JP2022033729A - 遺伝子改変細胞をポジティブに選択して、排除するための短ヘアピンrna(shrna734)およびその使用 - Google Patents
遺伝子改変細胞をポジティブに選択して、排除するための短ヘアピンrna(shrna734)およびその使用 Download PDFInfo
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Abstract
Description
本発明は、米国国立衛生研究所により授与されたAI028697、AI117941の下で政府の支援によりなされた。連邦政府は本発明に一定の権利を有する。
ファイルサイズ3kbの「UCLA239WOU1_SL」と命名された配列表のASCIIテキストファイルの内容は、2017年2月17日に作成され、本明細書とともにEFS-Web経由で電子提出された。配列表は、その全体が参照により本明細書に組み込まれる。
本発明は、短ヘアピンリボ核酸分子(shRNA)と、同リボ核酸分子を含みおよび/またはコードするポリヌクレオチドとを含み、これを用いてヒポキサンチングアニンホスホリポシルトランスフェラーゼ(HPRT)をノックダウンする(例えば、その発現を停止させる)ことができる、核酸分子、ならびに同分子を用いる方法に関する。本方法は、例えば、細胞においてHPRTをノックダウンする方法、細胞においてグアニン類似体代謝拮抗物質への耐性を付与する方法、選択可能な遺伝子改変細胞を作製する方法、目的の遺伝子で遺伝子改変した細胞を複数の細胞から選択する方法、目的の遺伝子で遺伝子改変した細胞を複数の細胞から除去する方法、およびある疾患または状態を有する対象、例えば、HIVに感染した対象を治療する方法を包含する。
このRNAに基づく技術には、既存のin vivo選択戦略に勝る利点がある。種々の薬剤耐性遺伝子を使用する以前のin vivo選択戦略を試験したが、許容できない毒性または不十分な選択効率を伴った。注目すべきことに、これらの手法は、大体において、外因性薬剤耐性遺伝子を過剰発現しているHSPCを、骨髄破壊的な放射線照射でプレコンディショニングされたレシピエントに移植することに依存してきた。
本出願において使用するすべての科学的および技術的用語は、特に定めない限り、当技術分野において通常使用される意味を有する。本出願で用いる場合、以下の語または句は明記する意味を有する。
本発明は、短ヘアピンリボ核酸分子(shRNA)と、同リボ核酸分子を含むポリヌクレオチドとを提供し、これを用いてヒポキサンチングアニンホスホリポシルトランスフェラーゼ(HPRT)をノックダウンする(例えば、その発現を停止させる)ことができる。一実施形態において、本発明は、shRNA734をコードする核酸配列を含むポリヌクレオチドを提供し、ここでshRNA734核酸配列は配列番号1である。
式中、
H1は、ヒトH1 RNAプロモーター(NCBI GenBank|S68670| H1 RNA遺伝子{プロモーター}ヒト、Genomic、497nt)であり、
UbCは、目的の遺伝子の発現を引き起こすために用いることができるヒトユビキチンプロモーター(ポリユビキチンのためのヒトUbC遺伝子、エクソン1~2、部分的コード領域、受入番号D63791)であり、
7SKは、ヒト7SK RNAプロモーター(ヒト細胞株HEK-293 7SK RNAプロモーター領域、完全配列、受入番号AY578685、配列番号3、あるいは配列番号4または5の新規変異型7SK RNAプロモーター)であり、
GFPは、緑色蛍光タンパク質(NCBI GenBank|L29345|オワンクラゲ(Aequorea victoria)緑色蛍光タンパク質(GFP)メッセンジャーmRNA、完全コード領域)であり、および
C46は、HIV融合阻害剤(Egelhofer M, Brandenburg G, Martinius H,ら,Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides.J Virol 2004;78(2):568-575.)である。
本発明は、細胞においてヒポキサンチングアニンホスホリボシルトランスフェラーゼ(HPRT)をノックダウンする方法をさらに提供し、該方法は細胞において配列番号1の発現を可能にする条件下で本発明のポリヌクレオチドと細胞を接触させることを含む。細胞においてグアニン類似体代謝拮抗物質に対する耐性を付与する方法も提供し、該方法は細胞において配列番号1の発現を可能にする条件下で本発明によるポリヌクレオチドと細胞を接触させることを含む。一実施形態において、グアニン類似体代謝物質は、6-チオグアニン(6TG)、6-メルカプトプリン(6-MP)またはアザチオプリン(AZA)である。細胞代表的な例としては、造血幹細胞、T細胞、末梢血単核球(PBMC)およびCD34+細胞が挙げられるが、これに限定されるものではない。本明細書に記載の方法での使用に適した他の細胞を当業者なら理解するであろう。
