TWI707951B - 過大腺相關載體之製造 - Google Patents
過大腺相關載體之製造 Download PDFInfo
- Publication number
- TWI707951B TWI707951B TW105110751A TW105110751A TWI707951B TW I707951 B TWI707951 B TW I707951B TW 105110751 A TW105110751 A TW 105110751A TW 105110751 A TW105110751 A TW 105110751A TW I707951 B TWI707951 B TW I707951B
- Authority
- TW
- Taiwan
- Prior art keywords
- aav
- raav
- genome
- aav2
- particles
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 133
- 239000013598 vector Substances 0.000 title description 234
- 239000002245 particle Substances 0.000 claims abstract description 337
- 238000000034 method Methods 0.000 claims abstract description 103
- 241000702421 Dependoparvovirus Species 0.000 claims abstract description 19
- 108700019146 Transgenes Proteins 0.000 claims description 110
- 102000001690 Factor VIII Human genes 0.000 claims description 106
- 108010054218 Factor VIII Proteins 0.000 claims description 106
- 229960000301 factor viii Drugs 0.000 claims description 103
- 150000007523 nucleic acids Chemical class 0.000 claims description 102
- 108090000623 proteins and genes Proteins 0.000 claims description 98
- 102000039446 nucleic acids Human genes 0.000 claims description 81
- 108020004707 nucleic acids Proteins 0.000 claims description 81
- 230000008488 polyadenylation Effects 0.000 claims description 59
- 241001655883 Adeno-associated virus - 1 Species 0.000 claims description 53
- 241001164825 Adeno-associated virus - 8 Species 0.000 claims description 51
- 230000006870 function Effects 0.000 claims description 48
- 239000013608 rAAV vector Substances 0.000 claims description 43
- 241001634120 Adeno-associated virus - 5 Species 0.000 claims description 39
- 241000972680 Adeno-associated virus - 6 Species 0.000 claims description 35
- 241001164823 Adeno-associated virus - 7 Species 0.000 claims description 33
- 241000649045 Adeno-associated virus 10 Species 0.000 claims description 33
- 238000002360 preparation method Methods 0.000 claims description 33
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 32
- 230000001225 therapeutic effect Effects 0.000 claims description 30
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 claims description 28
- 230000014509 gene expression Effects 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 108010006025 bovine growth hormone Proteins 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- 241000202702 Adeno-associated virus - 3 Species 0.000 claims description 24
- 241000580270 Adeno-associated virus - 4 Species 0.000 claims description 24
- 241000649046 Adeno-associated virus 11 Species 0.000 claims description 24
- 241000649047 Adeno-associated virus 12 Species 0.000 claims description 24
- 241000283690 Bos taurus Species 0.000 claims description 24
- 108010069091 Dystrophin Proteins 0.000 claims description 22
- 241000283707 Capra Species 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 102000057593 human F8 Human genes 0.000 claims description 14
- 239000013646 rAAV2 vector Substances 0.000 claims description 12
- 238000003146 transient transfection Methods 0.000 claims description 12
- 108091092195 Intron Proteins 0.000 claims description 11
- 241000288906 Primates Species 0.000 claims description 10
- 101100409194 Rattus norvegicus Ppargc1b gene Proteins 0.000 claims description 9
- 230000012010 growth Effects 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- 102000004168 Dysferlin Human genes 0.000 claims description 8
- 108090000620 Dysferlin Proteins 0.000 claims description 8
- 238000012258 culturing Methods 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 241000702423 Adeno-associated virus - 2 Species 0.000 claims 34
- 102000001039 Dystrophin Human genes 0.000 claims 7
- 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 claims 6
- 102000034356 gene-regulatory proteins Human genes 0.000 claims 2
- 108091006104 gene-regulatory proteins Proteins 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 230000009261 transgenic effect Effects 0.000 claims 1
- 239000013607 AAV vector Substances 0.000 abstract description 12
- 210000004027 cell Anatomy 0.000 description 242
