JP2021515572A - キャプシド改変による組織特異的遺伝子送達の増加 - Google Patents
キャプシド改変による組織特異的遺伝子送達の増加 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、2018年3月16日出願の米国仮特許出願第62/644,317号(その内容は、本明細書に参考として援用される)の優先権を主張する。
本発明は、国立衛生研究所および国立先進トランスレーショナル科学センターによって授与された助成金番号82081315の下で政府支援を受けてなされた。政府は、本発明において一定の権利を有する。
[0002.1]
配列表
本出願は、ASCIIフォーマットで電子提出されており、その全体において参考として援用される配列表を含む。上記ASCIIコピー(作成日:2019年2月26日)は、名称106887−7170_SL.txtであり、サイズ18,492バイトである。
遺伝子送達の改善のために、AAVキャプシドを改変する努力がなされてきた。例えば、WO 2017/165859A1は、Cas9をウイルスキャプシドタンパク質に融合または結合体化させてカスタマイズ可能な遺伝子編集を促進する、ウイルスキャプシド改変を記載する。さらなる参考文献は、DNAファミリーシャフリングの使用(Grimm and Kay)、AAVrh74に対するリジン置換(US 2015/006556)、AAVrh74の195位、199位、201位、または202位での変異(US 9,840,719)、およびAAVrh48に対する改変(EP 2359866)を記載している。なおさらなる参考文献は、AAV表面にディスプレイされているランダムペプチドライブラリー(例えば、Muller (2003) Nat. Biotechnol., Perabo (2003) Mol. Ther., および7,588,722(Grimm and Kay))を詳述する。
現在、全身性に注射されるウイルスのうちの50%超が、肝臓において喪失し、肝臓では、治療効果は通常はほとんど実現されない[4]。肝臓へのベクター送達の標的化を解除し、そして筋特異的結合および形質導入を増加させることによって、筋特異的遺伝子発現および患者に対する治療利益を有意に改善し得、それと同時に、潜在的副作用を低減し得る。現在、デュシェンヌ型筋ジストロフィーの処置の臨床試験は、筋において治療レベルの遺伝子発現を達成しようと試みるために、高レベルのベクター(>5E+12 ベクターゲノム/kg)の送達を要する。筋特異的プロモーターは、「オフターゲット」遺伝子発現を低減するために使用されるが、遺伝子発現の全体的レベルを増加させることに対しては何の効果もない。筋特異的形質導入の効率を増加させることによって、治療利益を達成するために必要とされる全体的な用量を、有意に低減し得る。
本開示は、先行技術の制限に対処し、関連する利点も提供する。
出願人は、ウイルスが循環するにつれて、肝細胞の感染を低減または排除することになる、筋細胞へのベクターの全身送達を増加させるためのアプローチを提唱する。出願人は、改変されたAAVrh74キャプシドが、改変されていないAAVrh74ベクターより効率的に筋肉の筋芽細胞およびサテライト細胞を標的化すると仮定する。
本開示に従う実施形態は、本明細書中以降、より詳細に記載される。しかし、本開示の局面は、異なる形態で具現化され得、本明細書で示される実施形態に限定されると解釈されるべきでない。むしろ、これらの実施形態は、本開示が完全で完璧であり、本発明の範囲を当業者に十分に伝えるように提供される。本明細書中の記載において使用される用語法は、特定の実施形態を記載する目的に過ぎず、限定されることは意図されない。
本技術の実施は、別段示されなければ、有機化学、薬理学、免疫学、分子生物学、微生物学、細胞生物学、および組換えDNAの従来の技術を使用し、これらの技術は、当該分野の技術範囲内である。例えば、以下を参照のこと:Sambrook, Fritsch and Maniatis, Molecular Cloning: A Laboratory Manual, 第2版(1989); Current Protocols In Molecular Biology (F. M. Ausubel, et al.編,(1987));シリーズ、Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor編(1995)), Harlow and Lane,編(1988) Antibodies, a Laboratory Manual, and Animal Cell Culture (R.I. Freshney, 編(1987))。
改変されたウイルスキャプシドおよび調製方法
