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WO1997032990A1 - Procede de transduction de cellules dans des vaisseaux sanguins a l'aide de vecteurs de virus adeno-associes (vaa) recombinants - Google Patents

Procede de transduction de cellules dans des vaisseaux sanguins a l'aide de vecteurs de virus adeno-associes (vaa) recombinants Download PDF

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Publication number
WO1997032990A1
WO1997032990A1 PCT/US1997/003134 US9703134W WO9732990A1 WO 1997032990 A1 WO1997032990 A1 WO 1997032990A1 US 9703134 W US9703134 W US 9703134W WO 9732990 A1 WO9732990 A1 WO 9732990A1
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WIPO (PCT)
Prior art keywords
cell
cells
blood vessel
transducing
vector
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/US1997/003134
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English (en)
Inventor
Randolf L. Geary
Carmel M. Lynch
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.)
Wake Forest University
Ampliphi Biosciences Corp
Original Assignee
Wake Forest University
Targeted Genetics Corp
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Filing date
Publication date
Application filed by Wake Forest University, Targeted Genetics Corp filed Critical Wake Forest University
Priority to JP53184097A priority Critical patent/JP2002514899A/ja
Priority to AU19806/97A priority patent/AU1980697A/en
Priority to EP97907934A priority patent/EP0906440A1/fr
Publication of WO1997032990A1 publication Critical patent/WO1997032990A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • This invention relates to gene delivery, and more specifically to methods for transducing cells in blood vessels using recombinant aden ⁇ -associated virus (AAV) vectors.
  • AAV aden ⁇ -associated virus
  • the adventitia forms the outermost layer of the artery wall and is separated from the media by the external elastic lamina.
  • the adventitia is generally composed of a loose matrix containing macrophages, fibroblasts, and other cell types, as well as the vasa vasorum (a rich network of adventitial micro vessels).
  • Microvessels may differ from the general structural model outlined above in that the three layers may not be well defined.
  • capillaries may comprise a monolayer of endothelial cells surrounded by a single layer of smooth muscle cells without any well-defined elastic layers.
  • Angiogenesis is the formation of new blood vessels. Angiogenesis occurs during fetal development ofthe vascular system, as well in a wide range of normal and postnatal pathological processes such as wound repair; neoplasia, and inflammation. [See, e.g., Diaz-Flores, 1994] Thus, a number of disease processes have abundant microvessels as key anatomical or pathological features.
  • microvessels may contribute directly or indirectly to the development of specific illnesses or may represent a benign morphological feature.
  • microvessels and angiogenesis are believed to play central roles in the pathogenesis of disease. These include, for example, the growth and metastasis of many cancers, diabetic retinopathy, retinitis, heart failure, arthritis, psoriasis, ischemia, wound healing, hemangiomas and other vascular malformations. [See, e.g., Diaz-Flores, 1994]
  • the cells comprising all tissues and organs require an extensive network of microvessels to support their normal function and viability. Since these microvessels may be functionally unique and distinct from larger blood vessels, microvessels provide unique targets for delivery of therapeutic polynucleotides to tissues.
  • the tissue or organ may be enhanced in a positive way.
  • retroviral vectors are advantageous because of their general potential for stable long-term gene expression, target cell replication is required for stable provirus integration.
  • most cells in the artery are generally quiescent.
  • Quiescent cells can sometimes be isolated and induced to divide in order to achieve significant and efficient gene transfer; but, this method often requires that the cells be induced and genetically modified ex vivo and thereafter transplanted back into the donor host.
  • Liposomal vector delivery systems have also been limited by inefficient uptake and transient episomal vector expression.
  • Adenoviral vectors that have been efficient at infecting endothelial cells have been limited by transient episomal vector expression and by antigenicity limiting the efficacy of repeated applications.
  • the present invention provides methods for transducing cells in blood vessels using recombinant AAV vectors.
  • Preferred embodiments ofthe present invention include the following: 1. A method of transducing a cell in a blood vessel of an individual, comprising introducing a recombinant adeno-associated viral (rAAV) vector to a blood vessel of said individual in vivo.
  • rAAV adeno-associated viral
  • a method of transducing a cell in a blood vessel according to embodiment 1 wherein said rAAV vector comprises a detectable marker gene.
  • said rAAV vector comprises a selectable marker gene.
  • a method of transducing a cell in a blood vessel according to embodiment 1 wherein said blood vessel is a microvessel selected from the group consisting of arteriole, capillary, venule, and adventitial microvessel.
  • a method of transducing a cell in a blood vessel according to embodiment 1 wherein said blood vessel is a microvessel and said cell is undergoing proliferation.
  • a method of transducing a cell in a blood vessel according to embodiment 1 wherein said cell is a proliferating cell.
  • a method for treating an individual for a disease condition comprising transducing a cell in a blood vessel of said individual according to the method of embodiment 4.
  • Recombinant as applied to a polynucleotide, means that the polynucleotide is the product of various combinations of cloning, restriction and/or ligation steps, and other procedures that result in a construct that is distinct from a polynucleotide found in nature.
  • helper virus for AAV refers to a second virus that allows wild-type AAV, which is a defective parvovirus, to be replicated and packaged by a host cell.
  • helper viruses have been identified in the art, including adenoviruses, herpesviruses, and poxviruses such as vaccinia.
