SG10201809075XA - Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues - Google Patents

Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues

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Publication number
SG10201809075XA
SG10201809075XA SG10201809075XA SG10201809075XA SG10201809075XA SG 10201809075X A SG10201809075X A SG 10201809075XA SG 10201809075X A SG10201809075X A SG 10201809075XA SG 10201809075X A SG10201809075X A SG 10201809075XA SG 10201809075X A SG10201809075X A SG 10201809075XA
Authority
SG
Singapore
Prior art keywords
aav
organs
tissues
cells
gene transfer
Prior art date
Application number
SG10201809075XA
Inventor
Katherine A High
Mustafa N Yazicioglu
Xavier Anguela
Original Assignee
Childrens Hospital Philadelphia
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.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=52343737&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=SG10201809075X(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Childrens Hospital Philadelphia filed Critical Childrens Hospital Philadelphia
Publication of SG10201809075XA publication Critical patent/SG10201809075XA/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/01—DNA viruses
    • C07K14/015—Parvoviridae, e.g. feline panleukopenia virus, human parvovirus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6402—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals
    • C12N9/6405—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals not being snakes
    • C12N9/6408—Serine endopeptidases (3.4.21)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21022—Coagulation factor IXa (3.4.21.22)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2750/14121—Viruses as such, e.g. new isolates, mutants or their genomic sequences
    • 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
    • C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination

Abstract

VARIANT AAV AND COMPOSITIONS, METHODS AND USES FOR GENE TRANSFER TO CELLS, ORGANS AND TISSUES The invention relates to adeno-associated virus (AAV) serotype AAV-Rh74 and related AAV vectors, and AAV-Rh74 and related AAV vector mediated gene transfer methods and uses. In particular, AAV- Rh74 and related AAV vectors target polynucleotides to cells, tissues or organs for expression (transcription) of genes encoding therapeutic proteins and peptides, and polynucleotides that function as or are transcribed into inhibitory nucleic acid sequences. Fig. 6 66
SG10201809075XA 2013-07-22 2014-07-22 Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues SG10201809075XA (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361857161P 2013-07-22 2013-07-22
US201461985365P 2014-04-28 2014-04-28

Publications (1)

Publication Number Publication Date
SG10201809075XA true SG10201809075XA (en) 2018-11-29

Family

ID=52343737

Family Applications (2)

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SG10201809075XA SG10201809075XA (en) 2013-07-22 2014-07-22 Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues
SG11201600518WA SG11201600518WA (en) 2013-07-22 2014-07-22 Variant aav and compositions, methods and uses for gene transfer to cells, organs and tissues

Family Applications After (1)

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Country Status (25)

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US (2) US9840719B2 (en)
EP (2) EP3613440A1 (en)
JP (3) JP6495273B2 (en)
KR (2) KR20220041963A (en)
CN (1) CN105579465B (en)
AU (4) AU2014293253B2 (en)
CA (2) CA2919103C (en)
DK (1) DK3024498T3 (en)
ES (1) ES2774966T3 (en)
HK (1) HK1223849A1 (en)
HU (1) HUE047996T2 (en)
IL (5) IL297919A (en)
MX (2) MX2016001044A (en)
MY (1) MY175477A (en)
NZ (1) NZ716102A (en)
PE (1) PE20160188A1 (en)
PH (2) PH12016500162A1 (en)
PL (1) PL3024498T3 (en)
PT (1) PT3024498T (en)
RU (2) RU2019124473A (en)
SA (1) SA516370442B1 (en)
SG (2) SG10201809075XA (en)
SI (1) SI3024498T1 (en)
WO (1) WO2015013313A2 (en)
ZA (1) ZA201600481B (en)

