cell or tissue. In some embodiments, the target cell or tissue is liver cell or tissue.

In some embodiments, the target cell includes, but is not limited to, neurons, glial cells, astrocytes, oligodendroglia, microglia, Schwann cells, ependymal cells, hepatocytes, stellate fat storing cells, Kupffer cells, liver endothelial cells, epithelial cells, cardiomyocytes, smooth muscle cells, T-cells, B cells, hematopoietic stem cells, and embryonic stem cells. In some embodiments, the compositions described herein are delivered to the central nervous system through the cerebral spinal fluid pathway. In some embodiments, compositions described herein are administered to the central nervous system via intraparenchymal delivery. In some embodiments, the compositions described herein are administered to the central nervous system via intracranial delivery. In some embodiments, the compositions described herein are delivered to the central nervous system via intraocular delivery. In some embodiments, the compositions described herein are administered to the brain. In some embodiments, the compositions described herein are administered to the brain via injection into the brain. In some embodiments, the compositions described herein are administered to the brain via intrahippocampal injection.

In some embodiments, the compositions described herein are administered as part of a composition that allows for extended release. In some embodiments, the compositions comprises a formulation that includes a depot.

Disclosed herein are methods of treatment using any of the compositions described herein (engineered AAV capsid sequences, AAV particles, and engineered AAV capsid proteins). In embodiments, the disclosed compositions can be used to treat any one or more of muscular or neuromuscular disorders, neurooncological disorders, neurological diseases/disorders, and neurodegenerative disorders, amongst others. In embodiments, the disclosed compositions can be used to treat any one or more of Alzheimer's disease, Huntington's disease; autism; Parkinson's disease; Spinal muscular atrophy, Friedreich's ataxia. In embodiments, the disclosed compositions are used in treatments through any of the methods of delivery described herein.

In some embodiments, disclosed are methods for treating, or ameliorating a disease or condition associated with abnormal gene and/or protein in a subject in need of treatment, the methods comprising administering to the subject any effective amount of at least one of the compositions described herein (e.g., engineered AAV capsid sequences, AAV particles, and engineered AAV capsid proteins), delivering the compositions described herein into targeted cells, inhibiting or activating the gene expression and protein production, and ameliorating symptoms of the disease or condition in the subject. Equivalents and Scope

Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Generally, nomenclature used in connection with, and techniques of neurology, medicine, medicinal and pharmaceutical chemistry, and cell biology described herein are those well-known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

The disclosure includes many equivalents to the specific embodiments described herein. A person of skill in the art will be able to ascertain equivalents to the specific embodiments, through routine experimentation.

It is assumed that words of this disclosure are for the purpose of description and not limitation. Changes to words in the claims can be made, while still retaining the scope of the disclosure in its broad embodiment. Specific embodiments of the disclosure have been described herein. However, these embodiments are not intended to be limiting of the broad scope of this disclosure. In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

Exemplary Embodiments

Non-limiting exemplary embodiments of the present disclosure are described below.

1. An adeno-associated virus (AAV) capsid protein comprising a peptide amino acid motif as indicated in a single row in Table 5 or Table 6, optionally wherein the peptide amino acid motif is located within a surface-exposed loop of the AAV capsid protein.

2. The AAV capsid protein of embodiment 1, wherein the amino acid motif is inserted into AAV9 (SEQ ID NO: 7006) and optionally the peptide insertion site is between amino acids 454 and 455, as shown in a single row in Table 5; or, wherein the amino acid motif is inserted into AAV6 (SEQ ID NO: 7007) and optionally the peptide insertion site is between amino acids 453 and 454, as shown in a single row in Table 6.

3. An AAV capsid protein comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) set forth in any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4.

4. The AAV capsid protein of embodiment 3, wherein the amino acid sequence is inserted into a parent capsid ("Parent Capsid”) at an insertion site (“Peptide Insertion Site”) as shown in a single row in Tables 1 to 4.

5. The AAV capsid protein of embodiment 4, wherein the amino acid sequence comprises a peptide sequence according to any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4, and optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row as shown in Tables 1 to 4.

6. The AAV capsid protein of embodiment 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 7, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 7.

7. The AAV capsid protein of embodiment 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 8, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 8. 8. The AAV capsid protein of embodiment 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 9, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 9.

9. The AAV capsid protein of any one of embodiments 1-8, wherein the amino acid sequence is inserted into a parental capsid, optionally wherein the parental capsid is selected from any one of AAV1, AAV2, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, AAVrhlO, AAVrh39, AAVrh74, or STAC-BBB.

10. An AAV capsid protein, wherein the AAV capsid protein is at least 80%, 85%, 90%, 95%, or 99% identical to or comprises a sequence set forth in any one of SEQ ID NOs: 7008- 7087, or 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403, CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409, CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415, CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461, CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467, CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473, CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479, CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505, CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511, CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517, CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523, CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529, CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535, CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315, CNSRCV316, CNSRCV317, CNSRCV319, or CNSRCV318.

11. The AAV capsid protein of any one of embodiments 1-10, wherein the AAV capsid protein interacts with tissue non-specific alkaline phosphatase (ALPL), thereby enabling delivery of the AAV capsid protein to a cell or a tissue, optionally wherein interaction with tissue non-specific alkaline phosphatase (ALPL) enables the AAV capsid protein to cross a BBB.

12. A nucleic acid molecule encoding an engineered AAV capsid protein of any one of embodiments 1-11. 13. A host cell comprising the nucleic acid molecule of embodiment 12.

14. A composition comprising: 1) an AAV capsid protein comprising of any one of embodiments 1-11; and 2) an expression construct comprising a coding sequence for a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload.

15. The composition of embodiment 14, wherein the payload of interest is a therapeutic payload, and wherein the therapeutic payload comprises a DNA binding domain, optionally wherein the therapeutic payload comprises a fusion protein.

