JP6938459B2 - エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 - Google Patents
エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 Download PDFInfo
- Publication number
- JP6938459B2 JP6938459B2 JP2018241945A JP2018241945A JP6938459B2 JP 6938459 B2 JP6938459 B2 JP 6938459B2 JP 2018241945 A JP2018241945 A JP 2018241945A JP 2018241945 A JP2018241945 A JP 2018241945A JP 6938459 B2 JP6938459 B2 JP 6938459B2
- Authority
- JP
- Japan
- Prior art keywords
- raav
- aav
- genome
- exon
- capsids
- 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.)
- Active
Links
- 108091026823 U7 small nuclear RNA Proteins 0.000 title claims description 40
- 241000702421 Dependoparvovirus Species 0.000 title claims description 13
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 claims description 37
- 108090000623 proteins and genes Proteins 0.000 claims description 26
- 210000003205 muscle Anatomy 0.000 claims description 24
- 230000006872 improvement Effects 0.000 claims description 23
- 210000000234 capsid Anatomy 0.000 claims description 19
- 108020004414 DNA Proteins 0.000 claims description 16
- 102000004169 proteins and genes Human genes 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000002773 nucleotide Substances 0.000 claims description 11
- 125000003729 nucleotide group Chemical group 0.000 claims description 11
- 230000004220 muscle function Effects 0.000 claims description 9
- 108700024394 Exon Proteins 0.000 claims description 7
- 241000580270 Adeno-associated virus - 4 Species 0.000 claims description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 2
- 238000000034 method Methods 0.000 description 56
- 210000004027 cell Anatomy 0.000 description 51
- 241000699670 Mus sp. Species 0.000 description 24
- 239000013598 vector Substances 0.000 description 17
- 239000013612 plasmid Substances 0.000 description 16
- 108010069091 Dystrophin Proteins 0.000 description 14
- 102000001039 Dystrophin Human genes 0.000 description 13
- 241000700605 Viruses Species 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 230000000692 anti-sense effect Effects 0.000 description 9
- 201000006938 muscular dystrophy Diseases 0.000 description 9
- 238000004806 packaging method and process Methods 0.000 description 9
- 241000701161 unidentified adenovirus Species 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 8
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 238000003757 reverse transcription PCR Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 102100021244 Integral membrane protein GPR180 Human genes 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 210000002950 fibroblast Anatomy 0.000 description 6
- 238000010255 intramuscular injection Methods 0.000 description 6
- 239000007927 intramuscular injection Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- 101001023030 Toxoplasma gondii Myosin-D Proteins 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 101150015424 dmd gene Proteins 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 238000010172 mouse model Methods 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 210000002027 skeletal muscle Anatomy 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 230000001605 fetal effect Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 210000000663 muscle cell Anatomy 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 229960004618 prednisone Drugs 0.000 description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 4
- 239000013645 rAAV1 vector Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000013607 AAV vector Substances 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 101100524324 Adeno-associated virus 2 (isolate Srivastava/1982) Rep78 gene Proteins 0.000 description 3
- 101150044789 Cap gene Proteins 0.000 description 3
- 108090000565 Capsid Proteins Proteins 0.000 description 3
- 102100023321 Ceruloplasmin Human genes 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000007838 multiplex ligation-dependent probe amplification Methods 0.000 description 3
- 239000013608 rAAV vector Substances 0.000 description 3
- 101150066583 rep gene Proteins 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 241000972680 Adeno-associated virus - 6 Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108090000362 Lymphotoxin-beta Proteins 0.000 description 2
- 241000282560 Macaca mulatta Species 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108020005067 RNA Splice Sites Proteins 0.000 description 2
- 108010017842 Telomerase Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000002459 blastocyst Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 230000036973 muscularity Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 101150042523 myod gene Proteins 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- 208000018360 neuromuscular disease Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000014621 translational initiation Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 1
- 241001164825 Adeno-associated virus - 8 Species 0.000 description 1
- 101100524319 Adeno-associated virus 2 (isolate Srivastava/1982) Rep52 gene Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102400000309 Beta-dystroglycan Human genes 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102100036912 Desmin Human genes 0.000 description 1
- 108010044052 Desmin Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 108010071885 Dystroglycans Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241001135569 Human adenovirus 5 Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010059343 MM Form Creatine Kinase Proteins 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100031790 Myelin expression factor 2 Human genes 0.000 description 1
- 101710107751 Myelin expression factor 2 Proteins 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 1