  • Packaging refers to a series of subcellular events that results in the assembly and encapsidation of a rAAV vector. Thus, when a suitable vector plasmid is introduced into a packaging cell line under appropriate conditions, it can be replicated and assembled into a viral particle.
  • a “therapeutic polynucleotide” or “therapeutic gene” refers to a nucleotide sequence that is capable, when transferred to an individual, of eliciting a prophylactic, curative or other beneficial effect in the individual.
  • an “individual” as used herein refers to a mammal, preferably a human.
  • “Treatment” or “therapy” as used herein refers to administering cells, other agents, or combinations thereof, to an individual, that are capable of eliciting a prophylactic, curative or other beneficial effect in the individual.
  • Gene delivery refers to the introduction of an exogenous polynucleotide into a cell for gene transfer, and may encompass targeting, binding, uptake, transport, localization, replicon integration and expression.
  • Gene transfer refers to the introduction of an exogenous polynucleotide into a cell which may encompass targeting, binding, uptake, transport, localization and replicon integration, but is distinct from and does not imply subsequent expression ofthe gene.
  • Gene expression or “expression” refers to the process of gene transcription, translation, and posttranslational modification.
  • Vasculature or "vascular” are terms referring to the system of vessels carrying blood (as well as lymph fluids) throughout the mammalian body.
  • Blood vessel refers to any ofthe vessels ofthe mammalian vascular system, including arteries, arterioles, capillaries, venules, veins, sinuses, and vasa vasorum.
  • the wall of an artery consists typically of an outer layer (adventitia) separated by an external elastic lamina from a middle layer (media) which is separated by an internal elastic lamina from an inner layer (intima).
  • the adventitia is a layer of loose connective tissue which generally includes a network of microvessels (vasa vasorum), fibroblasts, and immune cells such as lymphocytes and macrophages.
  • the media comprises circular layers of smooth muscle cells and elastic fibers.
  • the intima is made up of a monolayer of endothelial cells overlying, in some instances, smooth muscle cells.
  • Advanced microvessel refers to microvessels that supply blood to the adventitia of larger blood vessels such as arteries.
  • the network of these adventitial microvessels is commonly referred to as the vasa vasorum.
  • adventitial microvessels are believed to be supplied with blood from the lumen ofthe parent vessel (e.g., the artery) via small microvessels traversing the vessel intima and media.
  • Microvascular cell refers to cells that make up the structure of microvessels.
  • Endothelium refers to the layer of cells (i.e., “endothelial cells”) that generally lines the cavities ofthe heart and blood vessels, as well as vessels ofthe lymphatic system.
  • vessels such as arteries can contain both endothelial cells and smooth muscle cells which are distinguishable in terms of origin, functionality, and attributes such as cell surface markers.
  • endothelial cells derive from embryonic ectoderm, form the layer of cells that make up the endothelium, provide a non-thrombogenic surface, and can be readily distinguished using a number of well-known cell surface markers, including, by way of illustration, vWF, as exemplified below.
  • smooth muscle cells derive from embryonic mesoderm, provide structure and contractile function for blood vessel walls, do not provide a non-thrombogenic surface, and can be readily distinguished using a number of well-known surface markers, including, by way of illustration, alpha-actin, as exemplified below.
  • "Proliferating” or “proliferation” are terms referring to growth by cell multiplication.
  • Angiogenesis is the formation of new blood vessels which occurs during fetal development of the vascular system, as well in a wide range of normal and postnatal pathological processes such as wound repair, neoplasia, and inflammation.
  • Additional references describing cell types found in the blood vessels, and the structure ofthe vasculature which may be used in the methods ofthe present invention include the following: W. Bloom & D. Fawcett, A Textbook of Histology. 10th Ed.. (W.B. Saunders Co. 1975). Additional references describing AAV vectors which may be used in the methods ofthe present invention include the following: Carter, B., Handbook of Parvoviruses. vol. I, pp. 169-228 (1990); Berns, Virology, pp. 1743-1764 (Raven Press 1990); Muzyczka. N.. Current Topics in Microbiology and Immunology. 158: 92-129 (1992); and Kotin, R., Human Gene Therapy. 5: 793-801 (1994).
  • Carter, B. Handbook of Parvoviruses. vol. I, pp. 169-228 (1990). Carter, B., Current Opinions in Biotechnology. 3: 533-539 (1992).
  • Example 4 In Vivo Transduction of Microvascular Cells in Primates Using ACAPSN Introduced hv Intraluminal Delivery Following Denudation Pre-Treatment In order to determine whether endothelial cells function as a barrier to rAAV gene delivery deeper into the artery vessel wall, the ACAPSN vector was delivered by intraluminal infusion to carotid arteries which had been denuded of endothelium.
  • adventitial microvessels are believed to be supplied with blood from the lumen of the parent vessel (e.g., the artery) via small microvessels traversing the vessel media.
  • This study was designed to demonstrate that introduction of an rAAV vector into the adventitia can also be achieved indirectly, by injection directly into the lumen of an artery that had been pre-treated by prior balloon injury.
  • the artery was stimulated by repeated intraluminal passage of a large inflated balloon catheter five days prior to delivery of ACAPSN, which would be expected to increase the rate of cellular proliferation of the vessel wall prior to delivery of the vector.
  • An ACAPSN vector preparation was generated according to the procedures of Example 1. The transduction was conducted using an ACAPSN preparation with a concentration of 1 x 10 10 DNAse-resistant particles per ml. The animal was generally prepped, selected and maintained as described in Example 6, with the following exception: delivery occurred by intraluminal delivery as described in Example 3. Thus, in this Example, (1) both carotids received