16. The composition of embodiment 14 or embodiment 15, wherein the payload of interest comprises a therapeutic protein, a zinc finger protein, a CRISPR-associated DNA binding protein, a TALE protein, an antibody, an enzyme, a regulatory RNA, a Bxbl serine recombinase, or a DNA recombinase protein.

17. A method of delivering a payload of interest to a cell or a tissue, wherein a coding sequence for the payload of interest is encapsidated in an AAV capsid protein according to any one of embodiments 1-11, and wherein the AAV capsid protein interacts with ALPL.

18. The method of embodiments 17, wherein delivering the payload of interest to the cell or the tissue comprises crossing a BBB.

19. A method of activating, expressing, repressing, or modulating the expression of a therapeutically relevant gene of interest in a cell, comprising contacting the cell with the composition of any one of embodiments 14-16.

20. A method of treating a disease in a subject, comprising administering to the subject the composition of any one of embodiments 14-16.

20. Use of an AAV capsid protein of any one of embodiments 1-11, a nucleic acid construct of embodiment 12, or a host cell of embodiment 13 for the manufacture of a medicament in the method of any one of embodiments 17-20.

21. A method for identifying an AAV capsid variant that crosses a BBB, comprising selecting for variant AAV capsids that interact with ALPL.

22. A method for identifying an AAV capsid variant that crosses a BBB or exhibits enhanced delivery to a cell or a tissue, comprising selecting for AAV capsids that: i) comprise a peptide motif as indicated in a single row of Tables 5 or 6; or ii) comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) set forth in any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4.

23. A targeting molecule that interacts with ALPL, thereby enabling delivery of the targeting molecule to a cell or a tissue, optionally wherein the interaction with ALPL enables the targeting molecule to cross the blood-brain barrier (BBB).

24. The targeting molecule of embodiment 23, comprising a peptide amino acid motif as indicated below in a single row:

25. The targeting molecule of embodiment 23, comprising a peptide amino acid motif as indicated below in a single row:

26. The targeting molecule of embodiment 23, comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) according to any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4.

27. The targeting molecule of any one of embodiments 23-26, wherein the targeting molecule is fused or conjugated to an AAV, a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein.

28. A composition comprising: 1) a targeting molecule of any one of embodiments 23-26; and 2) a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload.

29. The composition of embodiment 28, wherein the payload of interest encodes or comprises a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein.

30. A method of delivering a payload of interest to a cell or a tissue, wherein a coding sequence for the payload of interest is associated with the targeting molecule according to any one of embodiments 23-27, and wherein the targeting molecule interacts with ALPL.

31. The method of embodiment 30, wherein delivering the payload of interest to the cell or the tissue comprises crossing a BBB.

32. A method of delivering a therapeutically relevant gene or protein of interest to a cell, comprising contacting the cell with the composition of any one of embodiments 28-29.

33. A method of modulating the expression or activity of a therapeutically relevant gene of interest or protein in a cell, comprising contacting the cell with the composition of any one of embodiments 28-29.

34. A method of treating a disease in a subject, comprising administering to the subject the composition of any one of embodiments 28-29.

35. A method for identifying a targeting molecule that targets a cell or a tissue, optionally wherein the targeting molecule crosses a BBB, comprising selecting for targeting molecules that interact with ALPL.

36. A method for identifying a targeting molecule that crosses the BBB or exhibits enhanced delivery to a cell or a tissue, comprising selecting for targeting molecules that: i) comprise a peptide motif as indicated in a single row of Tables 5 and 6; or ii) comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) set forth in any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4.

EXAMPLES

Example 1. Methods

1.1. AAV capsid library generation

Capsid libraries used in round 1 screening were constructed by insertion of peptides into the exposed loops of the parent capsid proteins. Gibson assembly was used to generate the capsid libraries where the introduced peptides were encoded by the primers used to amplify the assembly fragments. Two PCR products from the parent capsid gene sequence were amplified (left and right fragments), these included an overlap region to facilitate assembly using the Gibson assembly procedure into a plasmid backbone (see e.g. Gibson et al (2009) Nat Meth 6(5):343-345).

For subsequent rounds of selection capsid variants for library screening were synthesized as an oligo pool. Each capsid peptide was synthesized with unique nucleotide sequences encoding the peptide, and each peptide was linked to at least three distinct barcodes. The oligo pool was cloned into a linearized intermediate plasmid, followed by cloning of a constant donor sequence to separate the barcode and peptide region and generate the full AAV vector construct. Expression of barcodes was driven by a ubiquitous CMV promoter. The peptide sequences listed in Table 1 and 3 were inserted into AAV9 between amino acids 454 and 455. The peptide sequences listed in Table 2 and 4 were inserted into AAV6 between amino acids 453 and 454.

AAV capsid libraries were manufactured in HEK293 cells. Briefly, AAV libraries were produced by triple transient transfection of the capsid library plasmid, pXX6 helper (encodes essential adenovirus genes E4, E2A, and VA), and with supplementation of Rep in trans. Capsids were purified by cesium density centrifugation and buffer exchanged into PBS plus 0.001% PF-68 by dialysis. DNase-resistant viral genomic titers were measured by quantitative real time PCR.

1.2. Capsid library screening in cells overexpressing ALPL

HEK293T cells were seeded in 10 cm dishes coated with poly-D-lysine (PDL) at a density of 3E6 cells per dish. 24 hours later cells were transfected with 1 microgram of plasmid encoding human or cynomolgus macaque ALPL under the control of the ubiquitous cytomegalovirus (CMV) promoter. In parallel a transfection control plate was transfected with 1 microgram of plasmid encoding a fluorescent protein (GFP or mRuby) under the control of the ubiquitous cytomegalovirus (CMV) promoter. Lipofectamine 3000 was used for transfection of the plasmid DNA. Cell culture media was changed 24 hours post-transfection to remove transfection reagents. 48 hours after transfection of plasmid DNA, the cells were transduced with the AAV capsid library at a multiplicity of infection of 3E4 vector genomes per cell in reduced serum media (0.5% FBS). Capsid delivery was assessed by transduction or binding assays. For cell culture transduction assays the media was changed 24 hours post-transduction to fully supplemented media (10% FBS). 72 hours post-transduction, the plates were washed one time with phosphate buffered saline (with calcium and magnesium), and RNA was extracted using the Qiagen RNeasy kit following the manufacturers protocol and quantified by NanoDrop 8000 spectrophotometer. RNA was reverse transcribed to cDNA using the NEB Induro Reverse Transcriptase kit.

