JP2015514427A - Aavカプシドバリアントを使用した高効率な遺伝子導入のための組成物及び方法 - Google Patents
Aavカプシドバリアントを使用した高効率な遺伝子導入のための組成物及び方法 Download PDFInfo
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- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000003142 viral transduction method Methods 0.000 description 1
Classifications
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/01—DNA viruses
- C07K14/015—Parvoviridae, e.g. feline panleukopenia virus, human parvovirus
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
- C12N15/864—Parvoviral vectors, e.g. parvovirus, densovirus
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- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Abstract
Description
「遺伝子治療(Gene therapy)」は、疾患、一般的に遺伝性疾患を治療するために、個々の細胞及び/又は組織へと遺伝子を挿入することであり、欠損変異体対立遺伝子が交換又は機能的なもので補足される。
本発明の方法は、分裂細胞及び非分裂細胞の両方を含む幅広い宿主細胞へと、異種核酸配列を送達する手段を提供する。治療方法又はその他の方法として、本発明のベクター及び他の試薬、方法及び医薬製剤は、タンパク質又はペプチドを、必要とする対象に投与する方法おいて更に有用である。したがって、タンパク質又はペプチドは、対象の生体内で産生され得る。治療方法として又はその他の方法として、対象はタンパク質又はペプチドの欠損を有するため、当該タンパク質又はペプチドを必要とする場合がある、又は、対象におけるタンパク質又はペプチドの生産がいくつかの治療効果を与える可能性があるために、対象が当該タンパク質又はペプチドを必要とする場合があり、以下に更に説明する。
本発明は、獣医学分野及び医療分野の両方で利用が期待される。適切な対象としては、鳥類及び哺乳動物の両方が含まれ、哺乳類の方がより好適である。本明細書で使用される「鳥類(avian)」という言葉は、これに限定されないが、ニワトリ、アヒル、ガチョウ、ウズラ、シチメンチョウ及びキジを含む。本明細書で使用される「哺乳動物(mammal)」という言葉は、これに限定されないが、ヒト、ウシ、ヒツジ、ヤギ、ウマ、ネコ、イヌ、ウサギ等が含まれる。対象は、人間が最も好ましい。人間の対象としては、胎児、新生児、乳児、未成年及び成人が含まれる。
リジンからアルギニンへの変異による、AAV形質導入率及びMHC送達への影響
AAV1ベクター及びAAV8ベクターにおいて標的とすべきリジン残基の特定
位置 スコア ユビキチン化
26 0.59 No
31 0.55 No
33 0.47 No
38 0.61 No
51 0.54 No
61 0.72 Yes 中信頼度
77 0.63 Yes 低信頼度
84 0.72 Yes 中信頼度
122 0.17 No
123 0.26 No
137 0.90 Yes 高信頼度
142 0.62 Yes 低信頼度
143 0.81 Yes 中信頼度
161 0.70 Yes 中信頼度
168 0.25 No
169 0.26 No
258 0.49 No
310 0.14 No
315 0.15 No
322 0.48 No
459 0.81 Yes 中信頼度
476 0.43 No
491 0.20 No
493 0.28 No
508 0.62 Yes 低信頼度
528 0.67 Yes 低信頼度
533 0.70 Yes 中信頼度
545 0.65 Yes 低信頼度
567 0.66 Yes 低信頼度