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Abstract

Les techniques actuelles visant à exprimer les gènes recombinants dans les cellules de vaisseaux sanguins après le transfert direct de gènes in vivo, se heurtent à des problèmes ou limitations connexes. En outre, aucun procédé efficace n'a été trouvé qui permette d'effectuer la transduction de cellules microvasculaires et/ou de cellules jouant un rôle dans la formation de nouveaux vaisseaux sanguins (angiogenèse). Cette invention concerne des procédés permettant d'effectuer la transduction de cellules dans des vaisseaux sanguins à l'aide de vecteurs de virus adéno-associés (VAA) recombinants.
PCT/US1997/003134 1996-03-04 1997-02-28 Procede de transduction de cellules dans des vaisseaux sanguins a l'aide de vecteurs de virus adeno-associes (vaa) recombinants Ceased WO1997032990A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP53184097A JP2002514899A (ja) 1996-03-04 1997-02-28 組換えａａｖベクターを用いて血管中の細胞を形質導入するための方法
AU19806/97A AU1980697A (en) 1996-03-04 1997-02-28 Methods for transducing cells in blood vessels using recombinant AAV vec tors
EP97907934A EP0906440A1 (fr) 1996-03-04 1997-02-28 Procede de transduction de cellules dans des vaisseaux sanguins a l'aide de vecteurs de virus adeno-associes (vaa) recombinants

Applications Claiming Priority (2)

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US61066096A 1996-03-04 1996-03-04
US08/610,660 1996-03-04

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US79391697A A-371-Of-International 1996-03-04 1997-02-28
US09/938,200 Continuation US20020001581A1 (en) 1996-03-04 2001-08-23 Methods for transducing cells in blood vessels using recombinant AAV vectors

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WO1997032990A1 true WO1997032990A1 (fr) 1997-09-12