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 108010066816 Polypeptide N-acetylgalactosaminyltransferase Proteins 0.000 description 1
- 101100409194 Rattus norvegicus Ppargc1b gene Proteins 0.000 description 1
- 101150076399 Rep78 gene Proteins 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010043268 Tension Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010065729 Troponin I Proteins 0.000 description 1
- 102000011856 Utrophin Human genes 0.000 description 1
- 108010075653 Utrophin Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960001145 deflazacort Drugs 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000005045 desmin Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 1
- 229960004359 iodixanol Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- -1 phosphorodiamidate morpholinoethanol Chemical compound 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 208000026526 progressive weakness Diseases 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
Images
Classifications
-
- 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
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- 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
- 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
-
- 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
- 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
- C12N15/11—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
- 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
- C12N15/11—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
- 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
- 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
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- 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
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
- C12N2320/32—Special delivery means, e.g. tissue-specific
-
- 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
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
- C12N2320/33—Alteration of splicing
-
- 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
- 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
- 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
- C12N2750/14132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- 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
- 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
- C12N2750/14171—Demonstrated in vivo effect
-
- 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
- C12N2750/14311—Parvovirus, e.g. minute virus of mice
- C12N2750/14321—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
- C12N2750/14311—Parvovirus, e.g. minute virus of mice
- C12N2750/14333—Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
Description
発明の分野
録番号NC_1829で提供され;AAV−4の完全なゲノムは、GenBank登録番号NC_001829で提供され;AAV−5ゲノムは、GenBank登録番号AF085716で提供され;AAV−6の完全なゲノムは、GenBank登録番号NC_00 1862で提供され;AAV−7及びAAV−8ゲノムの少なくとも一部分は、それぞれ、GenBank登録番号AX753246及びAX753249で提供され(AAV−8に関する米国特許第7,282,199号及び同第7,790,449号を参照されたい);AAV−9ゲノムは、Gao et al., J. Virol., 78: 6381−6388 (2004)で提供され;AAV−10ゲノムは、Mol. Ther., 13(1): 67−76 (2006)で提供され;そしてAAV−11ゲノムは、Virology, 330(2): 375−383 (2004)Virology(330(2))で提供される。ここからウイルスDNA複製(rep)、カプシド形成/パッケージング、及び宿主細胞染色体組込みを指示するシス作用性配列が、AAV ITRs内に含有されている。3つのAAVプロモーター(p5、p19、及びp40、これらの相対的なマップ上の位置により命名された)は、repおよびcapの遺伝子をコードする2つのAAV内部のオープンリーディングフレームの発現を駆動する。1つのAAVイントロンのディファレンシャルスプライシング(ヌクレオチド2107及び2227における)と関連する2つのrepプロモーター(p5及びp19)により、rep遺伝子から4つのrepタンパク質(rep78、rep68、rep52、及びrep40)が生成する。Repタンパク質は、最終的にウイルスゲノムを複製する役割を果たす複数の酵素的特性を有する。cap遺伝子は、p40プロモーターから発現され、3つのカプシドタンパク質VP1、VP2、及びVP3をコードする。選択的スプライシング及び非コンセンサス翻訳開始部位は、3つの関連するカプシドタンパク質の生成を担う。1つのコンセンサスポリアデニル化部位は、AAVゲノムのマップ上の位置95に位置している。AAVの生活環および遺伝学は、Muzyczka, Current Topics in Microbiology and Immunology,
158: 97−129 (1992)で検討されている。
筋ジストロフィーは、個人、家族、及び地域に深刻な影響を与える確立された治療の無い一群の疾患である。コストは計り知れない。個人は、精神的緊張、及び自尊心の喪失と関連のある生活の質の低下に苦しむ。四肢機能の損失から生じる極度の肉体的問題により、日常生活の活動において困難が生じる。家族力動は、経済的損失及び対人関係の問題によって損なわれる。影響を受ける同胞は疎遠になり、配偶者間の不和は、特に、筋ジストロフィーに対する負担が親のパートナーの1人に負わせられる場合は、しばしば離婚となる。治療を見つけ出そうと探し求める負担は、しばしば、生活のすべての面を損ない且つ要求する、生涯にわたって続く非常に集中した苦労となる。家族を越えて、地域は、特別な教育、特別な輸送、そして再発性の呼吸器感染及び心臓合併症を治療するために繰り返し起こる入院の費用における筋ジストロフィー集団のハンディキャップに対処する更なる施設へのニーズを介して、経済的負担を分担する。経済的な負担は、州及び納税地域にまで負担を広げている連邦政府機関によって分担される。
従って、DMDを包含する筋ジストロフィーの治療に関して当該技術分野においてニーズが依然として存在する。
本発明は、DMD遺伝子のエクソン2の重複を包含しているDMDを防止するための、進行を遅延させるための、且つ/または治療するための方法及び生成物を提供する。本方法は、U7核内低分子RNAと、エクソン2標的アンチセンス配列とをコードするポリヌクレオチド構築物、すなわち「エクソン2標的U7snRNAポリヌクレオチド構築物」のための送達ベクターとしてAAVを用いることを包含している。例えば、ポリヌクレオチド構築物は、rAAV rh.74のゲノム、rAAV6のゲノム、またはrAAV9のゲノムに挿入される。AAV rh.74ゲノムのポリヌクレオチド配列は図7に配列番号1で示してある。
U7B TCAAAAGAAAACATTCACAAAATGGGTA(配列番号3);
U7Along GTTTTCTTTTGAAGATCTTCTCTTTCATcta(配列番号4);
U7Ashort AGATCTTCTCTTTCATcta(配列番号5);及びU7C GCACAATTTTCTAAGGTAAGAAT(配列番号6)
が挙げられるが、それらに限定されない。
rAAV U7_ACCAである。いくつかの実施形態では、rAAVはrAAV rh.74である。いくつかの実施形態では、rAAVはrAAV6である。いくつかの実施形態では、rAAVはrAAV9である。
Acad. Sci. USA, 88: 5680−5684 (1991)]、糖質コルチコイド応答エレメント(GRE)を包含するステロイド誘導エレメント及びプロモーター[Mader and White, Proc. Natl. Acad. Sci. USA, 90: 5603−5607 (1993)を参照されたい]及び他の制御エレメントが挙げられるが、それらに限定されない。
Opinions in Biotechnology, 1533−539;及びMuzyczka, 1992, Curr. Topics in Microbial. and Immunol., 158:97−129で検討されている。様々なアプローチは、Ratschin et al., Mol. Cell. Biol. 4:2072 (1984); Hermonat et al., Proc. Natl. Acad. Sci. USA, 81:6466 (1984); Tratschin et al., Mo1. Cell. Biol. 5:3251 (1985); McLaughlin et al., J. Virol., 62:1963 (1988);及びLebkowski et al., 1988 Mol. Cell. Biol., 7:349 (1988). Samulski et al. (1989, J. Virol., 63:3822−3828); 米国特許No. 5,173,414; WO 95/13365及び対応する米国特許No. 5,658.776 ; WO 95/13392; WO 96/17947; PCT/US98/18600; WO 97/09441 (PCT/US96/14423); WO 97/08298 (PCT/US96/13872); WO 97/21825 (PCT/US96/20777); WO 97/06243 (PCT/FR96/01064); WO 99/11764; Perrin et al.