- 241000700605 Viruses Species 0.000 description 122
- 230000008021 deposition Effects 0.000 description 81
- 108020004414 DNA Proteins 0.000 description 63
- 239000013612 plasmid Substances 0.000 description 62
- 238000004458 analytical method Methods 0.000 description 49
- 210000000234 capsid Anatomy 0.000 description 43
- 230000003612 virological effect Effects 0.000 description 42
- 101000772176 Mus musculus Transthyretin Proteins 0.000 description 38
- 238000013103 analytical ultracentrifugation Methods 0.000 description 36
- 239000000523 sample Substances 0.000 description 36
- 102100023419 Cystic fibrosis transmembrane conductance regulator Human genes 0.000 description 28
- 102100024108 Dystrophin Human genes 0.000 description 26
- 241000699666 Mus <mouse, genus> Species 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 108091033319 polynucleotide Proteins 0.000 description 21
- 102000040430 polynucleotide Human genes 0.000 description 21
- 239000002157 polynucleotide Substances 0.000 description 21
- 108091028043 Nucleic acid sequence Proteins 0.000 description 20
- 102000004196 processed proteins & peptides Human genes 0.000 description 20
- 108090000765 processed proteins & peptides Proteins 0.000 description 20
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 239000002751 oligonucleotide probe Substances 0.000 description 19
- 238000004806 packaging method and process Methods 0.000 description 19
- 229920001184 polypeptide Polymers 0.000 description 19
- 238000002105 Southern blotting Methods 0.000 description 18
- 238000003556 assay Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 238000001890 transfection Methods 0.000 description 17
- 241000701161 unidentified adenovirus Species 0.000 description 17
- 102100026735 Coagulation factor VIII Human genes 0.000 description 16
- 101001053946 Homo sapiens Dystrophin Proteins 0.000 description 16
- 239000012634 fragment Substances 0.000 description 16
- 239000002773 nucleotide Substances 0.000 description 16
- 125000003729 nucleotide group Chemical group 0.000 description 16
- 108090000565 Capsid Proteins Proteins 0.000 description 15
- 102100023321 Ceruloplasmin Human genes 0.000 description 15
- 238000005199 ultracentrifugation Methods 0.000 description 15
- 206010053567 Coagulopathies Diseases 0.000 description 14
- 238000002835 absorbance Methods 0.000 description 14
- 125000003275 alpha amino acid group Chemical group 0.000 description 14
- 238000009826 distribution Methods 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 13
- 201000003542 Factor VIII deficiency Diseases 0.000 description 13
- 208000009292 Hemophilia A Diseases 0.000 description 13
- 230000035602 clotting Effects 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 210000004185 liver Anatomy 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000002609 medium Substances 0.000 description 13
- 238000011529 RT qPCR Methods 0.000 description 12
- 239000012528 membrane Substances 0.000 description 11
- 101000907783 Homo sapiens Cystic fibrosis transmembrane conductance regulator Proteins 0.000 description 10
- 241000700584 Simplexvirus Species 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 10
- 230000000875 corresponding effect Effects 0.000 description 10
- 241000701022 Cytomegalovirus Species 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000002299 complementary DNA Substances 0.000 description 9
- 239000003623 enhancer Substances 0.000 description 9
- 230000001939 inductive effect Effects 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 9
- 125000000539 amino acid group Chemical group 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 238000012217 deletion Methods 0.000 description 8
- 230000037430 deletion Effects 0.000 description 8
- 230000029087 digestion Effects 0.000 description 8
- 230000002458 infectious effect Effects 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 230000010076 replication Effects 0.000 description 8
- 238000003151 transfection method Methods 0.000 description 8
- 239000013603 viral vector Substances 0.000 description 8
