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WO1999006073A1 - Procede de traitement des greffons - Google Patents

Procede de traitement des greffons Download PDF

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Publication number
WO1999006073A1
WO1999006073A1 PCT/US1998/015971 US9815971W WO9906073A1 WO 1999006073 A1 WO1999006073 A1 WO 1999006073A1 US 9815971 W US9815971 W US 9815971W WO 9906073 A1 WO9906073 A1 WO 9906073A1
Authority
WO
WIPO (PCT)
Prior art keywords
graft
nucleic acid
cells
vectors
grafts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1998/015971
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English (en)
Inventor
Jeffrey M. Isner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
St Elizabeths Medical Center of Boston Inc
Original Assignee
St Elizabeths Medical Center of Boston Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by St Elizabeths Medical Center of Boston Inc filed Critical St Elizabeths Medical Center of Boston Inc
Priority to AU87638/98A priority Critical patent/AU8763898A/en
Priority to CA002298811A priority patent/CA2298811A1/fr
Priority to EP98939149A priority patent/EP1009441A1/fr
Priority to JP2000504884A priority patent/JP2001511462A/ja
Publication of WO1999006073A1 publication Critical patent/WO1999006073A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the success of a transplant of an allograft in a host depends on such factors as the antigens on the transplanted tissue that are recognized by the recipient as foreign and can evoke the rejection response, the cells in the recipient's immune system that mediate rejection, and the reactions that modify either the presentation of the foreign antigen or the cellular response. While the immunological response to transplant tissue may be suppressed through the use of immunosuppressant drugs to minimize tissue rejection, immunosuppressant therapy is general in nature. Hence, immunosuppressant drugs tend to suppress the immune response, which reduces the transplant patient's ability to combat infection.
  • transplantation immunologists have sought methods for suppressing immune responsiveness in an antigen-specific manner (so that only the response to the donor alloantigen would be lost) .
  • the survival time of skin grafts has been prolonged by a factor of two by treatment in vitro with cortisone, thalidomide, or urethane before implantation into a laboratory animal.
  • the amount of drug locally applied to the skin was smaller than the amount required to achieve a similar effect by injecting the drug systemically.
  • the donor skin was treated in vitro with streptokinase/streptodornase, or with RNA and DNA preparations of the recipient. Further, treatment of transplant tissues with a solution of glutaraldehyde prior to transplantation was found to reduce their antigenicity. See U.S. Pat. No. 4,120,649.
  • TGF-beta has been found to suppress the expression of Class II histocompatibility antigens on human cells induced by human interferon- gamma and to inhibit constitutive expression of the Class II antigen message in the cells.
  • Use of recombinant TGF-beta as an immunosuppressive agent for the treatment of graphs prior to implantation has been proposed. See U.S. Pat. No. 5,135,915.
  • the present invention provides a method for treatment of grafts which comprises introducing a nucleic acid encoding an angiogenic agent into the cells of the graft.
  • the graft may be treated ex xA ⁇ o and then transplanted into the donor or may be treated after transplantation.
  • the graft may be autologous, allogenic, xenogenic or a tissue engineered graft ("bio-artifical" organ).
  • the nucleic acid may be introduced to the cultured cells used to form the tissue engineered graft. Expression of the angiogenic agent by the cells of the graft promotes growth of new blood vessels (angiogenesis) providing the graft with a blood supply thus increasing the chances for graft survival.
  • angiogenesis new blood vessels
  • Figure 1 is a photograph of the mouse model used in which a full thickness skin wound was created in the dorsal integument overlying the upper spine.
  • Figure 2 shows the gross appearance of a graft that has been placed over the wound shown in Figure 1.
  • the graft was generated by transfecting keratinocytes in culture with the adenovirus construct encoding beta-galactosidase. After the keratinocytes had been incorporated into the skin used to perform the grafting, the graft was allowed to survive for 7 days at which time it was removed along with a border of normal skin and then stained with X-Gal to identify the staining related to the expression of beta- galactosidase in the keratinocytes of the graft.
  • Figures 3A-3C shows photomicrographs of a control graft (3A) that was prepared from keratinocytes that were not transfected with beta galactosidase.