Families Citing this family (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2580044T3 (en) * 2005-04-07 2016-08-18 The Trustees Of The University Of Pennsylvania Method of increasing the function of an AAV vector
US9255154B2 (en) 2012-05-08 2016-02-09 Alderbio Holdings, Llc Anti-PCSK9 antibodies and use thereof
EP3134530B1 (en) 2014-04-25 2019-06-12 Genethon Treatment of hyperbilirubinemia
US10577627B2 (en) 2014-06-09 2020-03-03 Voyager Therapeutics, Inc. Chimeric capsids
CN112553229A (en) 2014-11-05 2021-03-26 沃雅戈治疗公司 AADC polynucleotides for treating Parkinson's disease
GB201420139D0 (en) 2014-11-12 2014-12-24 Ucl Business Plc Factor IX gene therapy
CN107207556B (en) 2014-11-14 2020-12-08 沃雅戈治疗公司 Regulatory polynucleotides
RU2020108189A (en) 2014-11-14 2020-03-11 Вояджер Терапьютикс, Инк. COMPOSITIONS AND METHODS OF TREATMENT OF LATERAL AMYOTROPHIC SCLEROSIS (ALS)
US11697825B2 (en) 2014-12-12 2023-07-11 Voyager Therapeutics, Inc. Compositions and methods for the production of scAAV
US10081659B2 (en) 2015-04-06 2018-09-25 The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services Adeno-associated vectors for enhanced transduction and reduced immunogenicity
GB201508026D0 (en) 2015-05-11 2015-06-24 Ucl Business Plc Capsid
CA2983593A1 (en) * 2015-05-14 2016-11-17 St. Jude Children's Research Hospital, Inc. Nucleic acid molecules containing spacers and methods of use thereof
MX2018000307A (en) * 2015-06-23 2018-05-02 Childrens Hospital Philadelphia Modified factor ix, and compositions, methods and uses for gene transfer to cells, organs and tissues.
PL3356390T3 (en) 2015-09-28 2021-07-05 The University Of North Carolina At Chapel Hill Methods and compositions for antibody-evading virus vectors
PE20231949A1 (en) * 2015-10-30 2023-12-05 Spark Therapeutics Inc VARIANTS OF FACTOR VIII REDUCED WITH CpG, COMPOSITIONS AND METHODS AND USES FOR THE TREATMENT OF HEMOSTASY DISORDERS
PE20181156A1 (en) 2015-11-05 2018-07-19 Bamboo Therapeutics Inc MODIFIED FRIEDREICH ATAXIA GENES AND VECTORS FOR GENE THERAPY
JP7444521B2 (en) * 2015-12-01 2024-03-06 スパーク セラピューティクス インコーポレイテッド A scalable method for producing recombinant adeno-associated virus (AAV) vectors in a serum-free suspension cell culture system suitable for clinical use.
WO2017096164A1 (en) 2015-12-02 2017-06-08 The Board Of Trustees Of The Leland Stanford Junior University Novel recombinant adeno-associated virus capsids with enhanced human skeletal muscle tropism
US10406244B2 (en) 2015-12-02 2019-09-10 The Board Of Trustees Of The Leland Stanford Junior University AAV vectors with expanded packaging capacity
WO2017096162A1 (en) 2015-12-02 2017-06-08 Voyager Therapeutics, Inc. Assays for the detection of aav neutralizing antibodies
US20180363000A1 (en) * 2015-12-14 2018-12-20 The Trustees Of The University Of Pennsylvania Aav-anti pcsk9 antibody constructs and uses thereof
AU2016370590B2 (en) 2015-12-14 2023-11-02 The Trustees Of The University Of Pennsylvania Composition for treatment of Crigler-Najjar syndrome
CN109415704B (en) 2016-02-16 2022-02-25 利兰斯坦福初级大学董事会 Novel recombinant adeno-associated virus capsids resistant to pre-existing human neutralizing antibodies
WO2017173043A1 (en) * 2016-03-30 2017-10-05 Spark Therapeutics, Inc. Cell line for recombinant protein and/or viral vector production
EP3448874A4 (en) 2016-04-29 2020-04-22 Voyager Therapeutics, Inc. Compositions for the treatment of disease