- 108091026890 Coding region Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 108010071690 Prealbumin Proteins 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000009190 Transthyretin Human genes 0.000 description 6
- 239000000306 component Substances 0.000 description 6
- 238000007405 data analysis Methods 0.000 description 6
- 229960000900 human factor viii Drugs 0.000 description 6
- 230000010354 integration Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 238000010361 transduction Methods 0.000 description 6
- 230000026683 transduction Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- 101150044789 Cap gene Proteins 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 230000008033 biological extinction Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 238000001415 gene therapy Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 238000004062 sedimentation Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 241000701447 unidentified baculovirus Species 0.000 description 5
- 108010089996 B-domain-deleted factor VIII Proteins 0.000 description 4
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 108700011259 MicroRNAs Proteins 0.000 description 4
- 241000714474 Rous sarcoma virus Species 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- -1 amino phosphate-phosphate diphosphate Ester Chemical class 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000011210 chromatographic step Methods 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000009396 hybridization Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000033001 locomotion Effects 0.000 description 4
- 239000002679 microRNA Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229950010131 puromycin Drugs 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 230000003362 replicative effect Effects 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 210000002845 virion Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
- 108090000994 Catalytic RNA Proteins 0.000 description 3
- 102000053642 Catalytic RNA Human genes 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 108010053770 Deoxyribonucleases Proteins 0.000 description 3
- 102000016911 Deoxyribonucleases Human genes 0.000 description 3
- 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 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 3
- 101710139464 Phosphoglycerate kinase 1 Proteins 0.000 description 3
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000003344 environmental pollutant Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000001502 gel electrophoresis Methods 0.000 description 3
- 230000009368 gene silencing by RNA Effects 0.000 description 3
- 102000056427 human CFTR Human genes 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000005499 meniscus Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 201000006938 muscular dystrophy Diseases 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 231100000719 pollutant Toxicity 0.000 description 3
- 101150066583 rep gene Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 108091092562 ribozyme Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 101001073212 Arabidopsis thaliana Peroxidase 33 Proteins 0.000 description 2
- 201000006935 Becker muscular dystrophy Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000007400 DNA extraction Methods 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 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 2
- 102100022054 Hepatocyte nuclear factor 4-alpha Human genes 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000933465 Homo sapiens Beta-glucuronidase Proteins 0.000 description 2
- 101001045740 Homo sapiens Hepatocyte nuclear factor 4-alpha Proteins 0.000 description 2
- 101001123325 Homo sapiens Peroxisome proliferator-activated receptor gamma coactivator 1-beta Proteins 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 241001135569 Human adenovirus 5 Species 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- 102000003792 Metallothionein Human genes 0.000 description 2
