JP2022107776A - 遺伝的状態の処置のための方法および組成物 - Google Patents
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Abstract
Description
本出願は、2013年5月15日に出願された米国仮特許出願第61/823,689号の利益を主張し、その開示は本明細書においてその全体が参考として援用される。
本開示は、ゲノム遺伝子操作の分野にある。
このCas9タンパク質は、少なくとも2つのヌクレアーゼドメインを有する:一方のヌクレアーゼドメインは、HNHエンドヌクレアーゼと類似しているが、他方は、Ruvエンドヌクレアーゼドメインと似ている。HNH型ドメインは、crRNAと相補的なDNA鎖を開裂させることを担うようであるが、Ruvドメインは、非相補鎖を開裂させる。
crRNA-tracrRNA複合体の要求は、crRNAおよびtracrRNAのアニーリングによって通常形成されるヘアピンを含む遺伝子操作された「単一ガイドRNA」(sgRNA)の使用によって回避され得る(Jinekら(2012年)Science 337巻:816頁およびCongら(2013年)Sciencexpress/10.1126/science.1231143を参照)。S.pyrogenesでは、遺伝子操作されたtracrRNA:crRNA融合物またはsgRNAは、Cas会合したRNAと標的DNAとの間で二本鎖RNA:DNAヘテロ二量体が形成する場合に、Cas9が標的DNAを開裂するようにガイドする。Cas9タンパク質とPAM配列を含む遺伝子操作されたsgRNAとを含むこの系は、RNAガイドされるゲノム編集に使用されており(Ramalingam同書を参照)、ZFNおよびTALENと類似の編集効率で、in vivoでゼブラフィッシュ胚ゲノム編集に有用である(Hwangら(2013年)Nature Biotechnology 31巻(3号):227頁を参照)。
associated with Antigen Processing)(TAP)1遺伝子、TAP2遺伝子、タパシン遺伝子(TAPBP)、クラスII主要組織適合複合体トランス活性化因子(CIITA)遺伝子、ジストロフィン遺伝子(DMD)、グルココルチコイド受容体遺伝子(GR)、IL2RG遺伝子、RFX5遺伝子、FAD2遺伝子、FAD3遺伝子、ZP15遺伝子、KASII遺伝子、MDH遺伝子および/またはEPSPS遺伝子からなる群から選択される。
本発明は、例えば、以下の項目も提供する。
(項目1)
細胞において内因性遺伝子の発現を修飾する方法であって、前記方法が、前記内因性遺伝子中の標的部位を認識する単一ガイドRNAを含む第1の核酸分子および機能的ドメインをコードする第2の核酸分子を前記細胞に投与するステップを含み、前記機能的ドメインが、前記標的部位上で前記単一ガイドRNAと会合し、それによって、前記内因性遺伝子の発現を修飾する、方法。
(項目2)
前記機能的ドメインが、転写活性化ドメイン、転写抑制ドメインおよびヌクレアーゼドメインからなる群から選択される、項目1に記載の方法。
(項目3)
前記機能的ドメインが、IIS型制限酵素ヌクレアーゼドメインまたはCasタンパク質である、項目2に記載の方法。
(項目4)
前記機能的ドメインが転写活性化ドメインであり、前記内因性遺伝子の発現が増加される、項目2に記載の方法。
(項目5)
前記機能的ドメインが転写抑制ドメインであり、前記内因性遺伝子の発現が阻害される、項目2に記載の方法。
(項目6)
前記機能的ドメインがヌクレアーゼであり、前記内因性遺伝子が開裂される、項目2に記載の方法。
(項目7)
前記ヌクレアーゼドメインが、前記Casタンパク質によって含まれる、項目6に記載の方法。
(項目8)
前記Casタンパク質が、もう1つのヌクレアーゼ開裂ドメインを含む、項目7に記載の方法。
(項目9)
前記細胞が、哺乳動物細胞または植物細胞である、項目1~8のいずれかに記載の方法。
(項目10)
前記哺乳動物細胞が幹細胞である、項目9に記載の方法。
(項目11)