  • Figures 3B and 3C show grafts that were prepared from keratinocytes that had been transduced with the adenovirus beta-glactosidase construct (driven by the cytomegalovirus promoter) at multiplicity of infections of 37 (3B) and 150 (3C).
  • the dark staining identifies keratinocytes which are actively expressing the Z ⁇ cZ transgene encoding for beta-glactosidase.
  • graft refers to biological material derived from a donor for transplantation into a recipient. Grafts include tissues and organs in which would benefit fro vascularization. Organs include, for example, skin, heart, liver, spleen, pancreas, thyroid lobe, lung, kidney, tubular organs (e.g., intestine, blood vessels, or esophagus), etc. The tubular organs can be used to replace damaged portions of esophagus, blood vessels, or bile duct.
  • the skin grafts can be used not only for ischemic skin ulcers and burns, but also as a dressing to damaged intestine or to close certain defects such as diaphragmatic hernia.
  • the graft is derived from any source, preferably mammalian, including human, whether from cadavers or living donors.
  • the graft may be a tissue engineered graft formed from a combination of cultured cells and scaffold material.
  • An example of such a tissue engineered graft is Appligraf ®.
  • Appligraf ® consists of a type I collagen gel seeded with allogenic fibroblasts covered with a confluent surface layer of allogenic keratinocytes.
  • host refers to any compatible transplant recipient. By “compatible” is meant a host that will accept the donated graft.
  • the host is mammalian, and more preferably human.
  • both the donor of the graft and the host are human, they are preferably matched for HLA class II antigens so as to improve histocompatibility.
  • the term "donor” as used herein refers to the species, dead or alive, from which the graft is derived. Preferably, the donor is mammalian. Human donors are preferably volunteer blood-related donors that are normal on physical examination and of the same major ABO blood group, because crossing major blood group barriers possibly prejudices survival of the allograft. It is, however, possible to transplant, for example, a kidney of a type O donor into an A, B or AB recipient.
  • transplant and “implant” are used interchangeably to refer to tissue or cells (xenogeneic or allogeneic) which may be introduced into the body of a host to replace or structure or function of the endogenous tissue.
  • angiogenic agent refers to any protein, polypeptide, mutein or portion that is capable of, directly or indirectly, inducing the formation of new blood vessels. Folkman, et al., Science, 235:442-447 (1987). Such proteins include, for example, acidic fibroblast growth factors (FGF-1), basic fibroblast growth factors (FGF-2)), FGF-4, FGF-5, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor ⁇ .
  • FGF-1 acidic fibroblast growth factors
  • FGF-2 basic fibroblast growth factors
  • FGF-4 FGF-4
  • FGF-5 vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • transforming growth factor ⁇ transforming growth factor ⁇ .
  • TGF- ⁇ and TFG- ⁇ platelet-derived endothelial growth factor
  • PD-ECGF platelet-derived endothelial growth factor
  • PDGF platelet-derived growth factor
  • TGF- ⁇ tumor necrosis factor ⁇
  • HGF hepatocyte growth factor
  • IGF insulin like growth factor
  • IL-8 proliferin, angiogenin, fibrin fragment E, angiotropin, erythropoietin, colony stimulating factor (CSF), macrophage-CSF (M-CSF), granulocyte/macrophage CSF (GM-CSF) and nitric oxidesynthase (NOS).
  • CSF colony stimulating factor
  • M-CSF macrophage-CSF
  • GM-CSF granulocyte/macrophage CSF
  • NOS nitric oxidesynthase
  • VEGF includes the various forms of VEGF such as VEGF121, VEGF ⁇ 45 , VEGFies, and VEGFies. See, Klagsbrun, et al., Anna. Rev. Physiol, 53:217-239 (1991); Folkman, et al., J. Biol Chem., 267: 10931-10934 (1992) and Symes, et al., Current Opinion in Lipidology, 5:305-312 (1994).
  • the angiogenic protein contains a secretory signal sequence that facilitates secretion of the protein.
  • Angiogenic proteins having native signal sequences e.g., VEGF
  • Angiogenic proteins that do not have native signal sequences e.g., bFGF
  • the angiogenic action of any given protein, peptide or mutein can be determined using a number of bioassays including, for example, the rabbit cornea pocket assay (Gaudric et al., Ophthalmic. Res. 24: 181-8 (1992)) and the chicken chorioallantoic membrane (CAM) assay (Peek et al., Exp. Pathol. 34:35- 40 (1988)).
  • nucleotide sequence of numerous angiogenic proteins are readily available through a number of computer data bases, for example, GenBank, EMBL and Swiss-Prot. Using this information, a DNA segment encoding the desired may be chemically synthesized or, alternatively, such a DNA segment may be obtained using routine procedures in the art, e.g, PCR amplification.
  • the nucleic acid is preferably inserted into a cassette where it is operably linked to a promoter.
