JP2020535828A - フェニルケトン尿症を処置するための、プロモーターとエンハンサーの組み合わせを有するベクター - Google Patents
フェニルケトン尿症を処置するための、プロモーターとエンハンサーの組み合わせを有するベクター Download PDFInfo
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Abstract
Description
本願は、「VECTORS WITH PROMOTER AND ENHANCER COMBINATIONS FOR TREATING PHENYLKETONURIA」という名称の2017年10月2日に出願された米国仮特許出願第62/566,979号の優先権を主張し、その開示内容全体が、参照により、本明細書に組み込まれる。
本開示は、治療用ベクターおよび細胞への治療用ベクターの送達に関する。実施形態において、治療用ベクターは、PAH配列またはその改変体および肝臓特異的エンハンサーを含む。実施形態において、治療用ベクターは、宿主(すなわち、内在性)PAHタンパク質発現を制御する低分子RNAも含む。
本明細書中に別段の定義が為されていなければ、本開示に関連して使用される科学用語および技術用語は、当業者によって一般的に理解されている意味を有するものとする。さらに、文脈によって別段の要求がされていなければ、単数形の用語は複数を含むものとし、複数形の用語は単数を含むものとする。一般的に、本明細書に記載されている、細胞および組織培養、分子生物学、免疫学、微生物学、遺伝学ならびにタンパク質および核酸化学およびハイブリダイゼーションと関連して使用される命名法およびこれらの技術は、周知のものであり、一般的に本分野において使用されているものである。別段の記載がなければ、本開示の方法および技術は、一般に、本分野において周知の慣用的な方法に従って、ならびに本明細書を通じて引用および論述されている様々な一般的およびより具体的な参考文献に記載されているとおりに実施される。例えば、Sambrook J.&Russell D.Molecular Cloning:A Laboratory Manual,3rd ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(2000);Ausubelら、Short Protocols in Molecular Biology:A Compendium of Methods from Current Protocols in Molecular Biology,Wiley,John&Sons,Inc.(2002);Harlow and Lane Using Antibodies:A Laboratory Manual;Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(1998);およびColiganら、Short Protocols in Protein Science,Wiley,John&Sons,Inc.(2003)を参照されたい。あらゆる酵素的反応または精製技術は、製造業者の仕様に従って、本分野で一般的に達成されるように、または本明細書に記載されているように行われる。本明細書に記載されている分析化学、合成有機化学および医化学および薬化学に関連して使用される命名法ならびにこれらの研究室手技および技術は、本分野において周知であり、一般的に使用されるものである。
本開示の一態様において、ウイルスベクターは治療用カーゴ部分を含み、治療用カーゴ部分は、PAH配列またはその改変体と、プロモーターと、肝臓特異的エンハンサーとを含み、PAH配列またはその改変体は、プロモーターおよび肝臓特異的エンハンサーの両方によって作動的に調節される。
PKUは、PAHの変異および/またはPAH補因子(すなわち、BH4)の合成または再生の欠陥によって引き起こされると考えられている。注目すべきことに、いくつかのPAH変異は、小胞体中でのタンパク質の折り畳みに影響を与えることが示されており、酵素触媒活性を減弱させまたは大きく消失させる、タンパク質構造中のミスセンス変異(63%)および小さな欠失(13%)に起因する加速された分解および/または凝集をもたらす。PAHの機能性に影響を及ぼすことができる多数の変異が存在するので、PKUを処置するための有効な治療的アプローチは、異常なPAHおよび代替PAHが投与され得る様式に対処することが必要であろう。