(1995) Vaccine 13:1244−1250; Paul et al. (1993) Human Gene Therapy 4:609−615; Clark et al. (1996) Gene Therapy 3:1124−1132;米国特許No. 5,786,211; 米国特許No. 5,871,982;及び米国特許No. 6,258,595に記載されている。前記文書は、参照により本明細書に完全に組み込まれるものであって、前記文書のそれらのセクションにおいて特に重点的に記載されていることはrAAVの作製である。
vg、1x1011 vg、1x1012 vg、1x1013 vg、1x1014
vg)で表すこともできる。
以下の実施例によって本発明の態様及び実施形態を例示する。
実施例1
AAV rh.74の単離
実施例2
DMDモデル
DMDエクソン2重複のモデルとしては、例えば、以下のようなin vivo及びin vitroモデルが挙げられる。
mdxdup2マウスモデル
不死化された条件誘導性のfibroMyoD細胞株
一過性MyoD形質移入初代細胞株
実施例3
エクソン2重複突然変異に関するU7snRNA媒介スキッピングの効果
306(5702): 1796−1799 (2004) またはGoyenvalle et al., Mol. Ther., 20(6): 179601799 (2004)に記載されているU7snRNA系に比べて改良された。
U7B TCAAAAGAAAACATTCACAAAATGGGTA(配列番号:3)
U7Along GTTTTCTTTTGAAGATCTTCTCTTTCATcta(配列番号:4)
U7Ashort AGATCTTCTCTTTCATcta(配列番号:5)
U7C GCACAATTTTCTAAGGTAAGAAT(配列番号:6)
エクソン2標的配列を包含するU7snRNA構築物を作製した。各U7snRNA構築物は標的配列のうちの1つを包含していた。選択された他のエクソンを標的にしたU7snRNA構築物も(上記したMyoD−転化分化された細胞株研究に基づいて)作製した。次いで、U7snRNA構築物のうちの1つ以上を包含しているゲノムを有する自己相補的(SC)AAVベクターを作製した。
Ther., 10:1528−1534 (2003)]。アデノウイルスヘルパープラスミド(pAdhelper)は、高力価rAAVを作製するのに必要なアデノウイルス5型E2A、E4ORF6、及びVA I/II RNA遺伝子を発現する。
実施例4
AAV1によるU7−ACCAの筋肉内送達は、Dup2マウスにおいて有意なN短縮型ジストロフィン発現をもたらす。
実施例5
Dup2マウスモデルにおけるAAV9−U7_ACCAの静脈内注射は、N短縮型イソホルムの有意な発現と、筋力不足の矯正をもたらす。
vg/kgで尾静脈を介して注射した。注射は4週齢で行った。
本発明の実施形態において、例えば、以下の項目が提供される。
(項目1)
必要に応じてDMDエクソン2重複を有する患者のデュシェンヌ筋ジストロフィーを改善する方法であって、前記患者に対して組換えアデノ随伴ウイルス(rAAV)を投与する工程を含み、ここで前記rAAVのゲノムが少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含む、前記方法。
(項目2)
必要に応じてDMDエクソン2重複を有する患者のデュシェンヌ筋ジストロフィーと関連のあるジストロフィー症状の進行を阻害する方法であって、前記患者に対してrAAVを投与する工程を含み、ここで前記rAAVのゲノムが少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含む、前記方法。
(項目3)
DMDエクソン2重複と関連のあるデュシェンヌ筋ジストロフィーに罹患している患者の筋肉機能を改善する方法であって、前記患者に対してrAAVを投与する工程を含み、ここで前記rAAVのゲノムが少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含む、前記方法。
(項目4)
前記筋肉機能の改善が、筋力の改善である項目3記載の方法。
(項目5)
前記筋肉機能の改善が、立っている時と歩いている時の安定性の改善である項目3記載の方法。
(項目6)
前記ウイルスゲノムが、自己相補的ゲノムである項目1〜5のいずれかに記載の方法。
(項目7)
前記エクソン2標的U7snRNAポリヌクレオチド構築物が、U7Along、U7Ashort、U7B、U7C、またはそれらの2種以上の組み合わせである項目1〜6のいずれかに記載の方法。
(項目8)
前記組換えアデノ随伴ウイルスが、SC rAAV U7_ACCAである項目1〜7のいずれかに記載の方法。
(項目9)
DMDエクソン2重複を有する患者に対してエクソン2標的U7snRNAポリヌクレオチド構築物を送達する方法であって、前記患者に対してrAAVを投与する工程を含み、ここで前記rAAVのゲノムが少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含む、前記方法。
(項目10)
前記rAAVのゲノムが、AAV rep及びcap DNAを欠いている項目8記載の方法。
(項目11)
前記ウイルスゲノムが、自己相補的ゲノムである項目9記載の方法。
(項目12)
前記組換えアデノ随伴ウイルスが、SC rAAV U7_ACCAである項目9、10または11記載の方法。
(項目13)
前記組換えアデノ随伴ウイルスが、組換えAAV rh74ウイルス、組換えAAV6ウイルスまたは組換えAAV9ウイルスである項目12の方法。
(項目14)
少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含むゲノムを含む組換えアデノ随伴ウイルス(AAV)。
(項目15)
AAV rh.74カプシド、AAV6カプシドまたはAAV9カプシド;及び少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物を含むゲノムを含む組換えアデノ随伴ウイルス(AAV)。
(項目16)
前記ゲノムが、順番に、4つのエクソン2標的U7snRNAポリヌクレオチド構築物:第一U7Along、第一U7C、第二U7C、及び第二U7Alongを含む項目14または項目15記載の組換えアデノ随伴ウイルス(AAV)。
(項目17)
前記rAAVのゲノムが、AAV rep及びcap DNAを欠いている項目14、15、または16記載のrAAV。
(項目18)
前記ゲノムが、自己相補的ゲノムである項目14、15、または16記載のrAAV。
Claims (18)
- 少なくとも1つのエクソン2標的U7snRNAポリヌクレオチド構築物をコードするヌクレオチド配列を含むゲノムを含む組換えアデノ随伴ウイルス(rAAV)であって、前記ヌクレオチド配列は、配列番号6、7もしくは8またはそれらの2つ以上の組合せによって表される、rAAV。
- 前記ヌクレオチド配列が、配列番号6によって表される、請求項1に記載のrAAV。
- 前記ヌクレオチド配列が、配列番号7によって表される、請求項1に記載のrAAV。
- 前記ヌクレオチド配列が、配列番号8によって表される、請求項1に記載のrAAV。
- 前記rAAVのゲノムが、それぞれが配列番号7によって表される2つのエクソン2標的ヌクレオチド配列の組み合わせを含む、請求項1に記載のrAAV。
- 前記rAAVのゲノムが、それぞれが配列番号8によって表される2つのエクソン2標的ヌクレオチド配列の組み合わせを含む、請求項1に記載のrAAV。
- 前記rAAVのゲノムが、エクソン2標的U7snRNAポリヌクレオチド構築物をコードする4つのヌクレオチド配列を順番に含み、前記ゲノムが、配列番号7によって表される第一U7Alongヌクレオチド配列、配列番号8によって表される第一U7Cヌクレオチド配列、配列番号8によって表される第二U7Cヌクレオチド配列、及び配列番号7によって表される第二U7Alongヌクレオチド配列を含む、請求項1,5,及び6のいずれか一項に記載のrAAV。
- 前記rAAVが、rAAV rh.74、rAAV−1、rAAV−2、rAAV−3、rAAV−4、rAAV−5、rAAV−6、rAAV−7、rAAV−8、rAAV−9、rAAV−10またはrAAV−11である、請求項1〜7のいずれか一項に記載のrAAV。
- 前記rAAVが、rAAV rh.74、rAAV−8またはrAAV−9である、請求項8に記載のrAAV。