For cell culture binding assays the cells were incubated with the AAV capsid library for 1 hour at 37°C and washed three times with phosphate buffered saline (with calcium and magnesium). DNA was extracted using the Qiagen DNeasy kit following the manufacturers protocol and quantified by NanoDrop 8000 spectrophotometer.

Samples from transduction and binding assays were prepared for next-generation sequencing (NGS) using Kapa HiFi Hotstart ReadyMix (Roche Catalog #KK2602). PCR amplification of library specific amplicons was performed with the following cycling conditions: 95°C for 3:00 min; 25 cycles at 98°C for 20 sec; 58°C for 15 sec; 72°C for 10 sec followed by 72°C for 1 minute. Amplification was qualitatively confirmed by agarose gel electrophoresis and relative apparent amplification was used to determine the dilution of amplicons needed for indexing. Illumina plate level i5 and well level i7 indices were added to the amplicons with 10 cycles of amplification: 95°C for 3:00 min; 10 cycles at 98°C for 20 sec; 60°C for 15 sec; 72°C for 15 sec followed by 72°C for 1 minute. Finally, samples were pooled and purified using Qiagen GeneRead Size Selection Kit following the manufacturer’s protocol. Samples were sequenced on the Illumina MiSeq platform using a MiSeq Reagent Kit v2. Following next-generation sequencing of library amplicons the reads were demultiplexed and features (the barcode or peptide sequence) were extracted using a custom bioinformatic pipeline. For barcoded libraries the extracted barcode was used to query a pre-determined lookup table and return the identity of the corresponding capsid variant. Finally, the log2 fold change (log2FC) enrichment of each capsid variant was normalized to its relative abundance in the administered AAV library.

1.3. Biotinylation of recombinant human ALPL

Recombinant human ALPL was diluted to 2 mg/mL in PBS (without calcium and magnesium). EZ-Link NHS-LC-Biotin (Thermo Fisher Catalog #21336) was added to a final concentration of 10 mM and the mixture was incubated on ice for 2 hours. After incubation, the biotinylation reaction was quenched by adding 500 mM glycine to a final concentration of 50 mM and incubating on ice for 30 minutes. The same procedure was applied to biotinylate bovine serum albumin for use as a blocking agent.

1.4. In vitro panning with recombinant human ALPL

To block non-specific interactions 1 mg of DynaBeads M-280 Streptavidin beads were rotated for one hour at room temperature with 4el3 molecules of biotinylated bovine serum albumin. The beads were then rotated for an hour at room temperature with 4el3 vg of AAV capsid library. After the one hour rotation, the pre-cleared AAV capsid library that did not bind to the streptavidin beads or biotinylated bovine serum albumin was separated using a tube magnet. One mg of Dynabeads M-280 Streptavidin beads was rotated at room temperature with 4el3 molecules of biotinylated human ALPL. The pre-cleared AAV capsid library was then added to the receptor-coated beads and rotated for an hour at room temperature. The unbound capsids were separated from the bead bound capsids using a tube magnet. The beads were washed three times with SuperBlock (PBS) Blocking Buffer (ThermoFisher Catalog #37515). The receptor bound AAV capsids were then eluted from the beads with Pierce IgG Elution Buffer pH 2.0 (ThermoFisher Catalog #21028). Vector genomes were extracted using the Maxwell RSC Viral Total Nucleic Acid Purification Kit (Promega Catalog # AS1330) and samples were prepared for NGS using Kapa HiFi Hotstart ReadyMix (Roche Catalog #KK2602). PCR amplification of library specific amplicons was performed with the following cycling conditions: 95°C for 3:00 min; 25 cycles at 98°C for 20 sec; 58°C for 15 sec; 72°C for 30 sec followed by 72°C for 1 minute. Amplification was qualitatively confirmed by agarose gel electrophoresis and relative apparent amplification was used to determine the dilution of amplicons needed for indexing. Illumina plate level i5 and well level i7 indices were added to the amplicons with 10 cycles of amplification: 95°C for 3:00 min; 10 cycles at 98°C for 20 sec; 60°C for 15 sec; 72°C for 30 sec followed by 72°C for 1 minute. Finally, samples were pooled and purified using Qiagen GeneRead Size Selection Kit following the manufacturer’s protocol. Samples were sequenced on Illumina MiSeq platform using MiSeq Reagent Kit v2. Following NGS of library amplicons the reads were demultiplexed and features were extracted using a custom bioinformatic pipeline.

Example 2. Results from round 1 capsid library screening The fold change enrichment of each capsid was determined by next-generation sequencing and normalized to capsid abundance in the administered library. The average log2FC for each assay is shown in Tables 1 and 2 for peptides inserted into AAV9 and AAV6 respectively. Empty table entries indicate that the capsid was not detected in that assay, potentially due to limited sample recovery or sequencing depth.

Table 1. Round 1 library performance for peptides inserted into the parent capsid AAV9

Table 1 is shown in Figure 11.

Table 2. Round 1 library performance for peptides inserted into the parent capsid AAV6

Table 2 is shown in Figure 11.