前記内因性遺伝子が、哺乳動物βグロビン遺伝子(HBB)、ガンマグロビン遺伝子(HBG1)、B細胞リンパ腫/白血病11A(BCL11A)遺伝子、Kruppel様因子1(KLF1)遺伝子、CCR5遺伝子、CXCR4遺伝子、PPP1R12C(AAVS1)遺伝子、ヒポキサンチンホスホリボシルトランスフェラーゼ(HPRT)遺伝子、アルブミン遺伝子、第VIII因子遺伝子、第IX因子遺伝子、ロイシンリッチリピートキナーゼ2(LRRK2)遺伝子、ハンチンチン(Hungtingin)(Htt)遺伝子、ロドプシン(RHO)遺伝子、嚢胞性線維症膜コンダクタンス調節因子(CFTR)遺伝子、サーファクタントタンパク質B遺伝子(SFTPB)、T細胞受容体アルファ(TRAC)遺伝子、T細胞受容体ベータ(TRBC)遺伝子、プログラム細胞死1(PD1)遺伝子、細胞傷害性Tリンパ球抗原4(CTLA-4)遺伝子、ヒト白血球抗原(HLA)A遺伝子、HLA B遺伝子、HLA C遺伝子、HLA-DPA遺伝子、HLA-DQ遺伝子、HLA-DRA遺伝子、LMP7遺伝子、抗原ペプチド輸送体(TAP)1遺伝子、TAP2遺伝子、タパシン遺伝子(TAPBP)、クラスII主要組織適合複合体トランス活性化因子(CIITA)遺伝子、ジストロフィン遺伝子(DMD)、グルココルチコイド受容体遺伝子(GR)、IL2RG遺伝子およびRFX5遺伝子からなる群から選択される、項目1~9のいずれかに記載の方法。
(項目12)
前記内因性遺伝子が、植物FAD2遺伝子、植物FAD3遺伝子、植物ZP15遺伝子、植物KASII遺伝子、植物MDH遺伝子および植物EPSPS遺伝子からなる群から選択される、項目1~9のいずれかに記載の方法。
(項目13)
哺乳動物βグロビン遺伝子(HBB)、ガンマグロビン遺伝子(HBG1)、B細胞リンパ腫/白血病11A(BCL11A)遺伝子、Kruppel様因子1(KLF1)遺伝子、CCR5遺伝子、CXCR4遺伝子、PPP1R12C(AAVS1)遺伝子、ヒポキサンチンホスホリボシルトランスフェラーゼ(HPRT)遺伝子、アルブミン遺伝子、第VIII因子遺伝子、第IX因子遺伝子、ロイシンリッチリピートキナーゼ2(LRRK2)遺伝子、ハンチンチン(Htt)遺伝子、ロドプシン(RHO)遺伝子、嚢胞性線維症膜コンダクタンス調節因子(CFTR)遺伝子、サーファクタントタンパク質B遺伝子(SFTPB)、T細胞受容体アルファ(TRAC)遺伝子、T細胞受容体ベータ(TRBC)遺伝子、プログラム細胞死1(PD1)遺伝子、細胞傷害性Tリンパ球抗原4(CTLA-4)遺伝子、ヒト白血球抗原(HLA)A遺伝子、HLA B遺伝子、HLA C遺伝子、HLA-DPA遺伝子、HLA-DQ遺伝子、HLA-DRA遺伝子、LMP7遺伝子、抗原ペプチド輸送体(TAP)1遺伝子、TAP2遺伝子、タパシン遺伝子(TAPBP)、クラスII主要組織適合複合体トランス活性化因子(CIITA)遺伝子、ジストロフィン遺伝子(DMD)、グルココルチコイド受容体遺伝子(GR)、IL2RG遺伝子およびRFX5遺伝子からなる群から選択される内因性遺伝子に結合する、単一ガイドRNA。
(項目14)
植物FAD2遺伝子、植物FAD3遺伝子、植物ZP15遺伝子、植物KASII遺伝子、植物MDH遺伝子および植物EPSPS遺伝子からなる群から選択される内因性遺伝子に結合する、単一ガイドRNA。
(項目15)
配列番号149~215からなる群から選択される、項目13または14に記載の単一ガイドRNA。
Brower、ソフトウェア著作権the Regents of the University of Californiaに対してのものである。ヒトゲノム座標は、ヒトゲノムのGRCh37/hg19アセンブリにおいて提供され、二本鎖DNA上の数字に対応する。したがって、ゲノム座標によって記載される任意の位置は、(+)鎖もしくはWatson鎖のいずれかに対応するか、またはその対応する(-)鎖もしくはCrick鎖を特定し得る。