- AAV rh.74カプシド、AAV−1カプシド、AAV−2カプシド、AAV−3カプシド、AAV−4カプシド、AAV−5カプシド、AAV−6カプシド、AAV−7カプシド、AAV−8カプシド、AAV−9カプシド、AAV−10カプシドまたはAAV−11カプシドをさらに含む、請求項1〜9のいずれか一項に記載のrAAV。
- 前記rAAVのゲノムが、AAV rep及びcap DNAを欠いている、請求項1〜10のいずれか一項に記載のrAAV。
- 前記rAAVのゲノムが、自己相補的ゲノムまたは一本鎖ゲノムである、請求項1〜11のいずれか一項に記載のrAAV。
- デュシェンヌ筋ジストロフィー(DMD)の改善を必要とするDMDエクソン2重複を有する患者におけるデュシェンヌ筋ジストロフィーの改善において使用するための、請求項1〜12のいずれか一項に記載のrAAVを含む組成物。
- 前記改善が、前記患者においてデュシェンヌ筋ジストロフィーと関連のあるジストロフィー症状の進行を阻害する、請求項13に記載の組成物。
- 前記改善が、前記患者における筋肉機能を改善する、請求項13に記載の組成物。
- 前記筋肉機能の改善が、筋力の改善である、請求項15に記載の組成物。
- 前記筋肉機能の改善が、立っている時および歩いている時の安定性の改善である、請求項15に記載の組成物。
- 前記改善が、前記患者においてジスロトフィンタンパク質の発現の増大をもたらす、請求項13に記載の組成物。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021114275A JP2021169489A (ja) | 2013-04-20 | 2021-07-09 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
JP2023125933A JP2023139282A (ja) | 2013-04-20 | 2023-08-02 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361814256P | 2013-04-20 | 2013-04-20 | |
US61/814,256 | 2013-04-20 | ||
JP2016509136A JP6461917B2 (ja) | 2013-04-20 | 2014-04-18 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016509136A Division JP6461917B2 (ja) | 2013-04-20 | 2014-04-18 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021114275A Division JP2021169489A (ja) | 2013-04-20 | 2021-07-09 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019059787A JP2019059787A (ja) | 2019-04-18 |
JP6938459B2 true JP6938459B2 (ja) | 2021-09-22 |
Family
ID=50933493
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016509136A Active JP6461917B2 (ja) | 2013-04-20 | 2014-04-18 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
JP2018241945A Active JP6938459B2 (ja) | 2013-04-20 | 2018-12-26 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
JP2021114275A Pending JP2021169489A (ja) | 2013-04-20 | 2021-07-09 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
JP2023125933A Pending JP2023139282A (ja) | 2013-04-20 | 2023-08-02 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016509136A Active JP6461917B2 (ja) | 2013-04-20 | 2014-04-18 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021114275A Pending JP2021169489A (ja) | 2013-04-20 | 2021-07-09 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
JP2023125933A Pending JP2023139282A (ja) | 2013-04-20 | 2023-08-02 | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 |
Country Status (11)
Country | Link |
---|---|
US (3) | US9862945B2 (ja) |
EP (2) | EP3461838A1 (ja) |
JP (4) | JP6461917B2 (ja) |
KR (4) | KR102268473B1 (ja) |
CN (2) | CN109652385A (ja) |
AU (4) | AU2014253730B2 (ja) |
CA (2) | CA3201710A1 (ja) |
EA (2) | EA201990558A3 (ja) |
HK (1) | HK1221962A1 (ja) |
MX (2) | MX2015014712A (ja) |
WO (1) | WO2014172669A1 (ja) |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2206781B1 (en) | 2004-06-28 | 2015-12-02 | The University Of Western Australia | Antisense oligonucleotides for inducing exon skipping and methods of use thereof |
KR101958491B1 (ko) | 2009-11-12 | 2019-03-15 | 더 유니버시티 오브 웨스턴 오스트레일리아 | 안티센스 분자 및 이를 이용한 질환 치료방법 |
BR112015023001B8 (pt) | 2013-03-14 | 2022-08-09 | Sarepta Therapeutics Inc | Oligonucleotídeo antisenso, composição farmacêutica compreendendo o mesmo e uso da dita composição para o tratamento de distrofia muscular de duchenne (dmd) |
WO2014144978A2 (en) | 2013-03-15 | 2014-09-18 | Sarepta Therapeutics, Inc. | Improved compositions for treating muscular dystrophy |
CN109652385A (zh) | 2013-04-20 | 2019-04-19 | 全国儿童医院研究所 | 外显子2靶向U7snRNA多核苷酸构建体的重组腺相关病毒递送 |
SG11201509419QA (en) * | 2013-05-15 | 2015-12-30 | Univ Minnesota | Adeno-associated virus mediated gene transfer to the central nervous system |
WO2015191508A1 (en) | 2014-06-09 | 2015-12-17 | Voyager Therapeutics, Inc. | Chimeric capsids |