- 108090000157 Metallothionein Proteins 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- JZTPOMIFAFKKSK-UHFFFAOYSA-N O-phosphonohydroxylamine Chemical group NOP(O)(O)=O JZTPOMIFAFKKSK-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102100028961 Peroxisome proliferator-activated receptor gamma coactivator 1-beta Human genes 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 241000125945 Protoparvovirus Species 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- 108091030071 RNAI Proteins 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000701093 Suid alphaherpesvirus 1 Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 235000013405 beer Nutrition 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- FLJPGEWQYJVDPF-UHFFFAOYSA-L caesium sulfate Chemical compound [Cs+].[Cs+].[O-]S([O-])(=O)=O FLJPGEWQYJVDPF-UHFFFAOYSA-L 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 238000009295 crossflow filtration Methods 0.000 description 2
- 238000005137 deposition process Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000003306 harvesting Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 229930027917 kanamycin Natural products 0.000 description 2
- 229960000318 kanamycin Drugs 0.000 description 2
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 2
- 229930182823 kanamycin A Natural products 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 238000009126 molecular therapy Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000013600 plasmid vector Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000013074 reference sample Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 241000201370 Autographa californica nucleopolyhedrovirus Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000037663 Best vitelliform macular dystrophy Diseases 0.000 description 1
- 102100026031 Beta-glucuronidase Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108091035707 Consensus sequence 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
- 230000003682 DNA packaging effect Effects 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
- 108091027757 Deoxyribozyme Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 101150071673 E6 gene Proteins 0.000 description 1
- UPEZCKBFRMILAV-JNEQICEOSA-N Ecdysone Natural products O=C1[C@H]2[C@@](C)([C@@H]3C([C@@]4(O)[C@@](C)([C@H]([C@H]([C@@H](O)CCC(O)(C)C)C)CC4)CC3)=C1)C[C@H](O)[C@H](O)C2 UPEZCKBFRMILAV-JNEQICEOSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 1
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101001029059 Homo sapiens ATP-binding cassette sub-family C member 10 Proteins 0.000 description 1
- 101100166894 Homo sapiens CFTR gene Proteins 0.000 description 1
- 101001016184 Homo sapiens Dysferlin Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241001045988 Neogene Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 1
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000022583 Qualitative or quantitative defects of dysferlin Diseases 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000251131 Sphyrna Species 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 201000011212 X-linked dilated cardiomyopathy Diseases 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- UPEZCKBFRMILAV-UHFFFAOYSA-N alpha-Ecdysone Natural products C1C(O)C(O)CC2(C)C(CCC3(C(C(C(O)CCC(C)(C)O)C)CCC33O)C)C3=CC(=O)C21 UPEZCKBFRMILAV-UHFFFAOYSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000004507 artificial chromosome Anatomy 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- UUVBYOGFRMMMQL-UHFFFAOYSA-N calcium;phosphoric acid Chemical compound [Ca].OP(O)(O)=O UUVBYOGFRMMMQL-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000012501 chromatography medium Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000008395 clarifying agent Substances 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 208000027641 dilated cardiomyopathy 3B Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- UKWLRLAKGMZXJC-QIECWBMSSA-L disodium;[4-chloro-3-[(3r,5s)-1-chloro-3'-methoxyspiro[adamantane-4,4'-dioxetane]-3'-yl]phenyl] phosphate Chemical compound [Na+].