  • the promoter must be capable of driving expression of the protein in cells of the desired target tissue.
  • the selection of appropriate promoters can readily be accomplished. Preferably, one would use a high expression promoter.
  • An example of a suitable promoter is the 763- base-pair cytomegalovirus (CMV) promoter.
  • CMV 763- base-pair cytomegalovirus
  • RSV Rous sarcoma virus
  • MMT Mobility Management Function
  • a cassette can then be inserted into a vector, e.g., a plasmid vector such as pUCl 18, pBR322, or other known plasmid vectors, that includes, for example, an E. coli origin of replication. See, Sambrook, et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory press, (1989).
  • the plasmid vector may also include a selectable marker such as the ⁇ - lactamase gene for ampicillin resistance, provided that the marker polypeptide does not adversely effect the metabolism of the organism being treated.
  • the cassette can also be bound to a nucleic acid binding moiety in a synthetic delivery system, such as the system disclosed in WO 95/22618.
  • nucleic acid's encoding two or more different proteins in order optimize the therapeutic outcome.
  • DNA encoding two angiogenic proteins e.g., VEGF and bFGF
  • VEGF and bFGF can be used, and provides an improvement over the use of bFGF alone.
  • an angiogenic factor can be combined with other genes or their encoded gene products to enhance the activity of targeted cells, while simultaneously inducing angiogenesis, including, for example, nitric oxide synthase, L- arginine, fibronectin, urokinase, plasminogen activator and heparin.
  • the term "effective amount" means a sufficient amount of nucleic acid delivered to produce an adequate level of the angiogenic protein, i.e., levels capable of inducing angiogenesis.
  • the important aspect is the level of protein expressed. Accordingly, one can use multiple transcripts or one can have the gene under the control of a promoter that will result in high levels of expression. In an alternative embodiment, the gene would be under the control of a factor that results in extremely high levels of expression, e.g., tat and the corresponding tar element.
  • the nucleic acid encoding the angiogenic agent is formulated by mixing it at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the nucleic acids are introduced into the cells of the graft by any method which will result in the uptake and expression of the nucleic acid by the cells.
  • the introduction can be by standard techniques, e.g. infection, transfection, transduction or transformation.
  • modes of gene transfer include e.g., naked DNA, Ca3(PO ) 2 precipitation, DEAE dextran, electroporation, protoplast fusion, lipofecton, cell microinjection, viral vectors, adjuvant-assisted DNA, catheters, gene guns etc.
  • Vectors include chemical conjugates such as described in WO 93/04701, which has targeting moiety (e.g. a ligand to a cellular surface receptor), and a nucleic acid binding moiety (e.g.
  • viral vector e.g. a DNA or RNA viral vector
  • fusion proteins such as described in PCT/US 95/02140 (WO 95/22618) which is a fusion protein containing a target moiety (e.g. an antibody specific for a target cell) and a nucleic acid binding moiety (e.g. a protamine), plasmids, phage, etc.
  • the vectors can be chromosomal, non-chromosomal or synthetic.
  • Preferred vectors include viral vectors, fusion proteins and chemical conjugates.
  • Retroviral vectors include moloney murine leukemia viruses. DNA viral vectors are preferred.
  • These vectors include pox vectors such as orthopox or avipox vectors, herpes virus vectors such as a herpes simplex I virus (HSV) vector [A.I. Geller et al., J. Neurochem, 64:487 (1995); F. Lim et al., in DNA Cloning: Mammalian Systems, D. Glover, Ed. (Oxford Univ. Press, Oxford England) (1995); A.I. Geller et al., Proc Natl. Acad. Sci.: U.S.A.:90 7603 (1993); A.I. Geller et al., Proc Natl. Acad.
  • HSV herpes simplex I virus
  • Pox viral vectors introduce the gene into the cells cytoplasm.
  • Avipox virus vectors result in only a short term expression of the nucleic acid.
  • Adenovirus vectors, adeno-associated virus vectors and herpes simplex virus (HSV) vectors are preferred for introducing the nucleic acid into neural cells.
  • the adenovirus vector results in a shorter term expression (about 2 months) than adeno-associated virus (about 4 months), which in turn is shorter than HSV vectors.
  • the particular vector chosen will depend upon the target cell and the condition being treated.
  • Gene guns include those disclosed in U.S. Patent Numbers 5, 100,792 and 5,371,015 and PCT publication WO 91/07487.
  • the nucleic acid may also be used with a microdelivery vehicle such as cationic liposomes and adenoviral vectors.
  • a microdelivery vehicle such as cationic liposomes and adenoviral vectors.
  • the graft may submerged in the nucleic acid composition for a sufficient time to allow up take of the nucleic acid.