US11053494B2 (en) | 2014-08-09 | 2021-07-06 | Research Institute At Nationwide Children's Hospital | Methods and materials for activating an internal ribosome entry site in exon 5 of the DMD gene |
EP3215191A4 (en) | 2014-11-05 | 2018-08-01 | Voyager Therapeutics, Inc. | Aadc polynucleotides for the treatment of parkinson's disease |
CN107109407A (zh) | 2014-11-14 | 2017-08-29 | 沃雅戈治疗公司 | 治疗肌萎缩性侧索硬化(als)的组合物和方法 |
SG11201703419UA (en) | 2014-11-14 | 2017-05-30 | Voyager Therapeutics Inc | Modulatory polynucleotides |
US11697825B2 (en) | 2014-12-12 | 2023-07-11 | Voyager Therapeutics, Inc. | Compositions and methods for the production of scAAV |
EP3653216A1 (en) * | 2015-09-30 | 2020-05-20 | Sarepta Therapeutics, Inc. | Methods for treating muscular dystrophy |
WO2017136435A1 (en) | 2016-02-01 | 2017-08-10 | The Usa, As Represented By The Secretary, Department Of Health And Human Services Office Of Technology Transfer National Institute Of Health | Compounds for modulating fc-epsilon-ri-beta expression and uses thereof |
IL262211B2 (en) | 2016-04-15 | 2024-01-01 | Univ Pennsylvania | Gene therapy for the treatment of type II mucositis |
WO2017189964A2 (en) | 2016-04-29 | 2017-11-02 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
CA3024449A1 (en) | 2016-05-18 | 2017-11-23 | Voyager Therapeutics, Inc. | Compositions and methods of treating huntington's disease |
CN110214187B (zh) | 2016-05-18 | 2024-01-30 | 沃雅戈治疗公司 | 调节性多核苷酸 |
CN106086012A (zh) * | 2016-06-23 | 2016-11-09 | 百奥迈科生物技术有限公司 | 一种线性双链腺相关病毒基因组的体外制备方法 |
US11298041B2 (en) | 2016-08-30 | 2022-04-12 | The Regents Of The University Of California | Methods for biomedical targeting and delivery and devices and systems for practicing the same |
EP4245852A3 (en) * | 2017-03-17 | 2023-11-22 | Research Institute at Nationwide Children's Hospital | Adeno-associated virus vector delivery of muscle specific micro-dystrophin to treat muscular dystrophy |
SG11201909868YA (en) | 2017-05-05 | 2019-11-28 | Voyager Therapeutics Inc | Compositions and methods of treating huntington's disease |
EP3618839A4 (en) | 2017-05-05 | 2021-06-09 | Voyager Therapeutics, Inc. | COMPOSITIONS AND TREATMENT METHODS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) |
JOP20190269A1 (ar) | 2017-06-15 | 2019-11-20 | Voyager Therapeutics Inc | بولي نوكليوتيدات aadc لعلاج مرض باركنسون |
CN111132626B (zh) | 2017-07-17 | 2024-01-30 | 沃雅戈治疗公司 | 轨迹阵列引导系统 |
WO2019028306A2 (en) | 2017-08-03 | 2019-02-07 | Voyager Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR ADMINISTRATION OF ADENO-ASSOCIATED VIRUSES |
BR112020005249A2 (pt) | 2017-09-22 | 2020-09-24 | The Trustees Of The University Of Pennsylvania | terapia de gene para tratar mucopolissacaridose tipo ii |
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) |
US20210107948A1 (en) * | 2018-04-05 | 2021-04-15 | Genethon | Hybrid Recombinant Adeno-Associated Virus Serotype Between AAV9 and AAVrh74 with Reduced Liver Tropism |
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 |
CA3098565A1 (en) | 2018-04-29 | 2019-11-07 | Claire G. ZHANG | Scalable clarification process for recombinant aav production |
CN112469822A (zh) | 2018-06-14 | 2021-03-09 | 再生生物股份有限公司 | 用于重组aav生产的阴离子交换色谱 |
CA3108113A1 (en) | 2018-08-10 | 2020-02-13 | Michael GILLMEISTER | Scalable method for recombinant aav production |
EP3867412A1 (en) | 2018-10-15 | 2021-08-25 | REGENXBIO Inc. | Method for measuring the infectivity of replication defective viral vectors and viruses |
TW202102526A (zh) | 2019-04-04 | 2021-01-16 | 美商銳進科斯生物股份有限公司 | 重組腺相關病毒及其用途 |
HUE064411T2 (hu) | 2019-04-11 | 2024-03-28 | Regenxbio Inc | Méretkizárásos kromatográfiás módszerek rekombináns adeno-asszociált víruskészítmények jellemzésére |
EP4272817A3 (en) | 2019-04-19 | 2024-01-24 | RegenxBio Inc. | Adeno-associated virus vector formulations and methods |