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EP (1) EP0906440A1 (fr)
JP (1) JP2002514899A (fr)
AU (1) AU1980697A (fr)
CA (1) CA2247099A1 (fr)
WO (1) WO1997032990A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020779A1 (fr) * 1997-10-21 1999-04-29 Targeted Genetics Corporation Cassettes d'encapsidation de virus adeno-associe (aav) amplifiable pour la production de vecteurs de aav recombines
US5941868A (en) * 1995-12-22 1999-08-24 Localmed, Inc. Localized intravascular delivery of growth factors for promotion of angiogenesis
WO2001009360A1 (fr) * 1999-08-02 2001-02-08 Avigen, Inc. Utilisation du vecteur viral adeno-associe (raav) a des fins de prevention de la proliferation cellulaire du muscle lisse dans une greffe vasculaire
US6254573B1 (en) 1998-02-05 2001-07-03 Biosense, Inc. Intracardiac drug delivery device utilizing spring-loaded mechanism
WO2002014487A3 (fr) * 2000-08-17 2003-03-13 Keiya Ozawa Distribution de facteurs angiogeniques a mediation assuree par virus associe aux adenovirus
US6537540B1 (en) 1999-05-28 2003-03-25 Targeted Genetics Corporation Methods and composition for lowering the level of tumor necrosis factor (TNF) in TNF-associated disorders
US6566118B1 (en) 1997-09-05 2003-05-20 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US6591129B1 (en) 1996-02-15 2003-07-08 Biosense, Inc. Method for treating tissue through injection of a therapeutic agent
US6596535B1 (en) 1999-08-09 2003-07-22 Targeted Genetics Corporation Metabolically activated recombinant viral vectors and methods for the preparation and use
US6642051B1 (en) 1997-10-21 2003-11-04 Targeted Genetics Corporation Amplifiable adeno-associated virus(AAV) packaging cassettes for the production of recombinant AAV vectors
US6887463B2 (en) 1995-02-24 2005-05-03 The Trustees Of The University Of Pennsylvania Methods and compositions for the treatment of defects in lipoprotein metabolism
US6893865B1 (en) 1999-04-28 2005-05-17 Targeted Genetics Corporation Methods, compositions, and cells for encapsidating recombinant vectors in AAV particles
US6924128B2 (en) 1994-12-06 2005-08-02 Targeted Genetics Corporation Packaging cell lines for generation of high titers of recombinant AAV vectors
US6936466B2 (en) 1997-10-21 2005-08-30 Targeted Genetics Corporation Transcriptionally-activated AAV inverted terminal repeats (ITRs) for use with recombinant AAV vectors
US6989264B2 (en) 1997-09-05 2006-01-24 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US7051738B2 (en) 1996-07-28 2006-05-30 Uri Oron Apparatus for providing electromagnetic biostimulation of tissue using optics and echo imaging
US7078387B1 (en) 1998-12-28 2006-07-18 Arch Development Corp. Efficient and stable in vivo gene transfer to cardiomyocytes using recombinant adeno-associated virus vectors
EP1870473A1 (fr) * 2000-08-17 2007-12-26 Keiya Ozawa Libération de facteurs angiogéniques à médiation virale et adéno associée
EP1916258A2 (fr) 1999-08-09 2008-04-30 Targeted Genetics Corporation Améliorations de l'expression d'une séquence de nucléotides hétérologues à brin unique à partir de vecteurs viraux recombinants par la désignation de la séquence de manière à ce qu'elle forme des paires de bases intrabrins
US9415119B2 (en) 2009-05-02 2016-08-16 Genzyme Corporation Gene therapy for neurodegenerative disorders
US10214730B2 (en) 2011-04-19 2019-02-26 The Research Foundation For The State University Of New York Adeno-associated-virus Rep sequences, vectors and viruses