WO2017189964A2 (en) 2016-04-29 2017-11-02 Voyager Therapeutics, Inc. Compositions for the treatment of disease
JP7066635B2 (en) 2016-05-18 2022-05-13 ボイジャー セラピューティクス インコーポレイテッド Modulatory polynucleotide
US11951121B2 (en) 2016-05-18 2024-04-09 Voyager Therapeutics, Inc. Compositions and methods for treating Huntington's disease
CA2971303A1 (en) 2016-06-21 2017-12-21 Bamboo Therapeutics, Inc. Optimized mini-dystrophin genes and expression cassettes and their use
IL263801B2 (en) * 2016-07-26 2024-01-01 Biomarin Pharm Inc Novel adeno-associated virus capsid proteins
WO2018044933A1 (en) 2016-08-30 2018-03-08 The Regents Of The University Of California Methods for biomedical targeting and delivery and devices and systems for practicing the same
EP3293259A1 (en) 2016-09-12 2018-03-14 Genethon Acid-alpha glucosidase variants and uses thereof
EP3293260A1 (en) 2016-09-12 2018-03-14 Genethon Acid-alpha glucosidase variants and uses thereof
CN110050063B (en) 2016-09-12 2023-11-03 吉尼松公司 Acid alpha-glucosidase variants and uses thereof
EP3293203A1 (en) 2016-09-12 2018-03-14 Genethon Acid-alpha glucosidase variants and uses thereof
CA3041548A1 (en) * 2016-11-04 2018-05-11 The Children's Hospital Of Philadelphia Gene transfer compositions, methods and uses for treating neurodegenerative diseases
JP7215716B2 (en) 2017-01-13 2023-01-31 学校法人自治医科大学 AAV vectors for disrupting coagulation-related factor genes on the liver genome
US11541131B2 (en) 2017-03-10 2023-01-03 Genethon Treatment of glycogen storage disease III
US10550405B2 (en) 2017-03-15 2020-02-04 The University Of North Carolina At Chapel Hill Rational polyploid adeno-associated virus vectors and methods of making and using the same
EP4303225A3 (en) * 2017-03-15 2024-04-10 The University of North Carolina at Chapel Hill Polyploid adeno-associated virus vectors and methods of making and using the same
JP2020518258A (en) 2017-05-05 2020-06-25 ボイジャー セラピューティクス インコーポレイテッドＶｏｙａｇｅｒ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． Amyotrophic lateral sclerosis (ALS) treatment composition and method
US11752181B2 (en) 2017-05-05 2023-09-12 Voyager Therapeutics, Inc. Compositions and methods of treating Huntington's disease
WO2018213278A1 (en) * 2017-05-15 2018-11-22 The Trustees Of Columbia University In The City Of New York Reprogramming metabolism by inhibiting vhl for treatment of neurodegeneration
JOP20190269A1 (en) 2017-06-15 2019-11-20 Voyager Therapeutics Inc Aadc polynucleotides for the treatment of parkinson's disease
CN111132626B (en) 2017-07-17 2024-01-30 沃雅戈治疗公司 Track array guidance system
US20210228738A1 (en) 2017-07-17 2021-07-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Compositions and methods for increasing or enhancing transduction of gene therapy vectors and for removing or reducing immunoglobulins
JP2020530834A (en) * 2017-07-17 2020-10-29 スパーク セラピューティクス インコーポレイテッドＳｐａｒｋ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． Apheresis method and use
KR20200042935A (en) * 2017-08-25 2020-04-24 오비드 테라퓨틱스 인크. Recombinant adeno-related vectors
AU2018352236A1 (en) 2017-10-16 2020-04-23 The Curators Of The University Of Missouri Treatment of amyotrophic lateral sclerosis (ALS)
WO2019079242A1 (en) 2017-10-16 2019-04-25 Voyager Therapeutics, Inc. Treatment of amyotrophic lateral sclerosis (als)
BR112020014404A2 (en) 2018-01-17 2020-12-29 Adrenas Therapeutics, Inc. ADENO-ASSOCIATED VIRUS GENE THERAPY FOR 21-HYDROXYLASE DEFICIENCY