AU2020262416A1 (en) | 2019-04-24 | 2021-12-16 | Regenxbio Inc. | Fully-human post-translationally modified antibody therapeutics |
WO2021005223A1 (en) | 2019-07-10 | 2021-01-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of epilepsy |
JP2022544004A (ja) | 2019-07-26 | 2022-10-17 | リジェネックスバイオ インコーポレイテッド | 操作された核酸調節エレメントならびにその使用方法 |
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 |
TW202134260A (zh) | 2019-11-28 | 2021-09-16 | 美商銳進科斯生物股份有限公司 | 微小肌縮蛋白基因療法之構築體及其用途 |
EP4143216A1 (en) | 2020-04-29 | 2023-03-08 | Bristol-Myers Squibb Company | Miniaturized dystrophins having spectrin fusion domains and uses thereof |
JP2023540429A (ja) | 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) | てんかんを治療するための方法及び組成物 |
EP4214242A1 (en) | 2020-09-15 | 2023-07-26 | RegenxBio Inc. | Vectorized antibodies for anti-viral therapy |
WO2022060915A1 (en) | 2020-09-15 | 2022-03-24 | Regenxbio Inc. | Vectorized lanadelumab and administration thereof |
AU2021349277A1 (en) * | 2020-09-28 | 2023-05-11 | Research Institute At Nationwide Children's Hospital | Products and methods for treating muscular dystrophy |
AU2021356667A1 (en) | 2020-10-07 | 2023-06-08 | Regenxbio Inc. | Adeno-associated viruses for ocular delivery of gene therapy |
WO2022076750A2 (en) | 2020-10-07 | 2022-04-14 | Regenxbio Inc. | Recombinant adeno-associated viruses for cns or muscle delivery |
CA3195967A1 (en) | 2020-10-28 | 2022-05-05 | Xu Wang | Vectorized anti-tnf-? antibodies for ocular indications |
WO2022094157A1 (en) | 2020-10-28 | 2022-05-05 | Regenxbio Inc. | Vectorized anti-cgrp and anti-cgrpr antibodies and administration thereof |
WO2022094255A2 (en) | 2020-10-29 | 2022-05-05 | Regenxbio Inc. | Vectorized factor xii antibodies and administration thereof |
EP4237453A1 (en) | 2020-10-29 | 2023-09-06 | RegenxBio Inc. | Vectorized tnf-alpha antagonists for ocular indications |
CA3201743A1 (en) | 2020-12-16 | 2022-06-23 | Robert STADELMAN | Method of producing a recombinant adeno-associated virus particle |
TW202241943A (zh) | 2020-12-29 | 2022-11-01 | 美商銳進科斯生物股份有限公司 | Tau特異性抗體基因療法組合物、方法及其用途 |
CN116848255A (zh) | 2021-01-21 | 2023-10-03 | 再生生物股份有限公司 | 改进的重组多肽和病毒的生产 |
CA3216744A1 (en) | 2021-04-26 | 2022-11-03 | Regenxbio Inc. | Microdystrophin gene therapy administration for treatment of dystrophinopathies |
WO2022235614A2 (en) | 2021-05-04 | 2022-11-10 | Regenxbio Inc. | Novel aav vectors and methods and uses thereof |
WO2022241030A1 (en) | 2021-05-11 | 2022-11-17 | Regenxbio Inc. | Treatment of duchenne muscular dystrophy and combinations thereof |
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 |
WO2023077092A1 (en) | 2021-10-28 | 2023-05-04 | Regenxbio Inc. | Engineered nucleic acid regulatory elements and methods and uses thereof |
EP4230196A1 (en) | 2022-02-21 | 2023-08-23 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of dystrophinopathies |
TW202346590A (zh) | 2022-03-13 | 2023-12-01 | 美商銳進科斯生物股份有限公司 | 經修飾之肌肉特異性啟動子 |
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 |
WO2023201277A1 (en) | 2022-04-14 | 2023-10-19 | Regenxbio Inc. | Recombinant adeno-associated viruses for cns tropic delivery |
TW202400803A (zh) | 2022-05-03 | 2024-01-01 | 美商銳進科斯生物股份有限公司 | 載體化抗補體抗體與補體劑及其投與 |
WO2023215807A1 (en) | 2022-05-03 | 2023-11-09 | Regenxbio Inc. | VECTORIZED ANTI-TNF-α INHIBITORS FOR OCULAR INDICATIONS |
GB202208384D0 (en) * | 2022-06-08 | 2022-07-20 | Ucl Business Ltd | Modified U7 snRNA construct |
WO2023239627A2 (en) | 2022-06-08 | 2023-12-14 | Regenxbio Inc. | Methods for recombinant aav production |
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 |
WO2024044725A2 (en) | 2022-08-24 | 2024-02-29 | Regenxbio Inc. | Recombinant adeno-associated viruses and uses thereof |