AAVベクター送達は現在、そのウイルスの天然の向性に基づいて、または標的組織への直接注射によって、組織標的化のための血清型選択を使用することに依拠する。最大の治療利益を達成するために全身送達が必要とされる場合、血清型選択は、組織特異的プロモーターと合わせて、組織標的化のための唯一の利用可能な選択肢である。本明細書で記載される場合、出願人は、レセプター結合および進入を担う特定のアミノ酸を同定し、それによって、AAVrh74における重要なアミノ酸を同定するために精巧な変異誘発研究の必要性を低減するアプローチを有する[7−11](図1)。肝臓の標的化解除のための重要な領域を同定したが、出願人は、筋特異的ベクター形質導入を富化する改変されたキャプシドを開発した。肝臓におけるベクター喪失の低減と、目的の遺伝子の筋細胞特異的送達とを組み合わせるという実際的な影響は、神経筋疾患の全身処置において臨床上の有効性の閾値を満たす見込みを大いに改善する。
本明細書で記載されるとおりのウイルスベクター、単離された細胞、パッケージングシステム、ウイルス粒子およびキャリアのうちのいずれか1種またはこれより多くを含む組成物またはキットがまた、本発明によって提供される。一局面において、そのキャリアは、薬学的に受容可能なキャリアである。これらの組成物は、本明細書で記載されるように治療的に使用され得、他の公知の治療と組み合わせて使用され得る。
アミノ酸置換または1〜7個の間のアミノ酸の挿入によって改変された、改変されたウイルスキャプシドタンパク質を含む非ヒトトランスジェニック動物が、本明細書で提供される。いくつかの実施形態において、ウイルスキャプシドタンパク質は、VP1、必要に応じてAAVrh74のVP1である。さらなる実施形態において、その改変は、AAVrh74のVP1のアミノ酸502位でアスパラギンの代わりにイソロイシンを使用することまたは等価な改変を含む。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、その改変は、AAVrh74のVP1のアミノ酸505でのトリプトファンからアルギニンへの置換を含む。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、その改変は、主にサテライト細胞で、必要に応じて、筋幹細胞で見出されるレセプターを標的化する。いくつかの実施形態において、その改変は、AAVrh74のVP1のアミノ酸591位でのペプチドYIGまたはYIGSR(配列番号2)の挿入である。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、このペプチドは、α7β1インテグリンに対して高い親和性を有する、および/または正常なrh74レセプター結合を変化させる可能性のある領域に配置される。
本開示はまた、特定の実施形態、例えば、改変されたキャプシドを含むか、または代わりにそれから本質的になる組換えウイルス粒子を含む改変されたアデノ随伴ウイルス(AAV)を提供し、ここでその改変されたキャプシドは、アミノ酸置換または1〜7個の間のアミノ酸の挿入によって改変された、改変されたウイルスキャプシドタンパク質を含むか、または代わりにそれから本質的になるか、またはさらになおそれからなる改変されたウイルスキャプシドタンパク質を含む。いくつかの実施形態において、ウイルスキャプシドタンパク質は、VP1、必要に応じてAAVrh74のVP1である。さらなる実施形態において、その改変は、AAVrh74のVP1のアミノ酸502位でアスパラギンの代わりにイソロイシンを使用することまたは等価な改変を含む。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、その改変は、AAVrh74のVP1のアミノ酸505でのトリプトファンからアルギニンへの置換を含む。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、その改変は、主にサテライト細胞で、必要に応じて、筋幹細胞で見出されるレセプターを標的化する。いくつかの実施形態において、その改変は、AAVrh74のVP1のアミノ酸591位でのペプチドYIGまたはYIGSR(配列番号2)の挿入である。いくつかの局面において、そのペプチドにおける他のアミノ酸は改変されるが、この置換は維持される。いくつかの実施形態において、このペプチドは、α7β1インテグリンに対して高い親和性を有する、および/または正常なrh74レセプター結合を変化させる可能性のある領域に配置される。