[Na+].O1OC2([C@@H]3CC4C[C@H]2CC(Cl)(C4)C3)C1(OC)C1=CC(OP([O-])([O-])=O)=CC=C1Cl UKWLRLAKGMZXJC-QIECWBMSSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- UPEZCKBFRMILAV-JMZLNJERSA-N ecdysone Chemical compound C1[C@@H](O)[C@@H](O)C[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@@H]([C@H](O)CCC(C)(C)O)C)CC[C@]33O)C)C3=CC(=O)[C@@H]21 UPEZCKBFRMILAV-JMZLNJERSA-N 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 231100000221 frame shift mutation induction Toxicity 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Natural products O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 102000056610 human DYSF Human genes 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 238000001738 isopycnic centrifugation Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 239000012092 media component Substances 0.000 description 1
- 239000012533 medium component Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 101150091879 neo gene Proteins 0.000 description 1
- 208000018360 neuromuscular disease Diseases 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 108010079892 phosphoglycerol kinase Proteins 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 230000001718 repressive effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000013609 scAAV vector Substances 0.000 description 1
- 230000009450 sialylation Effects 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory 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
-
- 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
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- 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
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10041—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
- 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
- C12N2750/14151—Methods of production or purification of viral material
- C12N2750/14152—Methods of production or purification of viral material relating to complementing cells and packaging systems for producing virus or viral particles
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Toxicology (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Marine Sciences & Fisheries (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562144862P | 2015-04-08 | 2015-04-08 | |
| US62/144,862 | 2015-04-08 | ||
| US201562220067P | 2015-09-17 | 2015-09-17 | |
| US62/220,067 | 2015-09-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201710498A TW201710498A (zh) | 2017-03-16 |
| TWI707951B true TWI707951B (zh) | 2020-10-21 |
Family
ID=56943906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW105110751A TWI707951B (zh) | 2015-04-08 | 2016-04-06 | 過大腺相關載體之製造 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US10815497B2 (enExample) |
| EP (2) | EP3280799B1 (enExample) |
| JP (3) | JP6878299B2 (enExample) |
| KR (2) | KR102848324B1 (enExample) |
| CN (1) | CN107864657A (enExample) |
| AU (3) | AU2016245806A1 (enExample) |
| BR (1) | BR112017021505A2 (enExample) |
| CA (1) | CA2982123A1 (enExample) |
| CL (1) | CL2017002537A1 (enExample) |
| CO (1) | CO2017011344A2 (enExample) |
| CR (1) | CR20170505A (enExample) |
| DK (1) | DK3280799T3 (enExample) |
| EA (1) | EA201792236A1 (enExample) |
| EC (1) | ECSP17074016A (enExample) |
| ES (1) | ES3008382T3 (enExample) |
| GT (1) | GT201700214A (enExample) |
| HU (1) | HUE069779T2 (enExample) |
| IL (3) | IL294965A (enExample) |
| MX (1) | MX2017012935A (enExample) |
| PE (1) | PE20171800A1 (enExample) |
| PH (1) | PH12017501836A1 (enExample) |
| PL (1) | PL3280799T3 (enExample) |
| SG (3) | SG11201708203UA (enExample) |
| TN (1) | TN2017000431A1 (enExample) |
| TW (1) | TWI707951B (enExample) |
| UY (1) | UY36611A (enExample) |
| WO (1) | WO2016164609A2 (enExample) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE063051T2 (hu) | 2013-02-15 | 2023-12-28 | Bioverativ Therapeutics Inc | Optimalizált VIII. faktor gén |
| US10577627B2 (en) | 2014-06-09 | 2020-03-03 | Voyager Therapeutics, Inc. | Chimeric capsids |
| WO2016004113A1 (en) | 2014-06-30 | 2016-01-07 | Biogen Ma Inc. | Optimized factor ix gene |
| WO2016073693A2 (en) | 2014-11-05 | 2016-05-12 | Voyager Therapeutics, Inc. | Aadc polynucleotides for the treatment of parkinson's disease |
