JP6042825B2 - 改変された形質導入プロファイルを有するウイルスベクターならびにその製造および使用の方法 - Google Patents
改変された形質導入プロファイルを有するウイルスベクターならびにその製造および使用の方法 Download PDFInfo
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Description
本出願は、米国特許法第119(e)の下で、その全内容が引用することにより本明細書の一部をなすものとする2011年2月10日出願の米国仮特許出願第61/441,411号の利益を主張する。
本発明の態様は、国立衛生研究所からの助成金第HL089221号の下で資金提供されたものである。合衆国政府は、本発明において一定の権利を有する。
1 maadgylpdw lednlsegir ewwalkpgap qpkanqqhqd narglvlpgy kylgpgngld
61 kgepvnaada aalehdkayd qqlkagdnpy lkynhadaef qerlkedtsf ggnlgravfq
121 akkrlleplg lveeaaktap gkkrpveqsp qepdssagig ksgaqpakkr lnfgqtgdte
181 svpdpqpige ppaapsgvgs ltmasgggap vadnnegadg vgsssgnwhc dsqwlgdrvi
241 ttstrtwalp tynnhlykqi snstsggssn dnayfgystp wgyfdfnrfh chfsprdwqr
301 linnnwgfrp krlnfklfni qvkevtdnng vktiannlts tvqvftdsdy qlpyvlgsah
361 egclppfpad vfmipqygyl tlndgsqavg rssfycleyf psqmlrtgnn fqfsyefenv
421 pfhssyahsq sldrlmnpli dqylyylskt ingsgqnqqt lkfsvagpsn mavqgrnyip
481 gpsyrqqrvs ttvtqnnNSE FAWPgasswa lngrnslmnp gpamashkeg edrffplsgs
541 lifgkqgtgr dnvdadkvmi tneeeikttn pvatesygqv aTNHQSAqaQ AQTGWvqnqg
601 ilpgmvwqdr dvylqgpiwa kiphtdgnfh psplmggfgm khpppqilik ntpvpadppt
661 afnkdklnsf itqystgqvs veiewelqke nskrwnpeiq ytsnyyksnn vefavntegv
721 yseprpigtr yltrnl
単数形「a」、「an」および「the」は、文脈が明らかに他を示さない限り、複数形も同様に含むことが意図される。
本発明は、AAV(例えば、AAV9またはクレードF AAV)のカプシドタンパク質における改変が、改変されたAAVカプシドタンパク質を含むウイルスベクターに、肝臓の形質導入の低下が含まれるがこれに限定されない1つまたは複数の所望の特性を付与できるという、予想外の発見に基づいている。従って、本発明は、従来のAAVベクターに関連する制限のいくつかに取り組むものである。例えば、AAV8ベクターおよびrAAV9ベクターに基づくベクターは、内皮細胞障壁を容易に横切るので、全身性核酸送達には魅力的である;しかし、rAAV8またはrAAV9の全身性投与では、殆どのベクターが肝臓に送達されるという結果をまねき、それにより、骨格筋などの他の重要な標的組織の形質導入が低下する。
本発明は、本発明のウイルスベクターを生成する方法をさらに提供する。1つの代表的実施形態では、本発明は、ウイルスベクターを生成する方法を提供し、この方法は、(a)少なくとも1つのTR配列(例えば、AAV TR配列)を含む核酸鋳型と、(b)核酸鋳型の複製およびAAVカプシド中へのカプシド封入に充分なAAV配列(例えば、本発明のAAVカプシドをコードするAAV rep配列およびAAV cap配列)とを、細胞に提供するステップを含む。任意選択的に、核酸鋳型は、少なくとも1つの異種核酸配列をさらに含む。特定の実施形態では、核酸鋳型は2つのAAV ITR配列を含み、これらは、(存在する場合)異種核酸配列に対して5’側および3’側に位置するが、異種核酸配列と直接隣接している必要はない。
本発明のウイルスベクターは、in vitro、ex vivoおよびin vivoで細胞に核酸を送達するために有用である。特に、ウイルスベクターは、例えば哺乳動物細胞を含む動物細胞に核酸を送達または移入するために有利に使用され得る。
本発明に従うウイルスベクターおよびカプシドは、獣医学適用および医療適用の両方において用途を見出す。適切な対象には、トリおよび哺乳動物の両方が含まれる。用語「トリ」には、本明細書中で使用する場合、ニワトリ、アヒル、ガチョウ、ウズラ、シチメンチョウ、キジ、オウム、インコなどが含まれるがこれらに限定されない。用語「哺乳動物」には、本明細書中で使用する場合、ヒト、非ヒト霊長類、ウシ、ヒツジ、ヤギ、ウマ、ネコ、イヌ、ウサギなどが含まれるがこれらに限定されない。ヒト対象には、新生児、乳幼児、若年、成人および老人の対象が含まれる。