114巻(8号):1457~58頁を参照)。腫瘍は、PD1リガンドPD-L1を発現することが見出されており、または、より稀には、CTLにおけるPD1の上方調節と組み合わせた場合にT細胞機能性における損失およびCTLが有効な抗腫瘍応答を媒介できないことにおける寄与因子であり得るPD1リガンドPDL2を発現することが見出されている。研究者は、リンパ球性脈絡髄膜炎ウイルス(LCMV)に慢性に感染したマウスでは、抗PD1抗体の投与がPD1-PDL相互作用を遮断し、あるT細胞機能性(増殖およびサイトカイン分泌)を回復でき、ウイルス負荷における減少をもたらしたことを示している(Barberら(2006年)Nature 439巻(9号):682~687頁)。さらに、完全ヒトPD-1特異的IgG4モノクローナル抗体が、種々の疾患背景(進行メラノーマ、腎細胞癌、非小細胞肺がん、結腸直腸がんまたは前立腺がん)を有する患者に対して、腫瘍学設定においてクリニックで検査されてきた。臨床活性は、メラノーマ、腎細胞がんおよび非小細胞肺がんの患者において観察され、予備的データは、処置前の腫瘍によるPD1リガンド発現の検出が、臨床成績と相関することを示唆した(Wolfe(2012年)Oncology Business Review、7月;およびPardoll、同書を参照)。したがって、本発明の方法および組成物は、単一ガイドRNAがヒトPD1遺伝子(chr2:242792033~242801058)を標的化するための配列を含むCRISPR/Cas系を用いてPD1アレルを破壊するために使用され得る。ノックアウトのためにPD1遺伝子を標的化するための1つの好ましい領域は、そのATGタンパク質翻訳開始部位に近い領域またはその近傍にある。これは、PD1遺伝子のヌクレオチドchr2:242800981~242800982に対応する。S.pyogenes Cas9についてのPAM位置が、242800980位~242800981位、242800975位~242800976位、242800971位~242800972位、242800970位~242800971位、242800967位~242800968位および242800965位~242800966位において第2染色体またはその近傍に位置する、PD1遺伝子の標的部位が、特に好ましい。別の特に好ましい標的化位置は、PD-1リガンド結合ドメイン(第2染色体、ヌクレオチド242794834~242794835および242794828~242794829)の近くの領域周辺である。標的化のための別の好ましい領域は、免疫受容体チロシンベースのスイッチモチーフ(例えば、第2染色体242793349~242793350、242793338~242793339、242793330~242793331または242793327~242793328)の近くの領域またはその近傍にある。この領域中の突然変異は、PD1機能を無効にする。第2染色体:242800953~242800979、242794976~242795005、242794416~242794444および242793405~242793433またはその近傍の位置におけるS.pyogenes Cas9タンパク質のための標的部位が、特に好ましい。第VIII因子遺伝子のための好ましい標的化領域は、chrX:154064064~154250998に位置する遺伝子配列またはその近傍にある。第VIII因子遺伝子を標的化するために特に好ましいのは、イントロン22の領域であり、ここは、chrX:154091503~154124351またはその近傍に位置する、重症血友病A患者におけるFVIII突然変異の最大50%を占める一般的な逆位事象の部位である。第IX因子(F.IX)遺伝子について、標的化のために好ましいのは、chrX:138,612,895~138,645,617またはその近傍に位置する遺伝子配列である。例えば、chrX:138613760~138613816、chrX:138618832~138618887および/またはchrX:138613815~138613872またはその近傍において、イントロン1中の領域中の標的が、特に好ましい。したがって、sgRNAは、これらの好ましい標的化領域のうちの1または複数中の配列が含まれるがこれらに限定されない、PD1遺伝子座中のいずれかの場所の配列に結合するように設計され得る。標的化に適切な配列の非限定的な例を、表1に示す。