US10610606B2 (en) 2018-02-01 2020-04-07 Homology Medicines, Inc. Adeno-associated virus compositions for PAH gene transfer and methods of use thereof
US20210346519A1 (en) 2018-02-07 2021-11-11 Genethon Hybrid regulatory elements
WO2019161365A1 (en) 2018-02-19 2019-08-22 Homology Medicines, Inc. Adeno-associated virus compositions for restoring f8 gene function and methods of use thereof
KR20210010434A (en) * 2018-02-27 2021-01-27 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 Novel adeno-associated virus (AAV) vectors with reduced capsid deamidation and uses thereof
CA3092353A1 (en) * 2018-03-16 2019-09-19 Research Institute At Nationwide Children's Hospital Increasing tissue specific gene delivery by capsid modification
US11608510B2 (en) 2018-03-30 2023-03-21 The Board Of Trustees Of The Leland Stanford Junior University Recombinant adeno-associated virus capsids with enhanced human pancreatic tropism
BR112020020223A2 (en) 2018-04-05 2021-01-19 Genethon RECOMBINANT HYBRID ADENO-ASSOCIATED VIRUS SOROTYPE BETWEEN AAV9 AND AAVRH74 WITH TROPISM BY REDUCED LIVER
EP3784697A4 (en) * 2018-04-27 2022-07-06 Spark Therapeutics, Inc. Engineered aav capsids with increased tropism and aav vectors comprising the engineered capsids and methods of making and using same
CA3098566A1 (en) 2018-04-29 2019-11-07 Zhuchun WU Systems and methods of spectrophotometry for the determination of genome content, capsid content and full/empty ratios of adeno-associated virus particles
WO2019212921A1 (en) 2018-04-29 2019-11-07 Regenxbio Inc. Scalable clarification process for recombinant aav production
CN110691846A (en) * 2018-05-07 2020-01-14 北卡罗来纳-查佩尔山大学 Rational polyploid adeno-associated virus vectors and methods of making and using same
TW202005978A (en) 2018-05-14 2020-02-01 美商拜奧馬林製藥公司 Novel liver targeting adeno-associated viral vectors
CA3102817A1 (en) 2018-06-14 2019-12-19 Claire G. ZHANG Anion exchange chromatography for recombinant aav production
PL3833746T3 (en) 2018-08-08 2023-12-04 Genethon Mini-gde for the treatment of glycogen storage disease iii
EP3833745A1 (en) 2018-08-10 2021-06-16 REGENXBIO Inc. Scalable method for recombinant aav production
US10842885B2 (en) 2018-08-20 2020-11-24 Ucl Business Ltd Factor IX encoding nucleotides
WO2020081415A1 (en) 2018-10-15 2020-04-23 Regenxbio Inc. Method for measuring the infectivity of replication defective viral vectors and viruses
AU2019381803A1 (en) * 2018-11-16 2021-06-10 Asklepios Biopharmaceutical, Inc. Vectors comprising a nucleic acid encoding lysosomal enzymes fused to a lysosomal targeting sequence
KR20210143869A (en) * 2019-03-28 2021-11-29 더 제너럴 하스피탈 코포레이션 Engineered adeno-associated (AAV) vectors for transgene expression
TW202102526A (en) 2019-04-04 2021-01-16 美商銳進科斯生物股份有限公司 Recombinant adeno-associated viruses and uses thereof
DK3953483T3 (en) 2019-04-11 2023-12-18 Regenxbio Inc SIZE CHROMATOGRAPHY METHODS FOR CHARACTERIZING COMPOSITIONS OF RECOMBINANT ADENO-ASSOCIATED VIRUS
TW202332458A (en) 2019-04-19 2023-08-16 美商銳進科斯生物股份有限公司 Adeno-associated virus vector formulations and methods
WO2020212626A1 (en) 2019-04-19 2020-10-22 Genethon Gene therapy of fibroblast growth factor 23 related hypophosphatemic diseases
EP3959323A1 (en) 2019-04-24 2022-03-02 REGENXBIO Inc. Fully-human post-translationally modified antibody therapeutics