遺伝子医薬は、疾患の治療または予防を目的として、遺伝子構築物を宿主細胞に送達するために使用されるウイルスベクターへの言及を含む。
本明細書の様々な態様および実施形態にしたがうレンチウイルスのビリオン(粒子)は、ビリオン(ウイルス粒子)を産生するために必要なウイルスタンパク質をコードするベクター系によって発現される。様々な実施形態において、レンチウイルスのPolタンパク質をコードする核酸配列を含有する1つのベクターは、プロモーターに作動可能に連結されて、逆転写および組み込みのために提供される。別の実施形態において、Polタンパク質は、複数のベクターによって発現される。他の実施形態において、プロモーターに作動可能に連結された、ウイルスカプシドを形成するためのレンチウイルスのGagタンパク質をコードする核酸配列を含有するベクターが提供される。実施形態において、このgag核酸配列は、pol核酸配列の少なくともいくつかとは別個のベクター上にある。
開示されているベクター組成物は、目的の遺伝子または配列の短期、中期または長期発現および開示されたベクターのエピソームとしての維持を可能にする。したがって、投薬レジメンは、処置されている状態および投与の方法に基づいて変動し得る。
TCGCATTTCATCAAGATTAATCTCGAGATTAATCTTGATGAAATGCGATTTTT(配列番号13)
ACTCATAAAGGAGCATATAAGCTCGAGCTTATATGCTCCTTTATGAGTTTTTT(配列番号14)
Claims (38)
- 治療用カーゴ部分を含むウイルスベクターであって、前記治療用カーゴ部分が、
PAH配列またはその改変体と;
プロモーターと;
肝臓特異的エンハンサーと、
を含み、
前記PAH配列またはその改変体が、前記プロモーターおよび前記肝臓特異的エンハンサーの両方によって作動的に調節される、
ウイルスベクター。 - 前記肝臓特異的エンハンサーがプロトロンビンエンハンサーを含む、請求項1に記載のウイルスベクター。
- 前記プロモーターが肝臓特異的プロモーターを含む、請求項2に記載のウイルスベクター。
- 前記肝臓特異的プロモーターがhAATプロモーターを含む、請求項3に記載のウイルスベクター。
- 前記PAH配列またはその改変体が末端切断されている、請求項1に記載のウイルスベクター。
- 前記PAH配列またはその改変体の末端切断された部分が、前記PAH配列またはその改変体の3’非翻訳領域(UTR)である、請求項5に記載のウイルスベクター。
- 前記治療用カーゴ部分がβグロビンイントロンをさらに含む、請求項1に記載のウイルスベクター。
- 前記治療用カーゴ部分が、少なくとも1つの肝細胞核因子結合部位をさらに含む、請求項1に記載のウイルスベクター。
- 前記少なくとも1つの肝細胞核因子結合部位が、前記プロトロンビンエンハンサーの上流に配置されている、請求項8に記載のウイルスベクター。
- 前記少なくとも1つの肝細胞核因子結合部位が、前記プロトロンビンエンハンサーの下流に配置されている、請求項8に記載のウイルスベクター。
- 前記PAH配列またはその改変体が、配列番号1、配列番号2、配列番号3または配列番号4と少なくとも80%または少なくとも85%または少なくとも90%または少なくとも95%のパーセント同一性を有する配列を含む、請求項1に記載のウイルスベクター。
- 前記PAH配列またはその改変体が、配列番号1、配列番号2、配列番号3または配列番号4を含む、請求項11に記載のウイルスベクター。
- 前記プロトロンビンエンハンサーが、配列番号5と少なくとも80%または少なくとも85%または少なくとも90%または少なくとも95%のパーセント同一性を有する配列を含む、請求項2に記載のウイルスベクター。
- 前記プロトロンビンエンハンサーの配列が配列番号5を含む、請求項2に記載のウイルスベクター。
- 前記hAATプロモーターの配列が配列番号6を含む、請求項4に記載のウイルスベクター。
- βグロビンイントロンの配列が配列番号7または8を含む、請求項5に記載のウイルスベクター。
- 肝細胞核因子結合部位の配列が、配列番号9〜12のいずれか1つを含む、請求項6に記載のウイルスベクター。