Example 3. Results from round 2 capsid library screening

A subset of sequences enriched in round 1 library screening were synthesized as a round 2 capsid library. For the round 2 evaluation capsids were evaluated in cells overexpressing the human, cynomolgus macaque, or mouse ortholog of ALPL. Both a transduction and a binding assay were completed to assess cell entry and binding, respectively. The fold change enrichment of each capsid was determined by next-generation sequencing and normalized to capsid abundance in the administered library. The average log2FC for each assay is shown in Tables 3 and 4 for peptides inserted into AAV9 and AAV6 respectively. Empty cells indicate that the capsid was not detected in that assay, potentially due to limited sample recovery or sequencing depth.

Table 3. Round 2 library performance for peptides inserted into the parental capsid AAV9

Table 3 is shown in Figure 11.

Table 4. Round 2 library performance for peptides inserted into the parental capsid AAV6

Table 4 is shown in Figure 11.

Example 4. Enrichment of peptide motifs in capsids interacting with ALPL

Bioinformatic analysis of the round 1 and 2 library results highlighted the enrichment of specific peptide motifs in capsids that interacted with ALPL in protein binding and/or cell culture transduction assays. A subset of these enriched peptide motifs (or motif sequences) are listed in Tables 5 and 6.

Table 5. Peptide amino acid motifs that were enriched in the AAV9 library screen for capsid variants that interact with ALPL

Table 6. Peptide amino acid motifs that were enriched in the AAV6 library screen for capsid variants that interact with ALPL

Example 5. Evaluation of individual capsids engineered to target ALPL

Several representative capsids were selected for further confirmation of interaction with orthologs of ALPL. Capsids CNSRCV401, CNSRCV402, and CNSRCV403 were selected based on high performance in library screens and the presence of enriched sequence motifs. These capsids represent a few illustrative examples of the predictive nature of the library screens. AAV9 is the parent capsid for CNSRCV401, CNSRCV402, and CNSRCV403.

5.1. Methods for individual evaluation of receptor-targeted capsids in cells overexpressing ALPL

HEK293 cells were seeded in 96-well PDL coated plates at a density of 2.5E4 cells/well and transfected with 100 ng/well of an ALPL overexpression construct or a fluorescent protein transfection control using Lipofectamine 3000. The media was changed 24 hours post transfection. 48 hours post transfection, the cells were transduced with AAV in reduced serum media (0.5% FBS) at a multiplicity of infection of 1E3, 3E3, 1E4, or 3E4 viral genomes per cell. AAV capsids contained an expression cassette encoding a mCherry fluorescent protein under the control of the ubiquitous cytomegalovirus (CMV) promoter. 72 hours post transduction, the plates were washed one time with phosphate buffered saline (with calcium and magnesium) and cDNA was generated using a Cells-to-CT kit (Thermo Fisher Catalog #21336). Transgene expression was quantified by RT-qPCR using a Qiagen QuantiNova Probe PCR kit. A mRNA-specific primer probe was used to assess transgene expression and normalized to expression of the GAPDH housekeeping gene. Data normalization and analysis was performed using the Bio-Rad CFX Maestro software. For fold change calculations a nonlinear regression model was used to interpolate relative transgene expression values for each capsid-receptor condition. Images of mCherry fluorescent protein expression were taken at 10X magnification using a ThermoFisher EVOS FL Auto 2 microscope.

5.2. Results of individual capsid evaluation

Capsids CNSRCV400, CNSRCV401, and CNSRCV402 were evaluated individually to assess capsid transduction in cells expressing ALPL (Fig 6). The results show that these capsids exhibit enhanced transduction in cells overexpressing the human, cynomolgus macaque, or mouse ortholog of ALPL relative to a transfection control expressing a fluorescent protein. Enhanced transduction was evident based on increased transgene mRNA expression quantified by RT-qPCR as well as increased mCherry protein expression detected by fluorescent microscopy.

Example 6. Evaluation of additional individual capsids engineered to target ALPL

Additional capsids based on the parent capsids AAV6 or AAV9 were selected from the library screening data and a subset were evaluated individually to further demonstrate enhanced transduction in cells that overexpress orthologs of ALPL.

Table 7. Exemplary peptide amino acid sequences inserted into AAV9 that interact with

ALPL

Table 8. Exemplary peptide amino acid sequences inserted into AAV6 that interact with

ALPL

Methods for evaluation of additional individual capsids in cells overexpressing ALPL HEK293 cells were seeded in 96-well PDL coated plates at a density of 2.5E4 cells/well and transfected with 100 ng/well of an ALPL overexpression construct or a fluorescent protein transfection control using Lipofectamine 3000. The media was changed 24 hours post transfection. 48 hours post transfection, the cells were transduced with AAV in reduced serum media (0.5% FBS) at a multiplicity of infection of either 3E3 (Fig 12) or 1E3 (Fig 15) viral genomes per cell. AAV capsids contained an expression cassette encoding a GFP fluorescent protein under the control of the ubiquitous promoter. 72 hours post transduction, the plates were washed one time with phosphate buffered saline (with calcium and magnesium) and cDNA was generated using a Cells-to-CT kit (Thermo Fisher Catalog #21336). Transgene expression was quantified by RT-qPCR using a Qiagen QuantiNova Probe PCR kit. A mRNA-specific primer probe was used to assess transgene expression and normalized to expression of the GAPDH housekeeping gene. Data normalization and analysis was performed using the Bio-Rad CFX Maestro software.

6.2. Results of individual evaluation of additional engineered capsids targeting ALPL

The results indicate that additional representative examples of capsids based on AAV9 (Fig 12) or AAV6 (Fig 15) described herein also exhibit enhanced transduction in cells overexpressing the human, cynomolgus macaque, or mouse ortholog of ALPL relative to a transfection control expressing a fluorescent protein. Enhanced transduction was determined based on increased transgene mRNA expression as quantified by RT-qPCR.