筋サテライト細胞は、骨格筋における筋線維細胞より60倍豊富にある[2]。それらは、骨格筋の長期の再生能力を容易にする、自己再生する幹細胞集団である[12]。近年、いくつかのFACSソート可能なマーカーが、筋幹細胞の単離のために同定されている[13](図2)。α7β1インテグリンは、陽性の筋幹細胞選択マーカーとして同定されており、骨格筋芽細胞および成体筋線維上の主なラミニンレセプターでもある。発現試験から、α7β1インテグリンは心臓および骨格筋組織上で豊富に発現され、肝臓組織においてはごく低レベルが見出されることが示されている。出願人は、そのAAVrh74キャプシドを改変して、α7β1インテグリンタンパク質に高親和性で結合することが示されているペプチドを発現させた。出願人は、そのペプチドを、α7β1インテグリンを結合レセプターとして利用するために、正常なAAVrh74レセプター結合モチーフを変化させる可能性がある領域に配置した。肝臓特異的結合および進入に必要であると仮説を立てたAAVrh74の他のアミノ酸における2つのさらなる変異も同定され、ベクターの静脈内注射後に、レポーター遺伝子の増加した全体的および/または筋特異的送達を可能にすることが示された(図3〜5)。
別段定義されなければ、本明細書で使用される全ての技術用語および科学用語は、本技術が属する分野の当業者によって一般に理解されるものと同じ意味を有する。
Claims (15)
- AAVrh74のVP1のアミノ酸502位でアスパラギンの代わりにイソロイシンを使用すること、アミノ酸505でのトリプトファンからアルギニンへの置換、およびAAVrh74のVP1のアミノ酸591位でのペプチドYIGまたはYIGSR(配列番号2)の挿入、またはそれら各々の等価物の群から選択される1またはこれより多くの改変を含む、改変されたAAVrh74 VP1キャプシドタンパク質。
- 請求項1に記載の改変されたAAVrh74 VP1を含む組換えウイルス粒子。
- 前記組換えウイルス粒子は、改変されたAAVrh74である、請求項2に記載の組換えウイルス粒子。
- 導入遺伝子またはCRISPRシステムをさらに含む、請求項1〜3のいずれかに記載の組換えウイルス粒子。
- 必要に応じて、ベクター内に含まれる、請求項1に記載の改変されたAAVrh74 VP1をコードするポリヌクレオチドおよび/または請求項2もしくは3に記載の組換えウイルス粒子。
- 必要に応じて請求項5に記載のベクターを含む、請求項3に記載の組換えウイルス粒子を生成するための組換え発現系。
- 請求項5に記載のポリヌクレオチドまたはベクターを含む、宿主細胞。
- 細胞においてポリヌクレオチドおよび/またはタンパク質を改変するための方法であって、前記方法は、前記細胞に、有効量の、請求項1もしくは4に記載の改変されたキャプシドタンパク質を含む組換えウイルス粒子、または請求項2に記載のウイルス粒子を送達することを包含する方法。
- 前記細胞は、哺乳動物細胞である、請求項8に記載の方法。
- 前記哺乳動物細胞はヒト細胞である、請求項9に記載の方法。
- 被験体においてポリヌクレオチドおよび/またはタンパク質を改変するための方法であって、前記方法は、前記被験体に、有効量の、請求項1もしくは4に記載の改変されたキャプシドタンパク質を含む組換えウイルス粒子、または請求項2に記載のウイルス粒子を投与することを包含する方法。
- 前記被験体は、哺乳動物である、請求項11に記載の方法。
- 前記哺乳動物はヒトである、請求項12に記載の方法。
- 前記投与は、局所または全身である、請求項11〜13のいずれか1項に記載の方法。
- 請求項1もしくは4に記載の改変されたキャプシドタンパク質を含む組換えウイルス粒子、または請求項2に記載のウイルス粒子を含むキット。
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US20210087584A1 (en) | 2021-03-25 |
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CN111819286A (zh) | 2020-10-23 |
BR112020018354A2 (pt) | 2020-12-29 |
JP2023115149A (ja) | 2023-08-18 |
JP7304878B2 (ja) | 2023-07-07 |
EP3765624A4 (en) | 2022-05-25 |
KR20200131843A (ko) | 2020-11-24 |
RU2020131998A (ru) | 2022-04-18 |
WO2019178412A1 (en) | 2019-09-19 |
EP3765624A1 (en) | 2021-01-20 |
CN111819286B (zh) | 2024-05-24 |
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CA3092353A1 (en) | 2019-09-19 |
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