621 0.50 No
641 0.50 No
650 0.45 No
666 0.58 No
689 0.65 Yes 低信頼度
693 0.65 Yes 低信頼度
707 0.78 Yes 中信頼度
凡例:
表示 スコア範囲 感度 特異度
低信頼度 0.62<s<0.69 0.464 0.903
中信頼度 0.69<s<0.84 0.346 0.950
高信頼度 0.84<s<1.00 0.197 0.989
MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTGGTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAWTAGTKYHLNGRNSLANPGIAMATHKDDEERFFPSNGILIFGKQNAARDNADYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYLTRNL
位置 スコア ユビキチン化
26 0.52 No
31 0.51 No
33 0.16 No
38 0.62 Yes 低信頼度
51 0.56 No
61 0.68 Yes 低信頼度
77 0.65 Yes 低信頼度
122 0.17 No
123 0.32 No
137 0.92 Yes 高信頼度
142 0.53 No
143 0.65 Yes 低信頼度
162 0.28 No
163 0.29 No
170 0.24 No
259 0.49 No
312 0.09 No
317 0.12 No
324 0.43 No
333 0.75 Yes 中信頼度
478 0.59 No
510 0.50 No
530 0.71 Yes 中信頼度
547 0.40 No
569 0.66 Yes 低信頼度
623 0.47 No
643 0.44 No
652 0.51 No
668 0.64 Yes 低信頼度
691 0.66 Yes 低信頼度
695 0.67 Yes 低信頼度
709 0.68 Yes 低信頼度
凡例:
表示 スコア範囲 感度 特異度
低信頼度 0.62<s<0.69 0.464 0.903
中信頼度 0.69<s<0.84 0.346 0.950
高信頼度 0.84<s<1.00 0.197 0.989
MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL
位置 スコア ユビキチン化
24 0.20 No
26 0.49 No
33 0.38 No
39 0.89 Yes 高信頼度
51 0.53 No
61 0.67 Yes 低信頼度
77 0.68 Yes 低信頼度
92 0.56 No
105 0.58 No
122 0.14 No
123 0.18 No
137 0.87 Yes 高信頼度
142 0.58 No
143 0.77 Yes 中信頼度
161 0.70 Yes 中信頼度
169 0.31 No
258 0.51 No
309 0.14 No
314 0.17 No
321 0.46 No
490 0.73 Yes 中信頼度
507 0.61 No
527 0.78 Yes 中信頼度
532 0.75 Yes 中信頼度
544 0.61 No
549 0.68 Yes 低信頼度
556 0.62 Yes 低信頼度
620 0.47 No
640 0.45 No
649 0.42 No
665 0.54 No
688 0.68 Yes 低信頼度
692 0.68 Yes 低信頼度
706 0.66 Yes 低信頼度
凡例:
表示 スコア範囲 感度 特異度
低信頼度 0.62≦s≦0.69 0.464 0.903
中信頼度 0.69≦s≦0.84 0.346 0.950
高信頼度 0.84≦s≦1.00 0.197 0.989
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVESPVKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYNFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL
位置 スコア ユビキチン化
26 0.60 No
31 0.53 No
33 0.27 No
38 0.23 No
51 0.38 No
61 0.68 Yes 低信頼度
77 0.65 Yes 低信頼度
122 0.17 No
123 0.30 No
137 0.90 Yes 高信頼度
142 0.35 No
143 0.35 No
162 0.36 No
163 0.33 No
169 0.27 No
170 0.25 No
259 0.46 No
312 0.13 No
317 0.16 No
324 0.46 No
333 0.77 Yes 中信頼度
478 0.51 No
510 0.49 No
530 0.67 Yes 低信頼度
547 0.52 No
552 0.69 Yes 中信頼度
569 0.67 Yes 低信頼度
623 0.49 No
643 0.44 No
652 0.54 No
668 0.56 No
691 0.68 Yes 低信頼度
695 0.67 Yes 低信頼度
709 0.69 Yes 中信頼度
凡例:
表示 スコア範囲 感度 特異度
低信頼度 0.62<s<0.69 0.464 0.903
中信頼度 0.69<s<0.84 0.346 0.950
高信頼度 0.84<s<1.00 0.197 0.989
AAV1プライマー:
AAV1 K61R
センス:5’− CTT CAA CGG ACT CGA CAG GGG GGA GCC −3’
アンチセンス:5’− GGC TCC CCC CTG TCG AGT CCG TTG AAG −3’
AAV1 K84R
センス:5’− GCC TAC GAC CAG CAG CTC AGA GCG GGT GAC −3’
アンチセンス:5’− GTC ACC CGC TCT GAG CTG CTG GTC GTA GGC −3’
AAV1 K137R
センス:5’− TGG TTG AGG AAG GCG CTA GGA CGG CTC CT −3’
アンチセンス:5’− AGG AGC CGT CCT AGC GCC TTC CTC AAC CA −3’
AAV1 K143R
センス:5’− CTA AGA CGG CTC CTG GAA AGA GAC GTC CGG TAG −3’
アンチセンス:5’− CTA CCG GAC GTC TCT TTC CAG GAG CCG TCT TAG −3’
AAV1 K161R
センス:5’− CGG GCA TCG GCA GGA CAG GCC AGC A −3’
アンチセンス:5’− TGC TGG CCT GTC CTG CCG ATG CCC G −3’
AAV1 K459R
センス:5’− AGT CCG GAA GTG CCC AAA ACA GGG ACT TGC TGT −3’
アンチセンス:5’− ACA GCA AGT CCC TGT TTT GGG CAC TTC CGG ACT −3’
AAV1 K528R
センス:5’− GCA CTG CTA TGG CCT CAC ACA GAG ACG ACG AAG −3’
アンチセンス:5’− CTT CGT CGT CTC TGT GTG AGG CCA TAG CAG TGC −3’
AAV1 K533R
センス:5’− CAA AGA CGA CGA AGA CAG GTT CTT TCC CAT GAG CG −3’
アンチセンス:5’−CGC TCA TGG GAA AGA ACC TGT CTT CGT CGT CTT TG −3’
AAV1 K707R
センス:5’− TGCAGTACACATCCAATTATGCAAGATCTGCCAACG TTG −3’
アンチセンス:5’− CAACGTTGGCAGATCTTGCATAATTGGATGTGTACTGCA −3’
AAV8 K137R
センス:5’− GGT TGA GGA AGG CGC TAG GAC GGC TCC TGG −3’
アンチセンス:5’− CCA GGA GCC GTC CTA GCG CCT TCC TCA ACC −3’
AAV8 K333R
センス:5’− GCA GAA TGA AGG CAC CAG GAC CAT CGC CAA TAA CC −3’
アンチセンス:5’− GGT TAT TGG CGA TGG TCC TGG TGC CTT CAT TCT GC −3’
AAV8 K530R
センス:5’− GCA TCG CTA TGG CAA CAC ACA GAG ACG ACG AGG −3’
アンチセンス:5’− CCT CGT CGT CTC TGT GTG TTG CCA TAG CGA TGC −3’
AAV8 K709R
センス: 5’− GTACACCTCCAACTACTACAGATCTACAAGTGTGGACTTTG −3’
アンチセンス:5’− CAAAGTCCACACTTGTAGATCTGTAGTAGTTGGAGGTGTAC −3’
AAV2 K39R
センス:5’−GCCCGCAGAGCGGCATAGGGACGACAG−3’
アンチセンス:5’−CTGTCGTCCCTATGCCGCTCTGCGGGC−3’
AAV2 K137R
センス:5’−CCTGGTTGAGGAACCTGTTAGGACGGCTCCGG−3’
アンチセンス:5’−CCGGAGCCGTCCTAACAGGTTCCTCAACCAGG−3’
AAV2 K143R
センス:5’−AGACGGCTCCGGGAAAAAGGAGGCCGGTA−3’
アンチセンス:5’−TACCGGCCTCCTTTTTCCCGGAGCCGTCT−3’
AAV2 K161R
センス:5’−CCTCGGGAACCGGAAGGGCGGGCC−3’
アンチセンス:5’−GGCCCGCCCTTCCGGTTCCCGAGG−3’
AAV2 K490R
センス:5’−CCGCCAGCAGCGAGTATCAAGGACATCTGCGG−3’
アンチセンス:5’−CCGCAGATGTCCTTGATACTCGCTGCTGGCGG−3’
AAV2 K527R
センス:5’−CGGCCATGGCAAGCCACAGGGACGATGAA−3’
アンチセンス:5’−TTCATCGTCCCTGTGGCTTGCCATGGCCG−3’
AAV2 K532R
センス:5’−ACAAGGACGATGAAGAAAGGTTTTTTCCTCAGAGCGG−3’
アンチセンス:5’−CCGCTCTGAGGAAAAAACCTTTCTTCATCGTCCTTGT−3’
AAV−rh74プライマー
AAV−rh74 K137R
センス:5’−CTGGTTGAATCGCCGGTTAGGACGGCTCCTG−3’
アンチセンス:5’−GACCAACTTAGCGGCCAATCCTGCCGAGGAC−3’
AAV−rh74 K333R
センス:5’−GCAGAATGAAGGCACCAGGACCATCGCCAATAACC−3’
アンチセンス:5’−GGTTATTGGCGATGGTCCTGGTGCCTTCATTCTGC−3’
AAV−rh74 K530R
センス:5’−GTTGCCATGGCTACCCACAGGGACGACGAA−3’
アンチセンス:5’−TTCGTCGTCCCTGTGGGTAGCCATGGCAAC−3’
AAV−rh74 K552R
センス:5’−GGAAACAGGGAGCTGGAAGAGACAACGTGGACTAT−3’
アンチセンス:5’−ATAGTCCACGTTGTCTCTTCCAGCTCCCTGTTTCC−3’
AAV−rh74 K569R
センス:5’−CTAACCAGCGAGGAAGAAATAAGGACCACCAACCC−3’
アンチセンス:5’−GGGTTGGTGGTCCTTATTTCTTCCTCGCTGGTTAG−3’
AAV−rh74 K691R
センス:5’−CGAGTGGGAGCTGCAGAGGGAGAACAGCAA−3’
アンチセンス:5’−TTGCTGTTCTCCCTCTGCAGCTCCCACTCG−3’
AAV−rh74 K695R
センス:5’−GCTGCAGAAGGAGAACAGCAGACGCTGGAACC−3’
アンチセンス:5’−GGTTCCAGCGTCTGCTGTTCTCCTTCTGCAGC−3’
AAV−rh74 K709R
センス:5’−AGTACACTTCCAACTACTACAGATCTACAAATGTGGACTTTGC−3’
アンチセンス:5’−GCAAAGTCCACATTTGTAGATCTGTAGTAGTTGGAAGTGTACT−3’
本明細書に開示されるAAVリジン変異体のうちの特定のものを使用して形質導入された肝細胞のCTL傷害を評価した。形質導入された肝細胞のCTL傷害を評価するのに、次に記すような材料及び方法を用いた。
上記で説明したようなトリプルトランスフェクション法(Matsushita、1998年)を使用してHEK−239細胞にてAAVベクターを生成し、塩化セシウム勾配遠心分離法(Ayuso、2010)を用いて精製した。Genemed Synthesis社によって合成されたAAVエピトープペプチドを、100%DMSO中5mg/mlの濃度で再懸濁した。
ヒトPBMC(Cellular Technology LTD)を、解凍し、洗浄し、計数し、3%ヒト血清(Bioreclamation社)、1%Lグルタミン(Gibco社)及び1%ペニシリン/ストレプトマイシン(Gibco社)を含むAIM−Vリンパ球培地(Gibco社)中に、2×106細胞/mlの濃度で再懸濁した。拡張条件それぞれについて、500μlの体積の24ウェルプレート(BD Falcon社)の各ウェル毎に、1x106(500μl)細胞が添加された。2.5μg/mlのβ−2−ミクログロブリン(Lee Biosolutions社)及び10 ng/mlのヒト組換えIL−7(R&D Systems社)と共に、1x106(500μl)の自家照射脾細胞(3000rad)が更に各ウェルにフィーダー細胞として添加した。細胞が最終的に10μg/mlの濃度でAAVペプチド中に存在し、5%CO2中温度37℃で拡大された。
上記に記載したように、CLTアッセイを行った(Pien, 2009年)。
簡単に説明すると、CTL媒介標的の細胞溶解の後、乳酸脱水素酵素(LDH)の放出をCytoTox 96非放射性細胞傷害性アッセイ(Promega)を用いて測定した。4000個のHHL5肝細胞の標的細胞を、Microtest Primariaの平底96ウェルプレート(BDファルコン社)の各ウェルの、血清を含まないDMEM中に播種した。標的細胞は、5000、50,000及び500,000MOIのAAVカプシドで形質導入され、5%CO2で37℃で18時間インキュベートされた。処理及びインキュベーションの後、播種された標的細胞は、上記で説明したように拡大されたエピトープ特異的細胞傷害性Tリンパ球を添加する前に、培地で一回洗浄された。5%CO2で37℃で4時間、10:1のエフェクター‐標的細胞比で、CLTを添加し、室温で30分間酵素基質を使用してインキュベートした後、分光光度計(スペクトラマックス)を用いて490nmでLDHを測定した。
AAVの形質導入後、GFP発現をフローサイトメトリーにより測定した。
細胞株HHL5又はHuh7からのヒト肝細胞が、10%ウシ胎児血清、1%L−グルタミン(Gibco)及びび1%ペニシリン/ストレプトマイシン(Gibco)を含有するDMEM中に、Primaria Multiwell 24ウェルプレート(BD Falcon)において250,000細胞/ウェルの密度で播種された。細胞は、5000、 50000及び5000000MOIのAAVベクターで形質導入され、5%CO2で37℃で18時間インキュベートされた。インキュベーションの後、細胞を、トリプシン処理し、PBS2%FBSで2回洗浄し、2%パラホルムアルデヒドで固定した。FACSDiva(登録商標)(BD Biosciences)を使用して、FACS Canto II フローサイトメーターでサンプルを取得し、Flowjo(登録商標)ソフトウェア(Treestar)を使用して分析を行った。
ウィルス形質導入におけるリジン変異の効果についてさらに試験するために、我々はAAVベクターの機能性をテストするべく我々の研究室によって以前に開発されたインビトロでのCTL媒介細胞傷害性アッセイを利用した(PIEN他)。図4、5及び6に、AAV1及びAAV2形質導入の結果が示されている。図4には、AAV−1カプシドにおけるリジン変異が全て、標的のセルのCLT媒介傷害の減少をもたらしており、リジンの変異が、形質導入における効率的な処理を妨げ、表面抗原の存在につながっていることが示唆される。更に、リジン変異の効果は、相加的であるように思われ、3重及び4重リジン変異体の場合、CLT媒介傷害が最も減少している(図4A及び4B)。AAV−2カプシドへの変異も、同様な効果を示した。図5及び図6を参照されたい。図7は、Rh74変異体が試験された時に得られた形質導入の結果を示す。
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Claims (23)
- 一の又は複数のリジン置換を有するVP1カプシドタンパク質を含む改良されたアデノ随伴ウィルス(AAV)ベクターであって、
前記ベクターは更に、AAV末端逆位繰り返し配列及び異種核酸配列を含むミニ遺伝子を含み、
前記異種核酸配列は、宿主細胞における当該異種核酸配列からの産物の発現を指令する制御配列に作動可能に結合され、
前記リジン置換は、前記カプシドタンパク質のユビキチン化を阻害するのに有効であり、それによって前記AAVベクターの標的細胞への形質導入を増加させる、AAVベクター。 - AAV1、AAV2、AAV3、AAV4、AAV−rh74、AAV5、AAV6、AAV7、AAV8及びAAV9からなる群から選択される血清型を有する請求項1に記載のAAVベクター。
- 添付の表に示すリジン残基において少なくとも1つのリジン置換を有するVP1カプシドタンパク質を含み、
前記少なくとも1つのリジン置換は、形質導入効率を向上させる、請求項1に記載のAAVベクター。 - AAV8 K137R、AAV8 K333R及びAAV8 K530Rからなる群から選択される改変AAV8 VP1カプシドタンパク質を含む、請求項2に記載のAAVベクター。
- 前記異種核酸配列の発現産物は、治療用ペプチド又は治療用核酸である、請求項1から3の何れか一項に記載のAAVベクター。
- 前記治療用ペプチドは、第VIII因子、第IX因子又はこれらの機能的断片からなる群から選択される凝固因子である、請求項5に記載のAAVベクター。
- 前記異種核酸配列の発現産物は、IgG、IgM、IgA、IgD、IgE、キメラ免疫グロブリン、ヒト化抗体又は一本鎖抗体である、請求項4に記載のAAV8ベクター。
- 前記異種核酸配列の前記発現産物は、キメラ免疫グロブリンである請求項7に記載のAAV8ベクター。
- 前記異種核酸配列の発現産物は、一本鎖抗体である請求項4に記載のAAV8ベクター。
- 前記発現産物は、抗ウィルス性RNAiである、請求項5に記載のAAVベクター。
- 阻害性RNAが、HCV感染及びHCV複製を阻害するのに有効である請求項10に記載のAAVベクター。
- 阻害性RNAが、真核生物の標的遺伝子の発現を阻害するのに有効である請求項10に記載のAAVベクター。
- 導入遺伝子は、疾患修飾性サイトカインをコードする請求項4に記載のAAVベクター。
- 導入遺伝子は、一対のジンクフィンガーヌクレアーゼをコードする請求項4記載のAAVベクター。
- 2つ、3つ又は4つのリジン置換を含む、請求項1に記載のAAVベクター。
- 第2のAAVベクターを更に含み、
前記第2のAAVベクターは、添付の表に示すリジン残基において少なくとも1つのリジン置換を有するVP1カプシドタンパク質を含み、
前記置換は、形質導入効率を低下させ、
前記第2のAAVベクターの送達は、第1のAAVベクターに対する抗体応答を中和するのに有効である、請求項3に記載のAAVベクター。 - 請求項3に記載の前記AAVベクター及びその生理学的に適合する担体を含む医薬組成物。
- 請求項1に記載の前記AAVベクターを含む細胞培養物。
- 対象の細胞に導入遺伝子を送達する方法であって、
請求項17に記載の前記医薬組成物に、前記細胞を接触させる工程を備え、
前記AAVベクターは、前記導入遺伝子を含み、
前記VP1カプシドタンパク質における前記リジン置換の存在は、前記カプシドのユビキチン化の低減と関連し、それにより、前記AAVベクターを使用した標的細胞の形質導入効率を向上させる、方法。 - 前記導入遺伝子は第IX因子である、請求項19に記載の方法。
- 請求項16に記載の前記AAVベクター及びその生理学的に適合する担体を含む医薬組成物。
- 対象の細胞に導入遺伝子を送達する方法であって、
請求項21に記載の前記医薬組成物に、前記細胞を接触させる工程を備え、
前記第1のAAVベクターは、前記導入遺伝子を含み、
前記VP1カプシドタンパク質における前記リジン置換の存在は、前記カプシドのユビキチン化の低減と関連し、それにより、前記AAVベクターを使用した標的細胞の形質導入効率を向上させ、
前記第2のベクターは、野生型と比較して形質導入効率が低く、前記第1のAAVベクターに対する望ましくない抗体応答を中和させるのに有効である、方法。 - 前記導入遺伝子は、第IX因子である、請求項22に記載の方法。
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