本発明の態様は、肝臓トロピズムの選択的な喪失を示し、心臓および筋骨格遺伝子移入適用のための可能性を実証する、新規クラスのAAV9由来ベクターの開発に関する。主要AAV9カプシドタンパク質の表面曝露した領域内の残基のランダム変異誘発により、正二十面体の三回対称軸においてクラスター化した変異を有するカプシドライブラリーを得た。配列分析、構造モデルおよびin vivoスクリーニングの組み合わせを使用して、いくつかの機能的に多様なAAV9バリアントを同定した。後者を、親AAV9に関して、以下を示す3つの機能的下位群に分類した:(I)複数の組織にわたる減少した形質導入効率;(II)肝臓形質導入における選択的減少、または(III)類似の形質導入プロファイル。特に、バリアント9.45および9.61(下位群II)は、肝臓における10分の1〜25分の1の遺伝子移入効率を示したが、AAV9と同様に効率的に心筋および骨格筋を形質導入した。これらの結果は、ベクターゲノムコピーの定量およびレポーター(tdTomato)遺伝子発現の組織学的分析によって、さらに実証された。この研究は、他の標的化戦略と組み合わせた場合に明確に分離した遺伝子発現を可能にし得る、選択的に除去された組織トロピズムを有するAAVベクターを生成することの実行可能性を強調している。
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Claims (15)
- AAV9 VP1の番号付けによるW503R変異、N498Y及びL602F変異、E500D及びP468T変異、またはそれらの任意の組み合わせを含み、前記変異が、対照と比較して減少した肝臓形質導入の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるW503R変異、N498I変異、E500D及びP468T変異、またはそれらの任意の組み合わせを含み、前記変異が、対照と比較して減少した肝臓形質導入の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるW503R変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して減少した肝臓形質導入の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるN498Y及びL602F変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して減少した肝臓形質導入の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるN498I変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して減少した肝臓形質導入の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるW503R変異、N498Y及びL602F変異、E500D及びP468T変異またはそれらの任意の組み合わせを含み、前記変異が、対照と比較して低下したガラクトシル化グリカン結合親和性の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるW503R変異、N498I変異、E500D及びP468T変異、またはそれらの任意の組み合わせを含み、前記変異が、対照と比較して低下したガラクトシル化グリカン結合親和性の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるW503R変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して低下したガラクトシル化グリカン結合親和性の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるN498Y及びL602F変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して低下したガラクトシル化グリカン結合親和性の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- AAV9 VP1の番号付けによるN498I変異を含むAAV9またはクレードF AAVカプシドタンパク質であって、前記変異が、対照と比較して低下したガラクトシル化グリカン結合親和性の表現型を生じる、AAV9またはクレードF AAVカプシドタンパク質。
- 請求項1〜10のいずれか1項に記載のAAVカプシドタンパク質を含むAAVカプシド。
- (a)請求項11に記載のAAVカプシドと、
(b)少なくとも1つの末端反復配列を含む核酸と
を含むウイルスベクターであって、前記核酸が、AAVカプシドによってカプシド封入されている、ウイルスベクター。 - 薬学的に許容される担体中に、請求項12に記載のウイルスベクターを含む組成物。
- 請求項12に記載のウイルスベクターまたは請求項13に記載の組成物に、インビトロで細胞を接触させるステップを含む、細胞中に核酸を導入する方法。
- ヒト対象を治療するための、請求項13に記載の組成物。
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