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WO1995024202A1 (fr) * 1994-03-07 1995-09-14 Immusol, Inc. Therapie a base de ribozymes pour traiter la restenose
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GNATENKO D ET AL: "ADENO-ASSOCIATED VIRUS-2(AAV) AS A VEHICLE FOR GENE DELIVERY INTO VASCULAR ENDOTHELIAL CELLS", BLOOD, vol. 84, no. 10, SUPPL. 01, 15 November 1994 (1994-11-15), PHILADELPHIA US, pages 741A, XP002023084 *
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6924128B2 (en) 1994-12-06 2005-08-02 Targeted Genetics Corporation Packaging cell lines for generation of high titers of recombinant AAV vectors
US7306794B2 (en) 1995-02-24 2007-12-11 The Trustees Of The University Of Pennsylvania Methods and compositions for the treatment of defects in lipoprotein metabolism
US6887463B2 (en) 1995-02-24 2005-05-03 The Trustees Of The University Of Pennsylvania Methods and compositions for the treatment of defects in lipoprotein metabolism
US5941868A (en) * 1995-12-22 1999-08-24 Localmed, Inc. Localized intravascular delivery of growth factors for promotion of angiogenesis
US6591129B1 (en) 1996-02-15 2003-07-08 Biosense, Inc. Method for treating tissue through injection of a therapeutic agent
US7051738B2 (en) 1996-07-28 2006-05-30 Uri Oron Apparatus for providing electromagnetic biostimulation of tissue using optics and echo imaging
US6995006B2 (en) 1997-09-05 2006-02-07 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US6566118B1 (en) 1997-09-05 2003-05-20 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US6989264B2 (en) 1997-09-05 2006-01-24 Targeted Genetics Corporation Methods for generating high titer helper-free preparations of released recombinant AAV vectors
US6642051B1 (en) 1997-10-21 2003-11-04 Targeted Genetics Corporation Amplifiable adeno-associated virus(AAV) packaging cassettes for the production of recombinant AAV vectors
US6936466B2 (en) 1997-10-21 2005-08-30 Targeted Genetics Corporation Transcriptionally-activated AAV inverted terminal repeats (ITRs) for use with recombinant AAV vectors
WO1999020779A1 (fr) * 1997-10-21 1999-04-29 Targeted Genetics Corporation Cassettes d'encapsidation de virus adeno-associe (aav) amplifiable pour la production de vecteurs de aav recombines
US6309370B1 (en) 1998-02-05 2001-10-30 Biosense, Inc. Intracardiac drug delivery
US6254573B1 (en) 1998-02-05 2001-07-03 Biosense, Inc. Intracardiac drug delivery device utilizing spring-loaded mechanism
US7078387B1 (en) 1998-12-28 2006-07-18 Arch Development Corp. Efficient and stable in vivo gene transfer to cardiomyocytes using recombinant adeno-associated virus vectors
US6893865B1 (en) 1999-04-28 2005-05-17 Targeted Genetics Corporation Methods, compositions, and cells for encapsidating recombinant vectors in AAV particles
US6537540B1 (en) 1999-05-28 2003-03-25 Targeted Genetics Corporation Methods and composition for lowering the level of tumor necrosis factor (TNF) in TNF-associated disorders
WO2001009360A1 (fr) * 1999-08-02 2001-02-08 Avigen, Inc. Utilisation du vecteur viral adeno-associe (raav) a des fins de prevention de la proliferation cellulaire du muscle lisse dans une greffe vasculaire
US7125717B2 (en) 1999-08-09 2006-10-24 Targeted Genetics Corporation Metabolically activated recombinant viral vectors and methods for their preparation and use
EP2369002A1 (fr) 1999-08-09 2011-09-28 Targeted Genetics Corporation Améliorations de l'expression d'une séquence de nucléotides hétérologues à brin unique à partir de vecteurs viraux recombinants par la désignation de la séquence de manière à ce qu'elle forme des paires de bases intrabrins
US6596535B1 (en) 1999-08-09 2003-07-22 Targeted Genetics Corporation Metabolically activated recombinant viral vectors and methods for the preparation and use
US8093054B2 (en) 1999-08-09 2012-01-10 Genzyme Corporation Metabolically activated recombinant viral vectors and methods for their preparation and use
EP1916258A2 (fr) 1999-08-09 2008-04-30 Targeted Genetics Corporation Améliorations de l'expression d'une séquence de nucléotides hétérologues à brin unique à partir de vecteurs viraux recombinants par la désignation de la séquence de manière à ce qu'elle forme des paires de bases intrabrins
US7785888B2 (en) 1999-08-09 2010-08-31 Genzyme Corporation Metabolically activated recombinant viral vectors and methods for their preparation and use
US7846729B2 (en) 1999-08-09 2010-12-07 Genzyme Corporation Metabolically activated recombinant viral vectors and methods for their preparation and use
WO2002014487A3 (fr) * 2000-08-17 2003-03-13 Keiya Ozawa Distribution de facteurs angiogeniques a mediation assuree par virus associe aux adenovirus
EP1870473A1 (fr) * 2000-08-17 2007-12-26 Keiya Ozawa Libération de facteurs angiogéniques à médiation virale et adéno associée
US9415119B2 (en) 2009-05-02 2016-08-16 Genzyme Corporation Gene therapy for neurodegenerative disorders
US10369193B2 (en) 2009-05-02 2019-08-06 Genzyme Corporation Gene therapy for neurodegenerative disorders
US11911440B2 (en) 2009-05-02 2024-02-27 Genzyme Corporation Gene therapy for neurodegenerative disorders
US11975043B2 (en) 2009-05-02 2024-05-07 Genzyme Corporation Gene therapy for neurodegenerative disorders
US12350311B2 (en) 2009-05-02 2025-07-08 Genzyme Corporation Gene therapy for neurodegenerative disorders
US10214730B2 (en) 2011-04-19 2019-02-26 The Research Foundation For The State University Of New York Adeno-associated-virus Rep sequences, vectors and viruses

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AU1980697A (en) 1997-09-22
CA2247099A1 (fr) 1997-09-12
EP0906440A1 (fr) 1999-04-07
JP2002514899A (ja) 2002-05-21

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