WO2024081746A2 (en) | 2022-10-11 | 2024-04-18 | Regenxbio Inc. | Engineered nucleic acid regulatory elements and methods and uses thereof |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5173414A (en) | 1990-10-30 | 1992-12-22 | Applied Immune Sciences, Inc. | Production of recombinant adeno-associated virus vectors |
AU688428B2 (en) | 1993-11-09 | 1998-03-12 | Johns Hopkins University, The | Generation of high titers of recombinant AAV vectors |
WO1995013392A1 (en) | 1993-11-09 | 1995-05-18 | Medical College Of Ohio | Stable cell lines capable of expressing the adeno-associated virus replication gene |
US5658785A (en) | 1994-06-06 | 1997-08-19 | Children's Hospital, Inc. | Adeno-associated virus materials and methods |
US5856152A (en) | 1994-10-28 | 1999-01-05 | The Trustees Of The University Of Pennsylvania | Hybrid adenovirus-AAV vector and methods of use therefor |
JPH10511264A (ja) | 1994-12-06 | 1998-11-04 | ターゲティッド ジェネティックス コーポレイション | 高力価組換えaavベクターの生成のためのパッケージング細胞株 |
FR2737730B1 (fr) | 1995-08-10 | 1997-09-05 | Pasteur Merieux Serums Vacc | Procede de purification de virus par chromatographie |
JPH11511326A (ja) | 1995-08-30 | 1999-10-05 | ジエンザイム コーポレイション | アデノウィルスおよびaavの精製 |
EP0850313B8 (en) | 1995-09-08 | 2009-07-29 | Genzyme Corporation | Improved aav vectors for gene therapy |
US5910434A (en) | 1995-12-15 | 1999-06-08 | Systemix, Inc. | Method for obtaining retroviral packaging cell lines producing high transducing efficiency retroviral supernatant |
DE69739860D1 (de) | 1996-09-06 | 2010-06-02 | Univ Pennsylvania | Rekombinante AAV zur Herstellung eines Medikaments für die Gentherapie von Muskelzellen |
DK1944362T3 (en) | 1997-09-05 | 2016-01-25 | Genzyme Corp | Fremgangsmåder til fremstilling af hjælpevirusfri præparater med høj titer af rekombinante AAV-vektorer |
US6566118B1 (en) | 1997-09-05 | 2003-05-20 | Targeted Genetics Corporation | Methods for generating high titer helper-free preparations of released recombinant AAV vectors |
US6258595B1 (en) | 1999-03-18 | 2001-07-10 | The Trustees Of The University Of Pennsylvania | Compositions and methods for helper-free production of recombinant adeno-associated viruses |
CA2406743A1 (en) | 2000-04-28 | 2001-11-08 | The Trustees Of The University Of Pennsylvania | Recombinant aav vectors with aav5 capsids and aav5 vectors pseudotyped in heterologous capsids |
ES2602352T3 (es) | 2001-12-17 | 2017-02-20 | The Trustees Of The University Of Pennsylvania | Secuencias de serotipo 8 de virus adenoasociado (VAA), vectores que las contienen y usos de las mismas |
AU2003207708A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
WO2004083432A1 (en) * | 2003-03-21 | 2004-09-30 | Academisch Ziekenhuis Leiden | Modulation of exon recognition in pre-mrna by interfering with the secondary rna structure |
FR2874384B1 (fr) | 2004-08-17 | 2010-07-30 | Genethon | Vecteur viral adeno-associe pour realiser du saut d'exons dans un gene codant une proteine a domaines dispensables |
CN101981189A (zh) * | 2008-01-29 | 2011-02-23 | 西马生物医学计划公司 | 能够以协同方式引起基因表达转录后沉默的方法和组合物 |
WO2009101399A1 (en) | 2008-02-12 | 2009-08-20 | Isis Innovation Limited | Treatment of muscular dystrophy using peptide nucleic acid ( pna) |
WO2010108126A2 (en) | 2009-03-19 | 2010-09-23 | Fate Therapeutics, Inc. | Reprogramming compositions and methods of using the same |
KR101958491B1 (ko) | 2009-11-12 | 2019-03-15 | 더 유니버시티 오브 웨스턴 오스트레일리아 | 안티센스 분자 및 이를 이용한 질환 치료방법 |
WO2011078797A2 (en) * | 2009-12-22 | 2011-06-30 | Singapore Health Services Pte. Ltd | Antisense oligonucleotides and uses threreof |
WO2011113889A1 (en) * | 2010-03-17 | 2011-09-22 | Association Institut De Myologie | Modified u7 snrnas for treatment of neuromuscular diseases |
IT1400425B1 (it) * | 2010-06-08 | 2013-05-31 | Amsterdam Molecular Therapeutics Bv | Modified snrnas for use in therapy. |