WO2020223933A1 (en) * 2019-05-08 2020-11-12 中国科学院脑科学与智能技术卓越创新中心 Aav mutant that efficiently infects supporting cells
CN110205297A (en) * 2019-05-15 2019-09-06 华北理工大学 A kind of recombination fat stem cell and its recombination method
CA3144864A1 (en) 2019-06-27 2020-12-30 Pfizer Inc. Methods of treating duchenne muscular dystrophy using aav mini-dystrophin gene therapy
JP2022540632A (en) 2019-07-09 2022-09-16 ジェネトン Treatment of glycogen storage disease (GSD)
EP3997225A1 (en) 2019-07-10 2022-05-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of epilepsy
US20220265853A1 (en) 2019-07-12 2022-08-25 Gene Therapy Research Institution Co., Ltd. Adeno-associated virus virion for gene transfer to human liver
US20230042103A1 (en) 2019-07-26 2023-02-09 Regenxbio Inc. Engineered nucleic acid regulatory element and methods of uses thereof
RU2751592C2 (en) * 2019-08-22 2021-07-15 Общество С Ограниченной Ответственностью "Анабион" Isolated modified vp1 capsid protein of adeno-associated virus of serotype 5 (aav5), capsid and vector based on it
WO2021050666A1 (en) * 2019-09-11 2021-03-18 Aav Gene Therapeutics, Inc. Aav-zyme and use for infusion replacement therapy
CA3157700A1 (en) 2019-10-17 2021-04-22 Stridebio, Inc. Adeno-associated viral vectors for treatment of niemann-pick disease type c
WO2021078834A1 (en) 2019-10-22 2021-04-29 Genethon Chimeric acid-alpha glucosidase polypeptides and uses thereof
EP4048786A1 (en) 2019-10-22 2022-08-31 Genethon Chimeric polypeptides and uses thereof
BR112022009279A2 (en) * 2019-11-14 2022-09-06 Biomarin Pharm Inc TREATMENT OF HEREDITARY ANGIOEDEMA WITH LIVER-SPECIFIC GENE THERAPY VECTORS
US20230016983A1 (en) 2019-11-19 2023-01-19 lNSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) Antisense oligonucleotides and thier use for the treatment of cancer
KR20220107222A (en) 2019-11-28 2022-08-02 리젠엑스바이오 인크. Microdystrophin gene therapy constructs and uses thereof
CA3156611A1 (en) 2019-12-18 2021-06-24 Serge Braun Production of recombinant viral vectors from plant hairy roots
TW202140791A (en) 2020-01-13 2021-11-01 美商霍蒙拉奇醫藥公司 Methods of treating phenylketonuria
IL294638A (en) 2020-01-29 2022-09-01 Regenxbio Inc Treatment of mucopolysaccharidosis iva
EP3892720A1 (en) 2020-04-06 2021-10-13 Innovative Cellular Therapeutics Holdings, Ltd. Presenting cell and use thereof in cell therapy
WO2021229255A1 (en) 2020-05-14 2021-11-18 Genethon Tools and method for preventing a a¥ neutralization by antibodies
EP3913060A1 (en) 2020-05-22 2021-11-24 Genethon Vectors encoding a glucose-6-phosphatase (g6pase-a) for gene therapy
JP2023540429A (en) 2020-07-10 2023-09-25 アンセルム（アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル） Methods and compositions for treating epilepsy
US20230313152A1 (en) 2020-08-24 2023-10-05 Genethon C-terminal truncated gde for the treatment of glycogen storage disease iii
WO2022060915A1 (en) 2020-09-15 2022-03-24 Regenxbio Inc. Vectorized lanadelumab and administration thereof
EP4214242A1 (en) 2020-09-15 2023-07-26 RegenxBio Inc. Vectorized antibodies for anti-viral therapy
WO2022076750A2 (en) 2020-10-07 2022-04-14 Regenxbio Inc. Recombinant adeno-associated viruses for cns or muscle delivery
WO2022076711A2 (en) 2020-10-07 2022-04-14 Regenxbio Inc. Adeno-associated viruses for ocular delivery of gene therapy
EP4229204A1 (en) 2020-10-15 2023-08-23 F. Hoffmann-La Roche AG Nucleic acid constructs for simultaneous gene activation