- 前記治療用カーゴ部分が、少なくとも1つの所定の相補的mRNA配列に結合することが可能な少なくとも1つの低分子RNA配列をさらに含む、請求項1に記載のウイルスベクター。
- 前記少なくとも1つの低分子RNA配列が、完全長UTRを含有する相補的mRNA配列を標的とする、請求項18に記載のウイルスベクター。
- 前記少なくとも1つの所定の相補的mRNA配列がPAHmRNA配列である、請求項18に記載のウイルスベクター。
- 前記少なくとも1つの低分子RNA配列がshRNAを含む、請求項18に記載のウイルスベクター。
- 前記少なくとも1つの低分子RNA配列が第一のプロモーターの調節下にあり、かつ前記PAH配列またはその改変体が第二のプロモーターの調節下にある、請求項18に記載のウイルスベクター。
- 前記第一のプロモーターがH1プロモーターを含む、請求項20に記載のウイルスベクター。
- 前記第二のプロモーターが肝臓特異的プロモーターを含む、請求項20に記載のウイルスベクター。
- 前記肝臓特異的プロモーターがhAATプロモーターを含む、請求項24に記載のウイルスベクター。
- 前記少なくとも1つの低分子RNA配列が、配列番号13または配列番号14と少なくとも80%または少なくとも85%または少なくとも90%または少なくとも95%のパーセント同一性を有する配列を含む、請求項18に記載のウイルスベクター。
- 前記少なくとも1つの低分子RNA配列が配列番号13または配列番号14を含む、請求項21に記載のウイルスベクター。
- 前記ウイルスベクターがレンチウイルスベクターである、請求項1に記載のウイルスベクター。
- 標的細胞に感染することが可能なレンチウイルス粒子であって、前記レンチウイルス粒子が、
前記標的細胞に感染することに関して最適化されたエンベロープタンパク質と;
請求項1に記載のウイルスベクターと;
を含む、レンチウイルス粒子。 - 前記標的細胞が、肝細胞、筋肉細胞、上皮細胞、内皮細胞、神経細胞、神経内分泌細胞、内分泌細胞、リンパ球、骨髄系細胞、実質臓器内に存在する細胞または造血系統の細胞、造血幹細胞もしくは前駆造血幹細胞である、請求項29に記載のレンチウイルス粒子。
- 被験体中のPKUを処置する方法であって、治療的有効量の請求項29または30に記載のレンチウイルス粒子を前記被験体に投与することを含む、方法。
- 被験体中のPKUを予防する方法であって、治療的有効量の請求項29または30に記載のレンチウイルス粒子を前記被験体に投与することを含む、方法。
- PKU表現型と相関する、前記被験体においてPKU遺伝子型を診断することをさらに含む、請求項31または32に記載の方法。
- 前記被験体が子宮内に存在する、請求項31または32に記載の方法。
- 前記診断することが、前記被験体の出生前スクリーニングの間に行われる、請求項33に記載の方法。
- 前記診断することがインビトロで行われる、請求項33に記載の方法。
- 前記治療的有効量の前記レンチウイルス粒子が、複数の単回用量の前記レンチウイルス粒子を含む、請求項31または32に記載の方法。
- 前記治療的有効量の前記レンチウイルス粒子が、単回用量の前記レンチウイルス粒子を含む、請求項31または32に記載の方法。
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KR20200057766A (ko) | 2020-05-26 |
EP3692157A2 (en) | 2020-08-12 |
BR112020006672A2 (pt) | 2020-09-24 |
CN111433368A (zh) | 2020-07-17 |
IL273670A (en) | 2020-05-31 |
CA3077355A1 (en) | 2019-04-11 |
EP3692157A4 (en) | 2021-06-23 |
US20200318081A1 (en) | 2020-10-08 |
WO2019070674A3 (en) | 2019-05-23 |
AU2018345745A1 (en) | 2020-04-30 |
WO2019070674A2 (en) | 2019-04-11 |
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