  • the cells used to form the graft are transfected with the nucleic acid encoding the angiogenic agent.
  • the cells are transfected prior to formation of the graft.
  • a tissue engineered graft such as a synthetic skin equivalent, e.g., Apligraph® (Organogenesis, Canton, MA.) the keratinocytes used to form the graft can be transfected in culture with a vector containing a DNA encoding the angiogenic agent.
  • the nucleic acid may be introduced by direct injection into the graft prior to, or after, transplantation.
  • the nucleic acid can be applied topically, for example, painted onto a skin graft prior to transplantation.
  • a viscous solution such as a gel rather than a non-viscous solution.
  • This may be accomplished, for example, by mixing the solution of the nucleic acid with a gelling agent, such as a polysaccharide, preferably a water-soluble polysaccharide, such as, e.g., hyaluronic acid, starches, and cellulose derivatives, e.g., methylcellulose, hydroxyethyl cellulose, and carboxymethyl cellulose.
  • a gelling agent such as a polysaccharide, preferably a water-soluble polysaccharide, such as, e.g., hyaluronic acid, starches, and cellulose derivatives, e.g., methylcellulose, hydroxyethyl cellulose, and carboxymethyl cellulose.
  • the most preferred gelling agent is methylcellulose.
  • the polysaccharide is generally present in a gel formulation in the range of 1-90% by weight of the gel, more preferably 1-20%.
  • suitable polysaccharides for this purpose and a determination of the solubility of the polysaccharides, are found in EP 267,015, published May 11, 1988, the disclosure of which is incorporated herein by reference.
  • the nucleic acid is introduced by contacting the graft the nucleic acid in an appropriate composition.
  • the contact suitably involves incubating or perfusing the organ with the composition or applying the composition to one or more surfaces of the graft for a sufficient time to allow the nucleic acid to be taken up by the cells of the graft.
  • the treatment generally takes place for at least one minute, and preferably from 1 minute to 72 hours, and more preferably from 2 minutes to 24 hours, depending on such factors as the concentration of nucleic acid in the formulation, the graft to be treated, and the particular type of formulation. Perfusion is accomplished by any suitable procedure.
  • an organ can be perfused via a device that provides a constant pressure of perfusion having a pressure regulator and overflow situated between a pump and the organ, as described by DD 213,134 published Sep. 5, 1984.
  • the organ is placed in a hyperbaric chamber via a sealing door and perfusate is delivered to the chamber by a pump that draws the fluid from the reservoir while spent perfusate is returned to the reservoir by a valve, as described in EP 125,847 published Nov. 21, 1984.
  • the host Prior to transplantation, the host can be treated pre-transplant procedures that would be beneficial to the particular transplant recipient.
  • transplantation procedure itself will depend on the particular disorder being treated, the condition of the patient, etc. The medical practitioner will recognize the appropriate procedure to employ in any given case.
  • the transplants are optionally monitored systematically during the critical postoperative period (the first three months) using any suitable procedure. After the transplantation, immunosuppression therapy may be utilized as necessary to ensure graft survival.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Transplantation (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne un procédé de traitement des greffons consistant à introduire un acide nucléique codant un agent angiogénique dans les cellules du greffon. Le greffon peut être traité ex vivo, puis transplanté dans le donneur ou il peut être traité après la transplantation. Le greffon peut être autologue, allogénique, xénogénique ou il peut s'agir d'un greffon obtenue par synthèse de tissus (organe 'bio-artificiel'). L'acide nucléique peut être introduit dans les cellules cultivées utilisées pour former le greffon obtenu par synthèse de tissus. L'expression de l'agent angiogénique par les cellules du greffon facilite la croissance de nouveaux vaisseaux sanguins (angiogenèse), ce qui permet d'irriguer le greffon et donc d'augmenter les chances de survie de ce dernier.
PCT/US1998/015971 1997-07-31 1998-07-31 Procede de traitement des greffons Ceased WO1999006073A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU87638/98A AU8763898A (en) 1997-07-31 1998-07-31 Method for the treatment of grafts
CA002298811A CA2298811A1 (fr) 1997-07-31 1998-07-31 Procede de traitement des greffons
EP98939149A EP1009441A1 (fr) 1997-07-31 1998-07-31 Procede de traitement des greffons
JP2000504884A JP2001511462A (ja) 1997-07-31 1998-07-31 移植片処置法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5438697P 1997-07-31 1997-07-31
US60/054,386 1997-07-31