CA3197730A1 (en) 2020-10-15 2022-04-21 F. Hoffman-La Roche Ag Nucleic acid constructs for va rna transcription
WO2022094157A1 (en) 2020-10-28 2022-05-05 Regenxbio Inc. Vectorized anti-cgrp and anti-cgrpr antibodies and administration thereof
CN116528892A (en) 2020-10-28 2023-08-01 再生生物股份有限公司 Supported anti-TNF-alpha antibodies for ocular indications
WO2022094295A1 (en) 2020-10-29 2022-05-05 Regenxbio Inc. Vectorized tnf-alpha antagonists for ocular indications
WO2022094255A2 (en) 2020-10-29 2022-05-05 Regenxbio Inc. Vectorized factor xii antibodies and administration thereof
AU2021375404A1 (en) 2020-11-03 2023-06-08 Pfizer Inc. Methods for purification of aav vectors by anion exchange chromatography
WO2022122883A1 (en) 2020-12-09 2022-06-16 Genethon Lysosomal acid lipase variants and uses thereof
US20240052322A1 (en) 2020-12-15 2024-02-15 Pfizer Inc. HILIC UPLC-MS Method For Separating and Analyzing Intact Adeno-Associated Virus Capsid Proteins
CN116761892A (en) 2020-12-16 2023-09-15 再生生物股份有限公司 Method for producing recombinant adeno-associated virus particles
US20240043869A1 (en) 2020-12-23 2024-02-08 Pfizer Inc. Methods for purification of aav vectors by affinity chromatography
TW202241943A (en) 2020-12-29 2022-11-01 美商銳進科斯生物股份有限公司 Tau-specific antibody gene therapy compositions, methods and uses thereof
EP4281568A1 (en) 2021-01-21 2023-11-29 RegenxBio Inc. Improved production of recombinant polypeptides and viruses
AR125143A1 (en) 2021-03-19 2023-06-14 Adrenas Therapeutics Inc GENE THERAPIES FOR 21-HYDROXYLASE DEFICIENCY
WO2022208342A1 (en) 2021-04-01 2022-10-06 Pfizer Inc. Pharmaceutical compositions containing adeno-associated viral vector
JP2024515626A (en) * 2021-04-16 2024-04-10 アスクレピオス バイオファーマシューティカル， インコーポレイテッド Rational polyploid aav virions that cross the blood-brain barrier and elicit reduced humoral responses
CA3216420A1 (en) 2021-04-26 2022-11-03 Seungil Han Adeno-associated viral vector capsids with improved tissue tropism
KR20240004564A (en) 2021-04-26 2024-01-11 리젠엑스바이오 인크. Administration of microdystrophin gene therapy for the treatment of dystrophinopathy
EP4334454A2 (en) 2021-05-04 2024-03-13 RegenxBio Inc. Novel aav vectors and methods and uses thereof
EP4337267A1 (en) 2021-05-11 2024-03-20 RegenxBio Inc. Treatment of duchenne muscular dystrophy and combinations thereof
KR20240023638A (en) 2021-06-22 2024-02-22 화이자 인코포레이티드 Production of Adeno-Associated Viral Vectors in Insect Cells
WO2023004331A1 (en) 2021-07-19 2023-01-26 New York University Auf1 combination therapies for treatment of muscle degenerative disease
AR126839A1 (en) * 2021-08-20 2023-11-22 Llc «Anabion» MODIFIED VP1 CAPSID PROTEIN ISOLATED FROM ADENO-ASSOCIATED VIRUS SEROTYPE 9 (AAV9), CAPSID AND VECTOR BASED ON THIS
AR126840A1 (en) * 2021-08-20 2023-11-22 Llc «Anabion» MODIFIED VP1 CAPSID PROTEIN ISOLATED FROM ADENO-ASSOCIATED VIRUS SEROTYPE 5 (AAV5), CAPSID AND VECTOR BASED ON THIS
WO2023060113A1 (en) 2021-10-05 2023-04-13 Regenxbio Inc. Compositions and methods for recombinant aav production
WO2023060272A2 (en) 2021-10-07 2023-04-13 Regenxbio Inc. Recombinant adeno-associated viruses for cns tropic delivery
WO2023060269A1 (en) 2021-10-07 2023-04-13 Regenxbio Inc. Recombinant adeno-associated viruses for targeted delivery
WO2023060264A1 (en) * 2021-10-08 2023-04-13 Dyno Therapeutics, Inc. Capsid variants and methods of using the same