WO2013033407A2 (en) | 2011-08-30 | 2013-03-07 | The Regents Of The University Of California | Identification of small molecules that enhance therapeutic exon skipping |
CN109652385A (zh) | 2013-04-20 | 2019-04-19 | 全国儿童医院研究所 | 外显子2靶向U7snRNA多核苷酸构建体的重组腺相关病毒递送 |
-
2014
- 2014-04-18 CN CN201811631920.8A patent/CN109652385A/zh active Pending
- 2014-04-18 EA EA201990558A patent/EA201990558A3/ru unknown
- 2014-04-18 EP EP18192536.3A patent/EP3461838A1/en active Pending
- 2014-04-18 CN CN201480034373.9A patent/CN105324392A/zh active Pending
- 2014-04-18 US US14/785,769 patent/US9862945B2/en active Active
- 2014-04-18 KR KR1020157033190A patent/KR102268473B1/ko active IP Right Review Request
- 2014-04-18 KR KR1020227021096A patent/KR20220090593A/ko not_active Application Discontinuation
- 2014-04-18 CA CA3201710A patent/CA3201710A1/en active Pending
- 2014-04-18 EP EP14729770.9A patent/EP2986632B1/en active Active
- 2014-04-18 KR KR1020217018724A patent/KR102413498B1/ko active IP Right Grant
- 2014-04-18 EA EA201592014A patent/EA032706B1/ru unknown
- 2014-04-18 AU AU2014253730A patent/AU2014253730B2/en active Active
- 2014-04-18 CA CA2909807A patent/CA2909807C/en active Active
- 2014-04-18 KR KR1020237016263A patent/KR20230074604A/ko not_active Application Discontinuation
- 2014-04-18 MX MX2015014712A patent/MX2015014712A/es unknown
- 2014-04-18 JP JP2016509136A patent/JP6461917B2/ja active Active
- 2014-04-18 WO PCT/US2014/034702 patent/WO2014172669A1/en active Application Filing
-
2015
- 2015-10-20 MX MX2021002845A patent/MX2021002845A/es unknown
-
2016
- 2016-08-24 HK HK16110120.4A patent/HK1221962A1/zh not_active IP Right Cessation
-
2018
- 2018-07-11 US US16/032,744 patent/US11230707B2/en active Active
- 2018-12-13 AU AU2018278955A patent/AU2018278955B2/en active Active
- 2018-12-26 JP JP2018241945A patent/JP6938459B2/ja active Active
-
2020
- 2020-08-14 AU AU2020217441A patent/AU2020217441B2/en active Active
-
2021
- 2021-07-09 JP JP2021114275A patent/JP2021169489A/ja active Pending
- 2021-12-09 US US17/546,428 patent/US20230025574A1/en active Pending
-
2023
- 2023-01-13 AU AU2023200175A patent/AU2023200175A1/en active Pending
- 2023-08-02 JP JP2023125933A patent/JP2023139282A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6938459B2 (ja) | エクソン2標的U7snRNAポリヌクレオチド構築物の組換えアデノ随伴ウイルスによる送達 | |
JP6986444B2 (ja) | Dmd遺伝子のエクソン5内の内部リボソーム進入部位を活性化するための方法及び材料 | |
CA2839773C (en) | Recombinant virus products and methods for inhibition of expression of myotilin | |
JP2022046792A (ja) | 組織特異的発現のための改変u6プロモーターシステム | |
JP6966463B2 (ja) | 組換えウイルス産物及びdux4エクソンスキッピングを誘導するための方法 | |
JP2022543236A (ja) | エクソン44標的化核酸およびジストロフィンベースのミオパチーの治療のための当該核酸を含む組換えアデノ随伴ウイルス |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181226 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190904 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20191127 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200303 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200828 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201130 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20210310 |
|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20210531 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20210629 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210709 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20210709 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20210721 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20210727 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210824 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210901 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6938459 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |