JP2023055843A - 標的遺伝子導入のための方法および組成物 - Google Patents
標的遺伝子導入のための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は、合衆国法典第35巻第119条(e)の下で、2016年8月16日に出願された米国仮出願番号62/375,666の利益を主張し、その内容全体は本明細書中に参照により援用される。
本発明は、国立衛生研究所により授けられた助成金番号5103757の下での政府支援でなされた。政府は本発明における特定の権限を有する。
[本発明の分野]
本発明は、アデノ随伴ウイルス(AAV)およびウイルスキャプシド由来の改変されたキャプシドタンパク質、およびそれを含むウイルスベクターに関する。特に、本発明は、改変されたAAVキャプシドタンパク質およびそれを含むキャプシド(目的の標的組織に関して望ましい形質導入プロファイルを与えるためにウイルスベクターに組み込まれ得る)に関する。
動物組織およびアデノウイルスストックから単離された新規のアデノ随伴ウイルス(AAV)株は、治療的遺伝子導入の適用に利用可能なAAVベクターのパネルを拡張している。動物モデルにおけるこれらのAAV単離株の組織向性をマップする総合的な試みは、現在進行中である。AAVベクターのホーミングを選択臓器へ向ける能力は、遺伝子療法および他の治療的適用に有用である。
以下の用語は、本明細書における説明および添付の特許請求の範囲において用いられる:
MTDGYLPDWLEDNLSEGVREWWALQPGAPKPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQQRLQGDTSFGGNLGRAVFQAKKRVLEPLGLVEQAGETAPGKKRPLIESPQQPDSSTGIGKKGKQPAKKKLVFEDETGAGDGPPEGSTSGAMSDDSEMRAAAGGAAVEGGQGADGVGNASGDWHCDSTWSEGHVTTTSTRTWVLPTYNNHLYKRLGESLQSNTYNGFSTPWGYFDFNRFHCHFSPRDWQRLINNNWGMRPKAMRVKIFNIQVKEVTTSNGETTVANNLTSTVQIFADSSYELPYVMDAGQEGSLPPFPNDVFMVPQYGYCGLVTGNTSQQQTDRNAFYCLEYFPSQMLRTGNNFEITYSFEKVPFHSMYAHSQSLDRLMNPLIDQYLWGLQSTTTGTTLNAGTATTNFTKLRPTNFSNFKKNWLPGPSIKQQGFSKTANQNYKIPATGSDSLIKYETHSTLDGRWSALTPGPPMATAGPADSKFSNSQLIFAGPKQNGNTATVPGTLIFTSEEELAATNATDTDMWGNLPGGDQSNSNLPTVDRLTALGAVPGMVWQNRDIYYQGPIWAKIPHTDGHFHPSPLIGGFGLKHPPPQIFIKNTPVPANPATTFSSTPVNSFITQYSTGQVSVQIDWEIQKERSKRWNPEVQFTSNYGQQNSLLWAPDAAGKYTEPRAIGTRYLTHHL.
MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDKGEPVNEADAAALEHDKAYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCDSTWMGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQFSQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGVLIFGKQGSEKTNVDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL
MAADGYLPDLEDNLSEGIEWWALKPGAQPKANQQHQNARGLVLPGKYLGPGNGLDKGEPVNAADAALEHDKAYQQLKAGDNPLKYNHADAEQERLKEDTSGGNLGRAVFQAKKRLLEPLLVEEAAKTAGKKRPVEQSQEPDSSAGIKSGAQPAKKLNFGQTGDTESVPDPQPIGPPAAPSGVGLTMASGGGAVADNNEGADVGSSSGNWHDSQWLGDRVITTSTRTWALTYNNHLYKQSNSTSGGSSDNAYFGYSTWGYFDFNRFCHFSPRDWQRLINNNWGFRKRLNFKLFNQVKEVTDNNVKTIANNLTTVQVFTDSDQLPYVLGSAHEGCLPPFPAVFMIPQYGYTLNDGSQAVRSSFYCLEYPSQMLRTGNFQFSYEFENVPFHSSYAHSSLDRLMNPLDQYLYYLSKINGSGQNQQLKFSVAGPSMAVQGRNYIPGPSYRQQRVTTVTQNNNSFAWPGASSWLNGRNSLMNGPAMASHKEEDRFFPLSGSLIFGKQGTGDNVDADKVMTNEEEIKTTPVATESYGQATNHQSAQAAQTGWVQNQGILPGMVWQDDVYLQGPIWKIPHTDGNFPSPLMGGFGKHPPPQILINTPVPADPPTAFNKDKLNSITQYSTGQVVEIEWELQKNSKRWNPEIYTSNYYKSNVEFAVNTEGVYSEPRPIGTYLTRNL
MSFVDHPPDWLEEVGEGLREFLGLEAGPPKPKPNQQHQDQARGLVLPGYNYLGPGNGLDRGEPVNRADEVAREHDISYNEQLEAGDNPYLKYNHADAEFQEKLADDTSFGGNLGKAVFQAKKRVLEPFGLVEEGAKTAPTGKRIDDHFPKRKKARTEEDSKPSTSSDAEAGPSGSQQLQIPAQPASSLGADTMSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVTKSTRTWVLPSYNNHQYREIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQRLINNYWGFRPRSLRVKIFNIQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGNGTEGCLPAFPPQVFTLPQYGYATLNRDNTENPTERSSFFCLEYFPSKMLRTGNNFEFTYNFEEVPFHSSFAPSQNLFKLANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYKNWFPGPMGRTQGWNLGSGVNRASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYALENTMIFNSQPANPGTTATYLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPATGTYNLQEIVPGSVWMERDVYLQGPIWAKIPETGAHFHPSPAMGGFGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFITQYSTGQVTVEMEWELKKENSKRWNPEIQYTNNYNDPQFVDFAPDSTGEYRTTRPIGTRYLTRPL
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEQSPQEPDSSSGIGKTGQQPAKKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEEVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLLFSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDEDKFFPMSGVMIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNFQSSSTDPATGDVHAMGALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKNPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVSVEIEWELQKENSKRWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPAKKRPVEPSPQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSSVGSGTVAAGGGAPMADNNEGADGVGNASGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISSETAGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKKLRFKLFNIQVKEVTTNDGVTTIANNLTSTIQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQSVGRSSFYCLEYFPSQMLRTGNNFEFSYSFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLARTQSNPGGTAGNRELQFYQGGPSTMAEQAKNWLPGPCFRQQRVSKTLDQNNNSNFAWTGATKYHLNGRNSLVNPGVAMATHKDDEDRFFPSSGVLIFGKTGATNKTTLENVLMTNEEEIRPTNPVATEEYGIVSSNLQAANTAAQTQVVNNQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPANPPEVFTPAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNFEKQTGVDFAVDSQGVYSEPRPIGTRYLTRNL
MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTGGTANTQTLGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAWTAGTKYHLNGRNSLANPGIAMATHKDDEERFFPSNGILIFGKQNAARDNADYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYLTRNL.
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLD61KGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQ121AKKRVLEPLGLVEEAAKTAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGES181ESVPDPQPIGEPPAGPSGLGSGTMAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRV241ITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQ301RLINNNWGFRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSA361HQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYTFED421VPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTQGTQQLLFSQAGPANMSAQAKNW481LPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSS541GVLMFGKQGAGRDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQANTGPIVGNVNS601QGALPGMVWQNRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADP661PTTFSQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSTNVDFAVNTE721GTYSEPRPIGTRYLTRNL.
MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDKAYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPLESPQEPDSSSGIGKKGKQPARKRLNFEEDTGAGDGPPEGSDTSAMSSDIEMRAAPGGNAVDAGQGSDGVGNASGDWHCDSTWSEGKVTTTSTRTWVLPTYNNHLYLRLGTTSSSNTYNGFSTPWGYFDFNRFHCHFSPRDWQRLINNNWGLRPKAMRVKIFNIQVKEVTTSNGETTVANNLTSTVQIFADSSYELPYVMDAGQEGSLPPFPNDVFMVPQYGYCGIVTGENQNQTDRNAFYCLEYFPSQMLRTGNNFEMAYNFEKVPFHSMYAHSQSLDRLMNPLLDQYLWHLQSTTSGETLNQGNAATTFGKIRSGDFAFYRKNWLPGPCVKQQRFSKTASQNYKIPASGGNALLKYDTHYTLNNRWSNIAPGPPMATAGPSDGDFSNAQLIFPGPSVTGNTTTSANNLLFTSEEEIAATNPRDTDMFGQIADNNQNATTAPITGNVTAMGVLPGMVWQNRDIYYQGPIWAKIPHADGHFHPSPLIGGFGLKHPPPQIFIKNTPVPANPATTFTAARVDSFITQYSTGQVAVQIEWEIEKERSKRWNPEVQFTSNYGNQSSMLWAPDTTGKYTEPRVIGSRYLTNHL
MAADGYLPDWLEDNLSEGIREWWALKPGVPQPKANQQHQDNRRGLVLPGYKYLGPGNGLDKGEPVNEADAAALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRILEPLGLVEEAAKTAPGKKRPVDQSPQEPDSSSGVGKSGKQPARKRLNFGQTGDSESVPDPQPLGEPPAAPTSLGSNTMASGGGAPMADNNEGADGVGNSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKKLSFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQGTTSGTTNQSRLLFSQAGPQSMSLQARNWLPGPCYRQQRLSKTANDNNNSNFPWTAASKYHLNGRDSLVNPGPAMASHKDDEEKFFPMHGNLIFGKEGTTASNAELDNVMITDEEEIRTTNPVATEQYGTVANNLQSSNTAPTTRTVNDQGALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKHPPPQIMIKNTPVPANPPTTFSPAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL.
MAADGYLPDW LEDNLSEGIR EWWALKPGAP QPKANQQHQD NGRGLVLPGY KYLGPFNGLD KGEPVNEADA AALEHDKAYD KQLEQGDNPY LKYNHADAEF QQRLATDTSF GGNLGRAVFQ AKKRILEPLG LVEEGVKTAP GKKRPLEKTP NRPTNPDSGK APAKKKQKDG EPADSARRTL DFEDSGAGDG PPEGSSSGEM SHDAEMRAAP GGNAVEAGQG ADGVGNASGD WHCDSTWSEG RVTTTSTRTW VLPTYNNHLY LRIGTTANSN TYNGFSTPWG YFDFNRFHCH FSPRDWQRLI NNNWGLRPKS MRVKIFNIQV KEVTTSNGET TVANNLTSTV QIFADSTYEL PYVMDAGQEG SFPPFPNDVF MVPQYGYCGV VTGKNQNQTD RNAFYCLEYF PSQMLRTGNN FEVSYQFEKV PFHSMYAHSQ SLDRMMNPLL DQYLWHLQST TTGNSLNQGT ATTTYGKITT GDFAYYRKNW LPGACIKQQK FSKNANQNYK IPASGGDALL KYDTHTTLNG RWSNMAPGPP MATAGAGDSD FSNSQLIFAG PNPSGNTTTS SNNLLFTSEE EIATTNPRDT DMFGQIADNN QNATTAPHIA NLDAMGIVPG MVWQNRDIYY QGPIWAKVPH TDGHFHPSPL MGGFGLKHPP PQIFIKNTPV PANPNTTFSA ARINSFLTQY STGQVAVQID WEIQKEHSKR WNPEVQFTSN YGTQNSMLWA PDNAGNYHEL RAIGSRFLTH HL.
本発明のウイルスベクターは、インビトロ、エクスビボ、およびインビボでの細胞への核酸の送達に有用である。特に、ウイルスベクターは、哺乳類を含む動物の細胞に核酸を送達または移行するために有利に用いられ得る。
本発明に係るウイルスベクターおよびキャプシドは、獣医および医療用途の両方において使用を見いだす。適切な対象は、鳥類および哺乳類の両方を含む。本明細書において用いられる用語「鳥類」は、制限されないが、ニワトリ、アヒル、ガチョウ、ウズラ、ターキー、キジ、オウム、インコなどを含む。本明細書において用いられる用語「哺乳類」は、制限されないが、ヒト、非ヒト霊長類、齧歯類、ウシ、ヒツジ、ヤギ、ウマ、ネコ、イヌ、ウサギなどを含む。ヒト対象は、新生児、幼児、青少年、成人および老人対象を含む。
組み換えアデノ随伴ウイルス(rAAV)は、網膜の遺伝子導入のための好ましいベクターとなっている。硝子体を通した網膜へのrAAVの送達は、網膜を効率的に形質導入する少数の血清型をもたらす。これらの少数の血清型は、ヘパラン硫酸プロテオグリカン(HSPG)に結合するキャプシドタンパク質を有する。キャプシドと受容体との間の相互作用は、改変された受容体の相互作用を有するrAAVキャプシドを用いて評価された。ウイルスは、成体マウスにおいて硝子体内に送達されて、8週後に評価された。rAAV2のヘパラン硫酸(HS)結合残基における突然変異は、内側網膜の形質導入を劇的に低減させた。非HS結合rAAV1のエレメントを、デザイナーキメラキャプシド、rAAV2.5を用いてrAAV2に付加した。rAAV2.5は、網膜血管に沿って形質導入して、ミューラーグリア細胞においてより多い発現を示した。rAAV1へのHS結合の付加は、rAAV2.5で観察される発現パターンに似た蛍光の増大を示した。HSおよびガラクトースの二重受容体相互作用を、最近になって設計されたキメラキャプシド、rAAV2G9を用いて評価して、ガラクトース結合の付加がキャプシド形質導入を高めるかどうかを決定した。rAAV2G9は、rAAV2と比較して、眼底による変更された蛍光パターンを明らかにした。rAAV2G9の形質導入プロファイルは、ミューラーグリアに対する向性におけるシフトを示した。合わせると、HS結合は、成功的な硝子体内形質導入に必須であり、この形質導入は、ガラクトース結合の付加によって特定の網膜細胞に曲げられ得る。
多くのアデノ随伴ウイルス(AAV)血清型は、網膜下の空間に送達された場合に網膜を効率的に形質導入するが、内境界膜(ILM)に起因して、硝子体に送達された場合は制限された成功を示す。rAAV2の網膜下送達およびそのHS結合欠損キャプシドは、HS非依存性のメカニズムによって引き起こされる外側網膜のrAAV2形質導入を示した。しかしながら、HS切断されたrAAV2の硝子体内送達は、rAAV2と比較して形質導入において300倍の低減をもたらす。AAV網膜トラフィッキングの蛍光in situハイブリダイゼーション(FISH)は、ILMにおけるAAV2蓄積のメカニズムが、HS結合によって影響を受けることを明らかにした。このメカニズムは、エクスビボでヒト網膜に対して試験されて、HS結合AAV2キャプシドでのみ同様の蓄積を示した。HS結合が他のAAV血清型に適合してそれらの形質導入を高めることができるかどうか評価するために、AAV1およびAAV8を、単一アミノ酸突然変異によってHSに結合するように改変して、マウスにおいて試験した。AAV1およびAAV8の両方のHS結合突然変異体は、それらの非HS結合の親キャプシドよりも高い硝子体内形質導入を有した。HS結合がAAV2向性に対して有する影響を理解するために、二重グリカン使用(dual glycan usage)のキメラキャプシドを、マウスにおいて硝子体内で試験した。HS結合のみと比較して、これらのキメラキャプシドは、向性における変化に相関する高い形質導入を示した。合わせると、これは、HS結合が、硝子体からILMへAAVキャプシドを隔離する役割を果たすが、向性に影響しないことを示す。HS結合キャプシドの高い網膜形質導入は、硝子体内送達に関する種を超えたキャプシド工学のための合理的な設計戦略を提供する。
Claims (9)
- 対象の網膜および/または網膜色素上皮の細胞に、核酸分子を導入する方法であって、
AAV4キャプシドタンパク質を含むアデノ随伴ウイルス(AAV)血清型4(AAV4)ベクターを硝子体内に投与するステップを含み、
前記AAV4キャプシドタンパク質は、アミノ酸残基K530において置換を含み、および/または、アミノ酸残基S584、N585、S586およびN587の1つまたは複数において任意の組み合わせで置換をさらに含み、
前記残基のナンバリングは、配列番号4(AAV4キャプシドタンパク質のアミノ酸配列)のアミノ酸配列に基づく、
方法。 - 対象の網膜および/または網膜色素上皮の細胞に、核酸分子を導入する方法であって、
AAV5キャプシドタンパク質を含むアデノ随伴ウイルス(AAV)血清型5(AAV5)ベクターを硝子体内に投与するステップを含み、
前記AAV5キャプシドタンパク質は、アミノ酸残基K517において置換を含み、および/または、アミノ酸残基S575、S576、T577およびT578の1つまたは複数において任意の組み合わせで置換をさらに含み、
前記残基のナンバリングは、配列番号5(AAV5キャプシドタンパク質のアミノ酸配列)のアミノ酸配列に基づく、
方法。 - 対象の網膜および/または網膜色素上皮の細胞に、核酸分子を導入する方法であって、
AAV7キャプシドタンパク質を含むアデノ随伴ウイルス(AAV)血清型7(AAV7)ベクターを硝子体内に投与するステップを含み、
前記AAV7キャプシドタンパク質は、アミノ酸残基K533において置換を含み、および/または、アミノ酸残基A587、A588、N589およびR590の1つまたは複数において任意の組み合わせで置換をさらに含み、
前記残基のナンバリングは、配列番号7(AAV7キャプシドタンパク質のアミノ酸配列)のアミノ酸配列に基づく、
方法。 - 対象の網膜および/または網膜色素上皮の細胞に、核酸分子を導入する方法であって、
AAV8キャプシドタンパク質を含むアデノ随伴ウイルス(AAV)血清型8(AAV8)ベクターを硝子体内に投与するステップを含み、
前記AAV8キャプシドタンパク質は、アミノ酸残基K533において置換を含み、および/または、アミノ酸残基Q587、Q588、N589およびT590の1つまたは複数において任意の組み合わせで置換をさらに含み、
前記残基のナンバリングは、配列番号8(AAV8キャプシドタンパク質のアミノ酸配列)のアミノ酸配列に基づく、
方法。 - 対象の網膜および/または網膜色素上皮の細胞に、核酸分子を導入する方法であって、
AAV9キャプシドタンパク質を含むアデノ随伴ウイルス(AAV)血清型9(AAV9)ベクターを硝子体内に投与するステップを含み、
前記AAV9キャプシドタンパク質は、アミノ酸残基K531において置換を含み、および/または、アミノ酸残基Q587、A588、N589およびT590の1つまたは複数において任意の組み合わせで置換をさらに含み、
前記残基のナンバリングは、配列番号9(AAV9キャプシドタンパク質のアミノ酸配列)のアミノ酸配列に基づく、
方法。 - 請求項1から5のいずれかの方法であって、
前記ベクターは、治療的タンパク質または治療的DNAをコードする核酸分子を含む、
方法。 - 対象における眼の障害または欠陥を治療する方法であって、
請求項1から6のいずれかのウイルスベクターを前記対象へ硝子体内に投与するステップを含み、
前記ウイルスベクターは、前記の対象における眼の障害または欠陥を治療するのに効果的な治療的タンパク質または治療的DNAをコードする核酸分子を含む、
方法。 - 請求項7の方法であって、
前記の眼の障害または欠陥は、加齢黄斑変性、レーバー先天性黒内障タイプ1、レーバー先天性黒内障タイプ2、網膜色素変性症、網膜分離症、色覚異常、色盲、先天性停止性夜盲症、またはそれらの任意の組み合わせに制限されない、
方法。 - 請求項1から8のいずれかの方法であって、
対象はヒトである、
方法。
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