| CA2975583A1 (en) | 2014-11-14 | 2016-05-19 | Voyager Therapeutics, Inc. | Modulatory polynucleotides |
| CN114717264A (zh) | 2014-11-14 | 2022-07-08 | 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 |
| US11697825B2 (en) | 2014-12-12 | 2023-07-11 | Voyager Therapeutics, Inc. | Compositions and methods for the production of scAAV |
| TWI707951B (zh) * | 2015-04-08 | 2020-10-21 | 美商健臻公司 | 過大腺相關載體之製造 |
| TWI756185B (zh) | 2015-09-24 | 2022-03-01 | 美商拜奧馬林製藥公司 | 腺相關病毒因子viii載體、相關病毒粒子及包含其之治療調配物 |
| ES2926585T3 (es) | 2016-02-01 | 2022-10-27 | Bioverativ Therapeutics Inc | Genes de Factor VIII optimizados |
| EP3448874A4 (en) | 2016-04-29 | 2020-04-22 | Voyager Therapeutics, Inc. | COMPOSITIONS FOR TREATING A DISEASE |
| US11299751B2 (en) | 2016-04-29 | 2022-04-12 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
| SG11201809643UA (en) | 2016-05-18 | 2018-12-28 | Voyager Therapeutics Inc | Compositions and methods of treating huntington's disease |
| IL262784B2 (en) | 2016-05-18 | 2023-10-01 | Voyager Therapeutics Inc | modulatory polynucleotides |
| 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 |
| US11518991B2 (en) | 2017-02-24 | 2022-12-06 | Georg-August-Universitaet Goettingen Stiftung Oeffentlichen Rechts, Universitaetsmedizin | Method for re-expression of different hypermethylated genes involved in fibrosis, like hypermethylated RASAL1 and use thereof in treatment of fibrosis as well as kit of parts for re-expression of hypermethylated genes including RASAL1 in a subject |
| MX2019013172A (es) | 2017-05-05 | 2020-09-07 | Voyager Therapeutics Inc | Composiciones y metodos para tratar la enfermedad de huntington. |
| WO2018204786A1 (en) | 2017-05-05 | 2018-11-08 | Voyager Therapeutics, Inc. | Compositions and methods of treating amyotrophic lateral sclerosis (als) |
| AU2018269050A1 (en) | 2017-05-19 | 2020-01-16 | Encoded Therapeutics, Inc. | High activity regulatory elements |
| JOP20190269A1 (ar) | 2017-06-15 | 2019-11-20 | Voyager Therapeutics Inc | بولي نوكليوتيدات aadc لعلاج مرض باركنسون |
| JP7229989B2 (ja) | 2017-07-17 | 2023-02-28 | ボイジャー セラピューティクス インコーポレイテッド | 軌道アレイガイドシステム |
| AU2018311069A1 (en) | 2017-08-03 | 2020-02-20 | Voyager Therapeutics, Inc. | Compositions and methods for delivery of AAV |
| JP7374883B2 (ja) | 2017-08-09 | 2023-11-07 | バイオベラティブ セラピューティクス インコーポレイテッド | 核酸分子およびその使用 |
| MX2020003042A (es) | 2017-09-29 | 2020-11-18 | Voyager Therapeutics Inc | Rescate del fenotipo neurológico central y periférico de la ataxia de friedreich mediante administración intravenosa. |
| US11434502B2 (en) | 2017-10-16 | 2022-09-06 | Voyager Therapeutics, Inc. | Treatment of amyotrophic lateral sclerosis (ALS) |
| WO2019079242A1 (en) | 2017-10-16 | 2019-04-25 | Voyager Therapeutics, Inc. | TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS (ALS) |
| CN118345115A (zh) | 2017-12-01 | 2024-07-16 | 编码治疗公司 | 工程化的dna结合蛋白 |
| EP3794126A1 (en) | 2018-05-15 | 2021-03-24 | Voyager Therapeutics, Inc. | Compositions and methods for the treatment of parkinson's disease |
| EP3824095A4 (en) * | 2018-07-20 | 2022-04-20 | University of Utah Research Foundation | GENE THERAPY FOR MACULATE GENERATION |
| MX2021001599A (es) | 2018-08-09 | 2021-07-02 | Bioverativ Therapeutics Inc | Moleculas de acido nucleico y sus usos para la terapia genica no viral. |
| SG11202103151RA (en) | 2018-09-28 | 2021-04-29 | Voyager Therapeutics Inc | Frataxin expression constructs having engineered promoters and methods of use thereof |
| EP3863662A1 (en) * | 2018-10-12 | 2021-08-18 | Genzyme Corporation | Generation of improved human pah for treatment of severe pku by liver-directed gene replacement therapy |
| EP4022097A4 (en) * | 2019-08-29 | 2022-12-14 | Siemens Healthcare Diagnostics Inc. | REAGENTS AND METHODS FOR DETECTING AAV EXCRETION |
| TW202126284A (zh) | 2019-09-30 | 2021-07-16 | 美商百歐維拉提夫治療公司 | 慢病毒載體配製物 |
| CN111218446B (zh) * | 2019-12-25 | 2023-03-28 | 劲帆生物医药科技（武汉）有限公司 | 一种肝脏特异性启动子及其应用 |
| IL296509A (en) * | 2020-03-16 | 2022-11-01 | Univ North Carolina Chapel Hill | Compositions and methods for the selective detection of tumor-derived viral dna |