Publications (1)

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WO1999006073A1 true WO1999006073A1 (fr) 1999-02-11

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PCT/US1998/015971 Ceased WO1999006073A1 (fr) 1997-07-31 1998-07-31 Procede de traitement des greffons

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EP (1) EP1009441A1 (fr)
JP (1) JP2001511462A (fr)
AU (1) AU8763898A (fr)
CA (1) CA2298811A1 (fr)
WO (1) WO1999006073A1 (fr)

Cited By (24)

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EP1190082A4 (fr) * 1999-06-25 2003-07-02 Yissum Res Dev Co Procede permettant d'induire une angiogenese au moyen de micro-organes
US7723293B2 (en) 1998-10-28 2010-05-25 Cornell Research Foundation, Inc. Methods for increasing capillary density and maintaining viability of microvascular cardiac endothelial cells using trk receptor ligands
US8088568B2 (en) 2001-11-05 2012-01-03 Medgentics, Inc. Dermal micro-organs, methods and apparatuses for producing and using the same
US8142990B2 (en) 2001-11-05 2012-03-27 Medgenics Inc. Dermal micro-organs, methods and apparatuses for producing and using the same
WO2012052953A1 (fr) 2010-10-20 2012-04-26 Fondazione Centro San Raffaele Del Monte Tabor Miarn
US20130165504A1 (en) * 2011-12-21 2013-06-27 modeRNA Therapeutics Methods of increasing the viability or longevity of an organ or organ explant
US8501396B2 (en) 2001-11-05 2013-08-06 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8685635B2 (en) 2002-11-05 2014-04-01 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8877175B2 (en) 2006-09-14 2014-11-04 Medgenics Medical Israel Ltd. Long lasting drug formulations
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
US8999380B2 (en) 2012-04-02 2015-04-07 Moderna Therapeutics, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
US9127084B2 (en) 2006-09-14 2015-09-08 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9155749B2 (en) 2006-09-14 2015-10-13 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9181319B2 (en) 2010-08-06 2015-11-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US9334328B2 (en) 2010-10-01 2016-05-10 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
US10323076B2 (en) 2013-10-03 2019-06-18 Modernatx, Inc. Polynucleotides encoding low density lipoprotein receptor

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US8853163B2 (en) 1998-10-28 2014-10-07 Cornell Research Foundation, Inc. Methods for increasing vascular density and maintaining viability of microvascular endothelial cells using trk receptor ligands
US7723293B2 (en) 1998-10-28 2010-05-25 Cornell Research Foundation, Inc. Methods for increasing capillary density and maintaining viability of microvascular cardiac endothelial cells using trk receptor ligands
EP1374889A1 (fr) * 1999-06-25 2004-01-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Procédé permettant d'induire une angiogénèse au moyen des micro-organes
EP1190082A4 (fr) * 1999-06-25 2003-07-02 Yissum Res Dev Co Procede permettant d'induire une angiogenese au moyen de micro-organes
US8501396B2 (en) 2001-11-05 2013-08-06 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8088568B2 (en) 2001-11-05 2012-01-03 Medgentics, Inc. Dermal micro-organs, methods and apparatuses for producing and using the same
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