WO2023069979A1 (en) 2021-10-20 2023-04-27 University Of Rochester Isolated glial progenitor cells for use in the competition treatment of age-related white matter loss
WO2023077092A1 (en) 2021-10-28 2023-05-04 Regenxbio Inc. Engineered nucleic acid regulatory elements and methods and uses thereof
WO2023081633A1 (en) 2021-11-02 2023-05-11 University Of Rochester Tcf7l2 mediated remyelination in the brain
WO2023114816A1 (en) 2021-12-14 2023-06-22 Neurogene, Inc. Recombinant optimized galc constructs and methods for treating galc-associated disorders
EP4215245A1 (en) 2022-01-19 2023-07-26 Innovative Cellular Therapeutics Holdings, Ltd. Enhanced chimeric antigen receptor cells in hypoxic tumor microenvironment
WO2023139496A1 (en) 2022-01-21 2023-07-27 Pfizer Inc. Gene therapy for gaucher disease
GB202201242D0 (en) 2022-01-31 2022-03-16 Univ Edinburgh Recombinant optimized mecp2 cassettes and methods for treating rett syndrome and related disorders
TW202346590A (en) 2022-03-13 2023-12-01 美商銳進科斯生物股份有限公司 Modified muscle-specific promoters
WO2023178220A1 (en) 2022-03-16 2023-09-21 Regenxbio Inc. Compositions and methods for recombinant aav production
WO2023183623A1 (en) 2022-03-25 2023-09-28 Regenxbio Inc. Dominant-negative tumor necrosis factor alpha adeno-associated virus gene therapy
WO2023198685A1 (en) 2022-04-13 2023-10-19 F. Hoffmann-La Roche Ag Method for determining aav genomes
WO2023201308A1 (en) 2022-04-14 2023-10-19 Regenxbio Inc. Gene therapy for treating an ocular disease
WO2023201277A1 (en) 2022-04-14 2023-10-19 Regenxbio Inc. Recombinant adeno-associated viruses for cns tropic delivery
GB202206336D0 (en) 2022-04-29 2022-06-15 Univ Edinburgh Recombinant therapeutic FMR1 constructs and methods of treating fragile X syndrome and related disorders
TW202400803A (en) 2022-05-03 2024-01-01 美商銳進科斯生物股份有限公司 Vectorized anti-complement antibodies and complement agents and administration thereof
WO2023215807A1 (en) 2022-05-03 2023-11-09 Regenxbio Inc. VECTORIZED ANTI-TNF-α INHIBITORS FOR OCULAR INDICATIONS
WO2023227438A1 (en) 2022-05-23 2023-11-30 F. Hoffmann-La Roche Ag Raman-based method for the differentiation of aav particle serotype and aav particle loading status
WO2023232922A1 (en) 2022-06-03 2023-12-07 F. Hoffmann-La Roche Ag Method for producing recombinant aav particles
WO2023239627A2 (en) 2022-06-08 2023-12-14 Regenxbio Inc. Methods for recombinant aav production
WO2023237731A1 (en) 2022-06-09 2023-12-14 Genethon N-terminal truncated gde for the treatment of glycogen storage disease iii
WO2024003687A1 (en) 2022-06-28 2024-01-04 Pfizer Inc. Nucleic acids encoding acid alpha-glucosidase (gaa) and vectors for gene therapy
WO2024013239A1 (en) 2022-07-14 2024-01-18 F. Hoffmann-La Roche Ag Method for producing recombinant aav particles
WO2024017990A1 (en) 2022-07-21 2024-01-25 Institut National de la Santé et de la Recherche Médicale Methods and compositions for treating chronic pain disorders
WO2024038002A1 (en) 2022-08-15 2024-02-22 F. Hoffmann-La Roche Ag Prevention or mitigation of adverse effects related to recombinant viral vectors
WO2024038365A1 (en) 2022-08-16 2024-02-22 Pfizer Inc. Methods for purification of aav vectors by anion exchange chromatography
WO2024044725A2 (en) 2022-08-24 2024-02-29 Regenxbio Inc. Recombinant adeno-associated viruses and uses thereof
WO2024056561A1 (en) 2022-09-12 2024-03-21 F. Hoffmann-La Roche Ag Method for separating full and empty aav particles