| BR112022026127A2 (pt) | 2020-06-24 | 2023-01-17 | Bioverativ Therapeutics Inc | Métodos para remoção de fator viii livre de preparações de vetores lentivirais modificados para expressar referida proteína |
| AU2021319208A1 (en) | 2020-07-30 | 2023-03-02 | Shape Therapeutics Inc. | Stable cell lines for inducible production of rAAV virions |
| JP2023538666A (ja) | 2020-08-23 | 2023-09-08 | バイオベラティブ セラピューティクス インコーポレイテッド | 閉端ＤＮＡ（ｃｅＤＮＡ）の改善された製造のための改変バキュロウイルス系 |
| CA3229345A1 (en) | 2021-08-23 | 2023-03-02 | Bioverativ Therapeutics Inc. | Closed-end dna production with inverted terminal repeat sequences |
| AR126846A1 (es) | 2021-08-23 | 2023-11-22 | Bioverativ Therapeutics Inc | Genes del factor viii optimizados |
| CA3229668A1 (en) | 2021-08-23 | 2023-03-02 | Bioverativ Therapeutics Inc. | Baculovirus expression system |
| IL311725A (en) | 2021-09-30 | 2024-05-01 | Bioverativ Therapeutics Inc | Nucleic acids encoding factor VIII polypeptides with reduced immunogenicity |
| MX2024004647A (es) | 2021-10-18 | 2024-05-02 | Regeneron Pharma | Celulas eucariotas que comprenden polinucleotidos de virus asociados a adenovirus. |
| AR132545A1 (es) * | 2023-04-26 | 2025-07-16 | Sanofi Sa | Líneas celulares hospedadoras y métodos para identificar y usar dichas líneas celulares hospedadoras |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2264482A1 (en) | 1996-09-06 | 1998-03-12 | The Trustees Of The University Of Pennsylvania | An inducible method for production of recombinant adeno-associated viruses utilizing t7 polymerase |
| US6566118B1 (en) | 1997-09-05 | 2003-05-20 | Targeted Genetics Corporation | Methods for generating high titer helper-free preparations of released recombinant AAV vectors |
| US6989264B2 (en) | 1997-09-05 | 2006-01-24 | Targeted Genetics Corporation | Methods for generating high titer helper-free preparations of released recombinant AAV vectors |
| EP2369002A1 (en) | 1999-08-09 | 2011-09-28 | Targeted Genetics Corporation | Enhancement of expression of a single-stranded, heterologous nucleotide sequence from recombinant viral vectors by designing the sequence such that it forms intrastrand base pairs |
| EP1224312A1 (en) * | 1999-10-12 | 2002-07-24 | The University of North Carolina at Chapel Hill | Adeno-associated virus vectors encoding factor viii and methods of using the same |
| ES2256265T3 (es) | 2000-06-01 | 2006-07-16 | University Of North Carolina At Chapel Hill | Vectores de parvovirus duplicados. |
| US6723551B2 (en) | 2001-11-09 | 2004-04-20 | The United States Of America As Represented By The Department Of Health And Human Services | Production of adeno-associated virus in insect cells |
| NZ618298A (en) | 2001-11-13 | 2015-04-24 | Univ Pennsylvania | A method of detecting and/or identifying adeno-associated virus (aav) sequences and isolating novel sequences identified thereby |
| US20040092008A1 (en) * | 2002-11-12 | 2004-05-13 | Snyder Richard O. | Recombinant AAV vectors for gene therapy of hemophilia A |
| US7510872B2 (en) | 2003-02-26 | 2009-03-31 | Nationwide Children's Hospital | Recombinant adeno-associated virus production |
| PT1625210E (pt) | 2003-05-21 | 2011-03-15 | Genzyme Corp | Métodos para produzir preparações de vírions de aav recombinantes substancialmente livres de capsídeos vazios |
| US8283151B2 (en) | 2005-04-29 | 2012-10-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isolation, cloning and characterization of new adeno-associated virus (AAV) serotypes |
| US7943374B2 (en) | 2005-08-21 | 2011-05-17 | Markus Hildinger | Super-size adeno-associated viral vector harboring a recombinant genome larger than 5.7 kb |
| US7588772B2 (en) | 2006-03-30 | 2009-09-15 | Board Of Trustees Of The Leland Stamford Junior University | AAV capsid library and AAV capsid proteins |
| HUE054940T2 (hu) | 2009-06-16 | 2021-10-28 | Genzyme Corp | Javított eljárások rekombináns AAV-vektorok tisztítására |
| US8663624B2 (en) | 2010-10-06 | 2014-03-04 | The Regents Of The University Of California | Adeno-associated virus virions with variant capsid and methods of use thereof |