組成物は、薬学的に許容された担体とともに、任意の適した様式で投与されることが多い。本発明と関連して処置を対象に施す適切な方法が利用可能であり、および特定の組成物を投与するために複数の経路を使用することができるが、特定の経路は別の経路よりも速効性で効果的な反応をもたらし得ることが多い。
以下の実施例は、本発明を例示し、当業者がそれを作製し、使用するのを支援するために提示する。これらの実施例は、本発明の範囲を多少なりとも限定することを意図しない。
HSPCに基づく抗HIV遺伝子治療により、HIV治癒への期待が大きくなっているが、これまでの臨床試験は、主に抗HIV遺伝子改変HSPCによる造血再構成の効率の低さにより、限定的にしか成功しなかった。この実施例では、この限定を克服するための新規の化学選択手法を述べる。
この実施例は、ヒト化BLTマウスにおいてGFP発現ベクター改変細胞のin vivoでの安定性を改善する変異型7SK RNAプロモーターを記述する。新規プロモーターは、配列番号4に示す配列を有する。
Claims (1)
- 明細書または図面に実質的に記載された発明。
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JP7410856B2 (ja) | 2017-07-18 | 2024-01-10 | シーエスエル・ベーリング・ジーン・セラピー・インコーポレイテッド | ドナー改変細胞の選択のための調節可能スイッチ |
CA3123045A1 (en) * | 2018-12-23 | 2020-07-02 | Csl Behring L.L.C. | Donor t-cells with kill switch |
WO2020139796A1 (en) * | 2018-12-23 | 2020-07-02 | Csl Behring L.L.C. | Haematopoietic stem cell-gene therapy for wiskott-aldrich syndrome |
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JP2010520757A (ja) * | 2007-03-08 | 2010-06-17 | カリフォルニア インスティテュート オブ テクノロジー | 細胞内で細胞毒性を低減して抗ウイルス性小rna分子を発現させる方法 |
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AU7605796A (en) | 1996-11-04 | 1998-05-29 | Saint Jude Children's Research Hospital | (in vivo) selection of primitive hematopoietic cells |
US20030032003A1 (en) | 2000-02-02 | 2003-02-13 | Schiestl Robert H. | In vivo selection |
AU2002219828A1 (en) | 2000-11-14 | 2002-05-27 | The General Hospital Corporation | Blockade of T cell migration into epithelial GVHD target tissues |
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EP3416660A1 (en) | 2018-12-26 |
KR20180114008A (ko) | 2018-10-17 |
JP2019509034A (ja) | 2019-04-04 |
CN108495640A (zh) | 2018-09-04 |
US20210310007A1 (en) | 2021-10-07 |
US20230076635A1 (en) | 2023-03-09 |
US11377659B2 (en) | 2022-07-05 |
WO2017143266A1 (en) | 2017-08-24 |
JP7350361B2 (ja) | 2023-09-26 |
CN108495640B (zh) | 2022-11-04 |
EP3416660A4 (en) | 2019-11-06 |
HK1257668A1 (zh) | 2019-10-25 |
CA3012332A1 (en) | 2017-08-24 |
AU2017221456A1 (en) | 2018-07-19 |
AU2017221456B2 (en) | 2024-04-04 |
JP6975465B2 (ja) | 2021-12-08 |
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