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NZ747049B2 - Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy - Google Patents
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NZ747049B2 - Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy - Google Patents

Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy

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Publication number
NZ747049B2
NZ747049B2 NZ747049A NZ74704917A NZ747049B2 NZ 747049 B2 NZ747049 B2 NZ 747049B2 NZ 747049 A NZ747049 A NZ 747049A NZ 74704917 A NZ74704917 A NZ 74704917A NZ 747049 B2 NZ747049 B2 NZ 747049B2
Authority
NZ
New Zealand
Prior art keywords
recombinant
vector
seq
muscle
composition
Prior art date
Application number
NZ747049A
Other versions
NZ747049A (en
Inventor
Jerry R Mendell
Klapac Louise Rodino
Original Assignee
Research Institute At Nationwide Children's Hospital
Filing date
Publication date
Application filed by Research Institute At Nationwide Children's Hospital filed Critical Research Institute At Nationwide Children's Hospital
Priority to NZ787316A priority Critical patent/NZ787316B2/en
Priority claimed from PCT/US2017/027636 external-priority patent/WO2017181015A1/en
Publication of NZ747049A publication Critical patent/NZ747049A/en
Publication of NZ747049B2 publication Critical patent/NZ747049B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/761—Adenovirus
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1719—Muscle proteins, e.g. myosin or actin
    • 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
    • A61K48/0008—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 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4707—Muscular dystrophy
    • C07K14/4708—Duchenne dystrophy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N15/65—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression using markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
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    • 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
    • C12N15/864—Parvoviral vectors, e.g. parvovirus, densovirus
    • C12N15/8645—Adeno-associated virus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy
    • C—CHEMISTRY; METALLURGY
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    • C12N2330/00—Production
    • C12N2330/50—Biochemical production, i.e. in a transformed host cell
    • C12N2330/51—Specially adapted vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
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    • C12N2800/00—Nucleic acids vectors
    • C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
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    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof

Abstract

The invention provides for recombinant AAV vectors comprising a miniaturized human micro-dystrophin gene and methods of using the recombinant vectors to reduce or prevent fibrosis in subjects suffering from muscular dystrophy.

Claims (15)

What is claimed:
1. A recombinant AAVrh74 vector comprising a muscle specific-control element operably linked to the nucleotide sequence of SEQ ID NO: 7.
2. A recombinant AAVrh74 vector comprising a muscle specific-control element operably linked to a nucleotide sequence encoding an amino acid sequence of SEQ ID NO: 8.
3. The recombinant AAVrh74 vector of claim 1 or claim 2, wherein the musclespecific control element is derived from muscle creatine kinase (MCK).
4. The recombinant AAVrh7.4 vector of any one of claims 1-3, further comprising in the 5’ to 3’ direction, a first ed terminal repeat (ITR), a chimeric intron sequence, a poly A tail, and a second ITR, wherein said muscle specific control element is located between the first ITR and the chimeric intron sequence, and wherein said tide sequence is located between the chimeric intron sequence and the poly A tail.
5. The recombinant AAVrh74 vector of any one of claims 1-4, wherein the muscle-specific l element comprises the nucleotide sequence of SEQ ID NO: 10 or SEQ ID NO: 11.
6. The recombinant AAVrh74 vector of claim 4, wherein the ic intron ce is set forth as nucleotides 844-993 of SEQ ID NO:9.
7. The recombinant AAVrh74 vector of claim 4 or claim 6, wherein the sequence of said poly A tail is set forth as tides 4585 to 4640 of SEQ ID NO:9.
8. A composition comprising the recombinant AAVrh7.4 vector of any one of claims 1-7 and a ceutically acceptable carrier.
9. Use of the recombinant AAVrh7.4 vector of any one of claims 1-7 or the composition of claim 8, for the preparation of a medicament for ent of muscular dystrophy.
10. Use of a recombinant AAVrh7.4 vector of any one of claims 1-7 or the composition of claim 8 for the preparation of a medicament for reducing or preventing fibrosis in a subject suffering from muscular dystrophy.
11. Use of the recombinant .4 vector of any one of claims 1-7 or the composition of claim 8 for the preparation of a medicament for the increasing muscular strength or muscle mass in a subject suffering from muscular dystrophy.
12. The use of any one of claims 9-11, wherein the ment is formulated for stration before fibrosis is observed in the subject or before muscle force is reduced in the subject or before muscle mass is reduced in the subject.
13. The use of any one of claims 9-12, wherein the subject is suffering from Duchenne muscular dystrophy or Becker ar dystrophy.
14. The composition or use of any one of claims 9-13, wherein the composition or medicament is formulated for intramuscular administration, intravenous injection, parental administration or systemic administration.
15. A method of producing a functional micro-dystrophin protein comprising infecting an ex vivo host cell with the recombinant AAVrh7.4 vector of any one of claims 1-7 and sing a functional micro-dystrophin protein in the host cell. s-cAéV?§1.7&CMV.miR2-9C SEQ ID NO: 2: miR-29C IN A miR-30 BACKBONE —GGCCGGCCtgmgqgtgagggéécggtqgttéetcagqgt?i??gQTGEAEATQTTQGAAAQAQTTQQTGQQATTAQT. TCTTCAGGTTAACCCAACAGAAGGCTCGAGAAGGTATATTGCTGTTGACAGTGAGCGCAACCGA MMAAATT TA A T AA A A AT TSTAGEA_C_QAT_T_T_G_AAA_T_C_9_G_T_T_AT.GC.QTACTG. FSE-I cut site (restriction site) miR.-.3Q.hackh9ne 'B-é? ! £9192 agggagagalg- @912 ?g. 51 IlliB:226_glli£1_eiaIltiSSLl§Q§£lLalli LTGTAECA_C_C_ATT_T_G_AAA_T_C_G9_T_T_A_;_S_EQ_ID_N9_= .4) Predicted hairpin structure (SEQ ID NO:6) G UUGA A C ----- 1=k “'U CUG CAGUG GCG MMWQWQWMGWA GUG A |||| ||||||||||||||||||||||||||||||| ||| > ---A GGC GUCAU CGU y?qggy?ggqgegqeggaqcv _CACG A UCC C I} GUAGA C a - ggc ucc ”N u m;R~29C ucummaca use: ugaccgauuuc u cagag (1 HM”!!! H HHiHHH HHiH ilHiu gggggaugu gu auuggcuaaag accacge guuuu g a 3 mm mm ecu u 3 us ~~~w~ a A gcg cuguaaacaucs gacuggaagcu gag a ““3303 m mmmm Hmmm m cgu ugtagg cugacuuncgg can g C ~"‘ g?d?’n c «WWus . mum A c i m A Sh R NA“m: R ( i U C} out; mama ace cgamma».mmucumuumm cm; A (sec mew Geo wcaemmwuuau (”As <3 “WNW”: um <3 lu‘
NZ747049A 2017-04-14 Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy NZ747049B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ787316A NZ787316B2 (en) 2017-04-14 Adeno-Associated Virus Vector Delivery of Micro-Dystrophin to Treat Muscular Dystrophy

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662323163P 2016-04-15 2016-04-15
US201762473253P 2017-03-17 2017-03-17
PCT/US2017/027636 WO2017181015A1 (en) 2016-04-15 2017-04-14 Adeno-associated virus vector delivery of micro-dystrophin to treat muscular dystrophy

Publications (2)

Publication Number Publication Date
NZ747049A NZ747049A (en) 2025-10-31
NZ747049B2 true NZ747049B2 (en) 2026-02-03

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