| SG10201601110VA (en) | 2011-02-17 | 2016-03-30 | Univ Pennsylvania | Compositions and methods for altering tissue specificity and improving aav9-mediated gene transfer |
| DK2911687T3 (da) * | 2012-10-26 | 2019-05-13 | Univ Brussel Vrije | Vektor til levermålrettet genterapi af hæmofili og fremgangsmåder og anvendelse deraf |
| SMT202000458T1 (it) * | 2013-09-12 | 2020-11-10 | Biomarin Pharm Inc | Vettori aav comprendenti un gene codificante il fattore viii |
| PT3137497T (pt) | 2014-05-02 | 2021-07-12 | Genzyme Corp | Vetores de aav para terapia genética na retina e snc |
| LT3256594T (lt) | 2015-02-10 | 2022-02-10 | Genzyme Corporation | Patobulintas virusinių dalelių tiekimas į dryžuotąjį kūną ir smegenų žievę |
| TWI707951B (zh) * | 2015-04-08 | 2020-10-21 | 美商健臻公司 | 過大腺相關載體之製造 |
-
2016
- 2016-04-06 TW TW105110751A patent/TWI707951B/zh active
- 2016-04-07 IL IL294965A patent/IL294965A/en unknown
- 2016-04-07 BR BR112017021505A patent/BR112017021505A2/pt not_active Application Discontinuation
- 2016-04-07 SG SG11201708203UA patent/SG11201708203UA/en unknown
- 2016-04-07 CN CN201680033119.6A patent/CN107864657A/zh active Pending
- 2016-04-07 ES ES16767050T patent/ES3008382T3/es active Active
- 2016-04-07 CA CA2982123A patent/CA2982123A1/en active Pending
- 2016-04-07 DK DK16767050.4T patent/DK3280799T3/da active
- 2016-04-07 SG SG10201912912QA patent/SG10201912912QA/en unknown
- 2016-04-07 HU HUE16767050A patent/HUE069779T2/hu unknown
- 2016-04-07 JP JP2017553005A patent/JP6878299B2/ja active Active
- 2016-04-07 KR KR1020177032062A patent/KR102848324B1/ko active Active
- 2016-04-07 IL IL283291A patent/IL283291B/en unknown
- 2016-04-07 PL PL16767050.4T patent/PL3280799T3/pl unknown
- 2016-04-07 SG SG10201909381W patent/SG10201909381WA/en unknown
- 2016-04-07 WO PCT/US2016/026486 patent/WO2016164609A2/en not_active Ceased
- 2016-04-07 KR KR1020257027291A patent/KR20250126875A/ko active Pending
- 2016-04-07 MX MX2017012935A patent/MX2017012935A/es unknown
- 2016-04-07 AU AU2016245806A patent/AU2016245806A1/en not_active Abandoned
- 2016-04-07 PE PE2017001997A patent/PE20171800A1/es unknown
- 2016-04-07 US US15/565,020 patent/US10815497B2/en active Active
- 2016-04-07 CR CR20170505A patent/CR20170505A/es unknown
- 2016-04-07 EP EP16767050.4A patent/EP3280799B1/en active Active
- 2016-04-07 EP EP24207442.5A patent/EP4512429A3/en active Pending
- 2016-04-07 TN TNP/2017/000431A patent/TN2017000431A1/en unknown
- 2016-04-07 EA EA201792236A patent/EA201792236A1/ru unknown
- 2016-04-08 UY UY0001036611A patent/UY36611A/es not_active Application Discontinuation
-
2017
- 2017-10-06 CL CL2017002537A patent/CL2017002537A1/es unknown
- 2017-10-06 PH PH12017501836A patent/PH12017501836A1/en unknown
- 2017-10-06 GT GT201700214A patent/GT201700214A/es unknown
- 2017-10-08 IL IL254933A patent/IL254933B/en active IP Right Grant
- 2017-11-03 CO CONC2017/0011344A patent/CO2017011344A2/es unknown
- 2017-11-08 EC ECIEPI201774016A patent/ECSP17074016A/es unknown
-
2021
- 2021-04-28 JP JP2021075526A patent/JP2021118724A/ja not_active Withdrawn
-
2022
- 2022-06-07 AU AU2022203942A patent/AU2022203942B2/en active Active
-
2023
- 2023-06-14 JP JP2023097370A patent/JP2023116678A/ja active Pending
-
2024
- 2024-03-12 AU AU2024201619A patent/AU2024201619A1/en active Pending
Non-Patent Citations (4)
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI707951B (zh) | 過大腺相關載體之製造 | |
| TWI745285B (zh) | 用於重組病毒粒子特徵化之分析性超速離心法 | |
| US20210095313A1 (en) | Adeno-associated virus (aav) systems for treatment of genetic hearing loss | |
| Pan et al. | Rational engineering of a functional CpG-free ITR for AAV gene therapy | |
| US20250179522A1 (en) | Human pah expression cassette for treatment of pku by liver-directed gene replacement therapy | |
| HK40120936A (en) | Production of oversized adeno-associated vectors | |
| TWI900667B (zh) | 藉由肝導向基因替代療法治療pku之人類pah表現匣 | |
| RU2848343C1 (ru) | Кассета экспрессии pah человека для лечения pku с помощью направленной на печень генной заместительной терапии | |
| HK1246339B (en) | Production of oversized adeno-associated vectors | |
| CN116648503A (zh) | 通过肝导向基因替代疗法治疗pku的人pah表达盒 |