Example 7. Binding kinetics of engineered capsids targeting ALPL

7.1. Methods for bio-layer interferometry (BLI) measurement of binding kinetics for ALPL-targeted capsids

Binding of AAV capsids to ALPL was measured by bio-layer interferometry on an Octet Red96e instrument. All steps were performed at 30°C shaking at 1,000 rpm. Purified human ALPL was diluted to 18 pg/mL and immobilized on amine reactive second-generation (AR2G) biosensors (Sartorius Catalog #18-5092) by amine coupling in 10 mM sodium acetate (pH 6) for 400 seconds. Activation and quenching steps were performed as per the manufacturer’s instructions. Baseline was established in lx kinetics buffer (Sartorius Catalog # 18-1105) before sensors were dipped into capsids diluted 6.25E10 to 1E12 vg/mL in lx kinetics buffer. Capsid association to each sensor was performed for 300 seconds followed by a 300 second dissociation step. 7.2. Results of bio-layer interferometry (BLI) measurement of binding kinetics for ALPL- targeted capsids

Bio-layer interferometry assays corroborate the results obtained in cell culture experiments. Engineered capsids that exhibit enhanced transduction of cells expressing human ALPL likewise exhibit robust binding responses to immobilized human ALPL. The parent capsid AAV9 exhibits no binding to human ALPL. These trends are consistent across a range of capsid concentrations tested as shown in Figure 18.

Example 8. Evaluation of a barcoded pool of STAC-BBB capsid variants engineered to target ALPL

Additional capsids based on the parent capsid STAC-BBB were selected from the library screening data from AAV9, the parental capsid for STAC-BBB, and a subset were evaluated to demonstrate enhanced transduction in cells that overexpress orthologs of ALPL.

Table 9. Exemplary peptide amino acid sequences inserted into STAC-BBB that interact with ALPL

8.1. Evaluation of a barcoded pool of STAC-BBB capsid variants in cells overexpressing

ALPL

AAV capsids were each manufactured individually with a unique barcoded transgene expression cassette and then pooled to create a barcoded pool of AAV capsids. The pool included STAC-BBB and variants of the STAC-BBB capsid that contain an ALPL targeting peptide (CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315, CNSRCV316, CNSRCV317, and CNSRCV319). HEK293 cells were seeded in a 6-well plate and then transfected 24 hours later with an ALPL overexpression construct or a fluorescent protein transfection control using Lipofectamine 3000. The media was changed 24 hours post transfection. 48 hours post transfection, the cells were transduced with the barcoded pool of capsids in reduced serum media (0.5% FBS) at a multiplicity of infection of 1E5 viral genomes per cell. Cells were incubated for 72 hours to allow for AAV-mediated expression of the barcoded transgene mRNA. RNA was extracted from cells, reverse transcribed to cDNA, and then PCR was used to amplify the barcoded AAV cDNA. Next-generation sequencing analysis was conducted to quantify enrichment of capsid variants in the pool relative to the input abundance of each capsid in the barcoded pool. These fold change enrichment values were then normalized relative to STAC-BBB. The results in Figure 19 show that insertion of ALPL targeting peptides into the STAC-BBB capsid confers STAC-BBB with enhanced transduction in cells overexpressing the human, cynomolgus macaque, or mouse ortholog of ALPL relative to a transfection control expressing a fluorescent protein.

Sequences

The amino acid sequences of the parental capsids are defined as follows:

AAV9 capsid amino acid sequence SEQ ID NO: 7006:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSW

ALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEI KTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQGPIWAK IPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVS VEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL

AAV6 capsid amino acid sequence SEQ ID NO: 7007:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGAS

KYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALDNVMITDEE EIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDVYLQGPIWA KIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVS VEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL

STAC-BBB capsid amino acid sequence SEQ ID NO: 7088:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING

SGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSW

ALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEI

KTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVWQDRDVY

LQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFIT

QYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGT

RYLTRNL

The amino acid sequences of individual capsids are defined as follows (inserted Peptide Sequence shown in bold):

CNSRCV400 capsid amino acid sequence SEQ ID NO: 7008:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP

GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF

GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA

KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS

SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW

GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN

LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY

CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING

SMTSSPHRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA

WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV

MITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYL

QGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQ

YSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRY LTRNL

CNSRCV401 capsid amino acid sequence SEQ ID NO: 7009:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP

GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF

GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA

KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS

SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW

GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN

LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY

CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING

SITGSPHHGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW

PGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVM

ITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVWQ

DRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDK

LNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEP RPIGTRYLTRNL

CNSRCV402 capsid amino acid sequence SEQ ID NO: 7010: MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS

SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW

GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN

LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY

CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING

STTSDSPHRYVGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE

FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD

KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM

VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV403 capsid amino acid sequence SEQ ID NO: 7011:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSGQSFDSPHKPGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR PIGTRYLTRPL

CNSRCV404 capsid amino acid sequence SEQ ID NO: 7012:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSTLMDTASPHKGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR PIGTRYLTRPL CNSRCV405 capsid amino acid sequence SEQ ID NO: 7013:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSFTESPHSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT RYLTRPL

CNSRCV406 capsid amino acid sequence SEQ ID NO: 7014:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING

SPLSNDPHLSRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV407 capsid amino acid sequence SEQ ID NO: 7015:

SSVLDYHHPQGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM

VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG

VYSEPRPIGTRYLTRNL

CNSRCV408 capsid amino acid sequence SEQ ID NO: 7016:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSDSSEFHSRQGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV409 capsid amino acid sequence SEQ ID NO: 7017:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STHRESEMHYSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV410 capsid amino acid sequence SEQ ID NO: 7018:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSQVSPEPHRRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV411 capsid amino acid sequence SEQ ID NO: 7019:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STPLSSEYHSSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV412 capsid amino acid sequence SEQ ID NO: 7020:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SLAKSSEYHQLGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV413 capsid amino acid sequence SEQ ID NO: 7021:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSSGYHPSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVM ITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVWQ DRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDK LNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEP RPIGTRYLTRNL

CNSRCV414 capsid amino acid sequence SEQ ID NO: 7022:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SLRTSSYHDTAGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV415 capsid amino acid sequence SEQ ID NO: 7023:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SVPAPDTYHLKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV416 capsid amino acid sequence SEQ ID NO: 7024:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SPDTEVYHSSRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV417 capsid amino acid sequence SEQ ID NO: 7025:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SRPVDDYSHVRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV418 capsid amino acid sequence SEQ ID NO: 7026:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SLRESPHKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV419 capsid amino acid sequence SEQ ID NO: 7027:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SRGGDYHYGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV460 capsid amino acid sequence SEQ ID NO: 7028:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSLSDRSRDFHEGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNN NSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTA

LDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV461 capsid amino acid sequence SEQ ID NO: 7029:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSVSTDYHLGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV462 capsid amino acid sequence SEQ ID NO: 7030:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSGSEREPHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV463 capsid amino acid sequence SEQ ID NO: 7031 :

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSTDPSSYHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN

FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD

NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV

YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT

RYLTRPL

CNSRCV464 capsid amino acid sequence SEQ ID NO: 7032:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSEREGYHQGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV465 capsid amino acid sequence SEQ ID NO: 7033: MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSEGDFHSSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT RYLTRPL

CNSRCV466 capsid amino acid sequence SEQ ID NO: 7034:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSPDFHVGVGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV467 capsid amino acid sequence SEQ ID NO: 7035:

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSILTTDPHNGVGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNN NSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTA LDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL CNSRCV468 capsid amino acid sequence SEQ ID NO: 7036:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSAQMDPHVGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV469 capsid amino acid sequence SEQ ID NO: 7037:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSVTTIDPHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN

FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD

NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV

YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT

RYLTRPL

CNSRCV470 capsid amino acid sequence SEQ ID NO: 7038:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSSSVYYEDTHHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR

PIGTRYLTRPL

CNSRCV471 capsid amino acid sequence SEQ ID NO: 7039:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSPVDYHNAGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV472 capsid amino acid sequence SEQ ID NO: 7040:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSSDYHTGLGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV473 capsid amino acid sequence SEQ ID NO: 7041:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSYVMEAHSSSTGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR PIGTRYLTRPL

CNSRCV474 capsid amino acid sequence SEQ ID NO: 7042:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSTEFHTTSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT RYLTRPL

CNSRCV475 capsid amino acid sequence SEQ ID NO: 7043:

QSHDDEFHKGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV476 capsid amino acid sequence SEQ ID NO: 7044:

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSLADEFHRGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV477 capsid amino acid sequence SEQ ID NO: 7045:

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSMSELHTSSYAGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNN NSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTA LDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV478 capsid amino acid sequence SEQ ID NO: 7046:

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSVLAVEPHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT RYLTRPL

CNSRCV479 capsid amino acid sequence SEQ ID NO: 7047:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN QSYIIAEPHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT RYLTRPL

CNSRCV500 capsid amino acid sequence SEQ ID NO: 7048:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SRMSQDPHVNKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNN SEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVD ADKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILP GMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNT EGVYSEPRPIGTRYLTRNL

CNSRCV501 capsid amino acid sequence SEQ ID NO: 7049:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SWKGPTDPHDHGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNN SEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVD ADKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILP GMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNT EGVYSEPRPIGTRYLTRNL

CNSRCV502 capsid amino acid sequence SEQ ID NO: 7050:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SHSDPHFRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV503 capsid amino acid sequence SEQ ID NO: 7051:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SMPFRDQMHSKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNN SEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVD ADKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILP GMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNT EGVYSEPRPIGTRYLTRNL

CNSRCV504 capsid amino acid sequence SEQ ID NO: 7052:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SPKEDYHMGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS

EPRPIGTRYLTRNL

CNSRCV505 capsid amino acid sequence SEQ ID NO: 7053:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SPREDYHKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV506 capsid amino acid sequence SEQ ID NO: 7054:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SLSSGGDYHLSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV507 capsid amino acid sequence SEQ ID NO: 7055:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSRAQPDYHGMGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNN SEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVD ADKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILP GMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNT EGVYSEPRPIGTRYLTRNL

CNSRCV508 capsid amino acid sequence SEQ ID NO: 7056: MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SFSLEPHGRMAGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV509 capsid amino acid sequence SEQ ID NO: 7057:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STQTEYHPVRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV510 capsid amino acid sequence SEQ ID NO: 7058:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STGHSVEYHQLGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL CNSRCV511 capsid amino acid sequence SEQ ID NO: 7059:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SDSGYHRPGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV512 capsid amino acid sequence SEQ ID NO: 7060:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SASPSNYHGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV513 capsid amino acid sequence SEQ ID NO: 7061 :

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SNTSDSMHGYKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE

GVYSEPRPIGTRYLTRNL

CNSRCV514 capsid amino acid sequence SEQ ID NO: 7062:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SQSPHRASGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV515 capsid amino acid sequence SEQ ID NO: 7063:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SVSPMHRAGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV516 capsid amino acid sequence SEQ ID NO: 7064:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSSPMHQAGYAGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV517 capsid amino acid sequence SEQ ID NO: 7065:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STQYGSESYHPGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV518 capsid amino acid sequence SEQ ID NO: 7066:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSHAPSYHPGPGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV519 capsid amino acid sequence SEQ ID NO: 7067:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SYETYHSKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV520 capsid amino acid sequence SEQ ID NO: 7068:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SATYSSNYHAQGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV521 capsid amino acid sequence SEQ ID NO: 7069:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STWTTIEDPHWGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV522 capsid amino acid sequence SEQ ID NO: 7070:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STWVDPHMSMKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNN SEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVD ADKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILP GMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPT AFNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNT EGVYSEPRPIGTRYLTRNL

CNSRCV523 capsid amino acid sequence SEQ ID NO: 7071:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSNDPHWSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV524 capsid amino acid sequence SEQ ID NO: 7072:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SWLDPHSSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV525 capsid amino acid sequence SEQ ID NO: 7073:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSLSLLEPHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN

FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD

NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV

YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT

RYLTRPL

CNSRCV526 capsid amino acid sequence SEQ ID NO: 7074:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSSQLEEYHTKLGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA

SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR

PIGTRYLTRPL

CNSRCV527 capsid amino acid sequence SEQ ID NO: 7075:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSIRDRTLEYHEGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNN

NSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTA

LDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV528 capsid amino acid sequence SEQ ID NO: 7076:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSVETGSREYHNGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA

SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR

PIGTRYLTRPL

CNSRCV529 capsid amino acid sequence SEQ ID NO: 7077:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSPMASEYHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV530 capsid amino acid sequence SEQ ID NO: 7078:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSLIEYHPSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSN

FTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTALD

NVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDV

YLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFIT

QYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGT

RYLTRPL

CNSRCV531 capsid amino acid sequence SEQ ID NO: 7079: MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSAQEFGHSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV532 capsid amino acid sequence SEQ ID NO: 7080:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSYVPYGPHDVSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA

SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR PIGTRYLTRPL

CNSRCV533 capsid amino acid sequence SEQ ID NO: 7081:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSETSDGYHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL CNSRCV534 capsid amino acid sequence SEQ ID NO: 7082:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSSPEGSGYHGTGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA

SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR

PIGTRYLTRPL

CNSRCV535 capsid amino acid sequence SEQ ID NO: 7083:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSGSPHANLGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV536 capsid amino acid sequence SEQ ID NO: 7084:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSLDNSSPHQKSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNN

NSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTA

LDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV537 capsid amino acid sequence SEQ ID NO: 7085:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSTADVTYHQSNGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDN

NNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASN

TALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQD

RDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFA

SFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPR

PIGTRYLTRPL

CNSRCV538 capsid amino acid sequence SEQ ID NO: 7086:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSFMDVDHHGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL

DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD

VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI

TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG

TRYLTRPL

CNSRCV539 capsid amino acid sequence SEQ ID NO: 7087:

MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLG

PFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTS

FGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPA

KKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGN

ASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTP

WGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIAN

NLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSF

YCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQN

QSDLSYGHSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNS

NFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSGVMIFGKESAGASNTAL DNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRD VYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFI TQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIG TRYLTRPL

CNSRCV306 capsid amino acid sequence SEQ ID NO: 7089:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SPLSNDPHLSRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV307 capsid amino acid sequence SEQ ID NO: 7090:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SSVLDYHHPQGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG VYSEPRPIGTRYLTRNL

CNSRCV308 capsid amino acid sequence SEQ ID NO: 7091:

CNSRCV310 capsid amino acid sequence SEQ ID NO: 7092:

CNSRCV311 capsid amino acid sequence SEQ ID NO: 7093:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING STPLSSEYHSSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSE FAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDAD KVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGM VWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAF NKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEG

VYSEPRPIGTRYLTRNL

CNSRCV313 capsid amino acid sequence SEQ ID NO: 7094:

CNSRCV314 capsid amino acid sequence SEQ ID NO: 7095:

CNSRCV315 capsid amino acid sequence SEQ ID NO: 7096:

CNSRCV316 capsid amino acid sequence SEQ ID NO: 7097:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SPDTEVYHSSRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV317 capsid amino acid sequence SEQ ID NO: 7098:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SRPVDDYSHVRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNS EFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDA DKVMITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPG MVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL

CNSRCV319 capsid amino acid sequence SEQ ID NO: 7099:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPI<RLNFI<LFNIQVI<EVTDNNGVI<TIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SMTSSPHRGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

CNSRCV318 capsid amino acid sequence SEQ ID NO: 7100:

MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGP

GNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSF GGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSSAGIGKSGAQPA KKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSS SGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANN LTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDGSQAVGRSSFY CLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTING SLRESPHKGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFA WPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKV MITNEEEIKTTNPVATESYGQVATNHQSAYVNIMDDMDQAQTGWVQNQGILPGMVW QDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKD KLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYS EPRPIGTRYLTRNL

Claims

WHAT IS CLAIMED IS:

2. The AAV capsid protein of claim 1, wherein the amino acid motif is inserted into AAV9 (SEQ ID NO: 7006) and optionally the peptide insertion site is between amino acids 454 and 455, as shown in a single row in Table 5; or, wherein the amino acid motif is inserted into AAV6 (SEQ ID NO: 7007) and optionally the peptide insertion site is between amino acids 453 and 454, as shown in a single row in Table 6.

4. The AAV capsid protein of claim 3, wherein the amino acid sequence is inserted into a parent capsid ("Parent Capsid”) at an insertion site (“Peptide Insertion Site”) as shown in a single row in Tables 1 to 4.

5. The AAV capsid protein of claim 4, wherein the amino acid sequence comprises a peptide sequence according to any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4, and optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row as shown in Tables 1 to 4.

6. The AAV capsid protein of claim 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 7, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 7.

7. The AAV capsid protein of claim 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 8, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 8.

8. The AAV capsid protein of claim 5, wherein the amino acid sequence comprises a peptide sequence as indicated in a single row in Table 9, optionally wherein the parent capsid and/or the insertion site is/are as indicated in the same single row in Table 9.

9. The AAV capsid protein of any one of claims 1-8, wherein the amino acid sequence is inserted into a parental capsid, optionally wherein the parental capsid is selected from any one of AAV1, AAV2, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, AAVrhlO, AAVrh39, AAVrh74, or STAC-BBB.