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1202962A (en) 1982-10-19 1986-04-08 David P. Clifford Substituted n-phenyl-n'-benzoyl ureas and their use as insecticides and acaricides
US4965188A (en) 1986-08-22 1990-10-23 Cetus Corporation Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
EP0931158A1 (en) 1996-09-06 1999-07-28 The Trustees Of The University Of Pennsylvania An inducible method for production of recombinant adeno-associated viruses utilizing t7 polymerase
US6156303A (en) 1997-06-11 2000-12-05 University Of Washington Adeno-associated virus (AAV) isolates and AAV vectors derived therefrom
WO1999003496A1 (en) 1997-07-21 1999-01-28 The University Of North Carolina At Chapel Hill Factor ix antihemophilic factor with increased clotting activity
US6468524B1 (en) 2000-03-22 2002-10-22 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services AAV4 vector and uses thereof
US20080220015A1 (en) 2001-08-03 2008-09-11 Nokad, S.A. Method of modulating neutralizing antibodies formation in mammals, and uses thereof in gene therapy, animal trangenesis and in functional inactivation of endogenous proteins
US20030138772A1 (en) 2001-11-13 2003-07-24 Guangping Gao Method of detecting and/or identifying adeno-associated virus (AAV) sequences and isolating novel sequences identified thereby
PT1453547T (en) * 2001-12-17 2016-12-28 Univ Pennsylvania Adeno-associated virus (aav) serotype 8 sequences, vectors containing same, and uses therefor
WO2003082195A2 (en) 2002-03-22 2003-10-09 Board Of Regents, The University Of Texas System Protamine-adenoviral vector complexes and methods of use
ATE405295T1 (en) 2002-05-01 2008-09-15 Univ Florida IMPROVED RAAV EXPRESSION SYSTEMS FOR GENETIC MODIFICATION OF SPECIFIC CAPSID PROTEINS
HUE034785T2 (en) * 2003-06-19 2018-02-28 Genzyme Corp AAV virions with decreased immunoreactivity and uses therefor
CA2580189C (en) 2004-09-29 2013-05-21 Children's Memorial Hospital Sirna-mediated gene silencing of alpha synuclein
ES2580044T3 (en) * 2005-04-07 2016-08-18 The Trustees Of The University Of Pennsylvania Method of increasing the function of an AAV vector
EP2007795B1 (en) 2006-03-30 2016-11-16 The Board Of Trustees Of The Leland Stanford Junior University Aav capsid proteins
WO2008027084A2 (en) 2006-04-28 2008-03-06 The Trustees Of The University Of Pennsylvania Modified aav vectors having reduced capsid immunogenicity and use thereof
GB0911870D0 (en) 2009-07-08 2009-08-19 Ucl Business Plc Optimised coding sequence and promoter
ES2911185T3 (en) 2010-04-23 2022-05-18 Univ Florida rAAV-guanylate cyclase compositions and methods for treating Leber congenital amaurosis 1 (LCA1)
EP3536781A1 (en) 2010-04-23 2019-09-11 University of Massachusetts Cns targeting aav vectors and methods of use thereof
US8609088B2 (en) * 2011-05-10 2013-12-17 Regents Of The University Of Minnesota Intranasal delivery of therapeutic enzymes to the central nervous system for the treatment of lysosomal storage diseases
WO2013078400A1 (en) * 2011-11-22 2013-05-30 The Children's Hospital Of Philadelphia Virus vectors for highly efficient transgene delivery
US9434928B2 (en) 2011-11-23 2016-09-06 Nationwide Children's Hospital, Inc. Recombinant adeno-associated virus delivery of alpha-sarcoglycan polynucleotides
HUE043537T2 (en) 2012-02-15 2019-08-28 Bioverativ Therapeutics Inc Recombinant factor viii proteins
SG11201404956PA (en) 2012-02-17 2014-09-26 Philadelphia Children Hospital Aav vector compositions and methods for gene transfer to cells, organs and tissues
BR122021020419B1 (en) * 2012-04-18 2023-01-17 The Children's Hospital Of Philadelphia ADENO-ASSOCIATED VIRUS (AAV) VECTOR COMPRISING A VP1 CAPSID PROTEIN, PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME, AND USES THEREOF
US20140271550A1 (en) 2013-03-14 2014-09-18 The Trustees Of The University Of Pennsylvania Constructs and Methods for Delivering Molecules via Viral Vectors with Blunted Innate Immune Responses
MX2018000307A (en) 2015-06-23 2018-05-02 Childrens Hospital Philadelphia Modified factor ix, and compositions, methods and uses for gene transfer to cells, organs and tissues.

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