10. An AAV capsid protein, wherein the AAV capsid protein is at least 80%, 85%, 90%, 95%, or 99% identical to or comprises a sequence set forth in any one of SEQ ID NOs: 7008-7087, or 7089-7100 designated as CNSRCV400, CNSRCV401, CNSRCV402, CNSRCV403, CNSRCV404, CNSRCV405, CNSRCV406, CNSRCV407, CNSRCV408, CNSRCV409, CNSRCV410, CNSRCV411, CNSRCV412, CNSRCV413, CNSRCV414, CNSRCV415, CNSRCV416, CNSRCV417, CNSRCV418, CNSRCV419, CNSRCV460, CNSRCV461, CNSRCV462, CNSRCV463, CNSRCV464, CNSRCV465, CNSRCV466, CNSRCV467, CNSRCV468, CNSRCV469, CNSRCV470, CNSRCV471, CNSRCV472, CNSRCV473, CNSRCV474, CNSRCV475, CNSRCV476, CNSRCV477, CNSRCV478, CNSRCV479, CNSRCV500, CNSRCV501, CNSRCV502, CNSRCV503, CNSRCV504, CNSRCV505, CNSRCV506, CNSRCV507, CNSRCV508, CNSRCV509, CNSRCV510, CNSRCV511, CNSRCV512, CNSRCV513, CNSRCV514, CNSRCV515, CNSRCV516, CNSRCV517, CNSRCV518, CNSRCV519, CNSRCV520, CNSRCV521, CNSRCV522, CNSRCV523, CNSRCV524, CNSRCV525, CNSRCV526, CNSRCV527, CNSRCV528, CNSRCV529, CNSRCV530, CNSRCV531, CNSRCV532, CNSRCV533, CNSRCV534, CNSRCV535, CNSRCV536, CNSRCV537, CNSRCV538, CNSRCV539, CNSRCV306, CNSRCV307, CNSRCV308, CNSRCV310, CNSRCV311, CNSRCV313, CNSRCV314, CNSRCV315, CNSRCV316, CNSRCV317, CNSRCV319, or CNSRCV318.

11. The AAV capsid protein of any one of claims 1-10, wherein the AAV capsid protein interacts with tissue non-specific alkaline phosphatase (ALPL), thereby enabling delivery of the AAV capsid protein to a cell or a tissue, optionally wherein interaction with tissue non-specific alkaline phosphatase (ALPL) enables the AAV capsid protein to cross a BBB.

12. A nucleic acid molecule encoding an engineered AAV capsid protein of any one of claims 1-11.

13. A host cell comprising the nucleic acid molecule of claim 12.

14. A composition comprising: 1) an AAV capsid protein comprising of any one of claims 1- 11; and 2) an expression construct comprising a coding sequence for a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload.

15. The composition of claim 14, wherein the payload of interest is a therapeutic payload, and wherein the therapeutic payload comprises a DNA binding domain, optionally wherein the therapeutic payload comprises a fusion protein.

16. The composition of claim 14 or claim 15, wherein the payload of interest comprises a therapeutic protein, a zinc finger protein, a CRISPR-associated DNA binding protein, a TALE protein, an antibody, an enzyme, a regulatory RNA, a Bxbl serine recombinase, or a DNA recombinase protein.

17. A method of delivering a payload of interest to a cell or a tissue, wherein a coding sequence for the payload of interest is encapsidated in an AAV capsid protein according to any one of claims 1-11, and wherein the AAV capsid protein interacts with ALPL.

18. The method of claims 17, wherein delivering the payload of interest to the cell or the tissue comprises crossing a BBB.

19. A method of activating, expressing, repressing, or modulating the expression of a therapeutically relevant gene of interest in a cell, comprising contacting the cell with the composition of any one of claims 14-16.

20. A method of treating a disease in a subject, comprising administering to the subject the composition of any one of claims 14-16.

20. Use of an AAV capsid protein of any one of claims 1-11, a nucleic acid construct of claim 12, or a host cell of claim 13 for the manufacture of a medicament in the method of any one of claims 17-20.

21 . A method for identifying an AAV capsid variant that crosses a BBB, comprising selecting for variant AAV capsids that interact with ALPL.

24. The targeting molecule of claim 23, comprising a peptide amino acid motif as indicated below in a single row:

25. The targeting molecule of claim 23, comprising a peptide amino acid motif as indicated below in a single row:

26. The targeting molecule of claim 23, comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) according to any one of SEQ ID NOs: 1-7005 as shown in a single row in Tables 1 to 4.

27. The targeting molecule of any one of claims 23-26, wherein the targeting molecule is fused or conjugated to an AAV, a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein.

28. A composition comprising: 1) a targeting molecule of any one of claims 23-26; and 2) a payload of interest, optionally wherein the payload of interest is a research, diagnostic, and/or therapeutic payload.

29. The composition of claim 28, wherein the payload of interest encodes or comprises a small molecule, an antibody, zinc finger protein, Cas protein, exosome, scFV, ASO (antisense oligonucleotide), siRNA, lipid, lipid nanoparticle, polymer, virus-like particle (VLP), bocavirus, dendrimer, aptamer, or recombinant protein.

30. A method of delivering a payload of interest to a cell or a tissue, wherein a coding sequence for the payload of interest is associated with the targeting molecule according to any one of claims 23-27, and wherein the targeting molecule interacts with ALPL.

31. The method of claim 30, wherein delivering the payload of interest to the cell or the tissue comprises crossing a BBB.

32. A method of delivering a therapeutically relevant gene or protein of interest to a cell, comprising contacting the cell with the composition of any one of claims 28-29.

33. A method of modulating the expression or activity of a therapeutically relevant gene of interest or protein in a cell, comprising contacting the cell with the composition of any one of claims 28-29.

34. A method of treating a disease in a subject, comprising administering to the subject the composition of any one of claims 28-29.

36. A method for identifying a targeting molecule that crosses the BBB or exhibits enhanced delivery to a cell or a tissue, comprising selecting for targeting molecules that: i) comprise a peptide motif as indicated in a single row of Tables 5 and 6; or ii) comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all contiguous amino acids of an amino acid sequence (“Peptide Sequence”) set forth in any one of SEQ ID NOs: 1- 7005 as shown in a single row in Tables 1 to 4.