本明細書に開示される方法、ならびに組成物の調製および使用の実施は、特に示さない限り、本技術分野の技術範囲内の、分子生物学、生化学、クロマチン構造および分析、計算機化学、細胞培養、組換えDNAならびに関連分野における従来の技術を用いる。これらの技術は、文献中に完全に説明されている。例えば、SambrookらMOLECULAR CLONING: A LABORATORY MANUAL、第2版、Cold Spring Harbor Laboratory Press、1989年および第3版、2001年;Ausubelら、CURRENT PROTOCOLS IN MOLECULAR BIOLOGY、John Wiley & Sons、New York、1987年および定期的更新;シリーズMETHODS IN ENZYMOLOGY、Academic Press、San Diego;Wolffe、CHROMATIN STRUCTURE AND FUNCTION、第3版、Academic Press、San Diego、1998年;METHODS IN ENZYMOLOGY、304巻、「Chromatin」(P.M. WassarmanおよびA. P. Wolffe編)、Academic Press、San Diego、1999年;ならびにMETHODS IN MOLECULAR BIOLOGY、119巻、「Chromatin Protocols」(P.B. Becker編)Humana Press、Totowa、1999年を参照されたい。
用語「核酸」、「ポリヌクレオチド」および「オリゴヌクレオチド」は、相互交換可能に使用され、直鎖状または環状コンフォメーションの、一本鎖形態または二本鎖形態のいずれかの、デオキシリボヌクレオチドまたはリボヌクレオチドのポリマーを指す。本開示の目的のため、これらの用語は、ポリマーの長さに関して限定的であると解釈すべきではない。これらの用語は、天然ヌクレオチドの公知のアナログ、ならびに塩基、糖および/またはリン酸部分(例えば、ホスホロチオエート骨格)において修飾されたヌクレオチドを包含し得る。一般に、特定のヌクレオチドのアナログは、同じ塩基対合特異性を有する;即ち、Aのアナログは、Tと塩基対合する。
CRISPR/Cas系
RNA、14巻:2572~2579頁)。crRNA-tracrRNA複合体の要求は、crRNAおよびtracrRNAのアニーリングによって通常形成されるヘアピンを含む遺伝子操作された「単一ガイドRNA」(sgRNA)の使用によって回避され得る(Jinekら(2012年)Science 337巻:816頁およびCongら(2013年)Sciencexpress/10.1126/science.1231143を参照)。S.pyrogenesでは、遺伝子操作されたtracrRNA:crRNA融合物またはsgRNAは、二本鎖RNA:DNAヘテロ二量体がCas関連RNAと標的DNAとの間で形成する場合、Cas9が標的DNAを開裂するようにガイドする。Cas9タンパク質とPAM配列を含む遺伝子操作されたsgRNAとを含むこの系は、RNAガイドされるゲノム編集に使用されており(Ramalingam同書を参照)、ZFNおよびTALENと類似の編集効率で、in vivoでゼブラフィッシュ胚ゲノム編集に有用である(Hwangら(2013年)Nature Biotechnology 31巻(3号):227頁を参照)。
他のCasタンパク質
B.機能的ドメイン
CRISPR/CasのRNA構成成分
ドナー
送達
植物の送達
所与のZFNに指定された遺伝子座のゲノム編集の際に使用するためのガイドRNA(sgRNAまたはgRNA)の配列は、(i)ZFNヘテロ二量体の認識配列を、関連ゲノム(ヒト、マウスまたは特定の植物種)の参照配列とアライメントし、(ii)ZFN-ハーフ部位間のスペーサー領域を同定し、(iii)スペーサー領域に最も近いモチーフG[N20]GGの位置を同定し(1つよりも多いそのようなモチーフがスペーサーと重複する場合、このスペーサーに対して中心にあるモチーフが選択された)、(iv)gRNAのコアとしてそのモチーフを使用することによって同定された。表1は、CRISPR/Cas系を用いて使用するための一連のsgRNAを示す。目的の細胞を、表1のsgRNAと接触させて遺伝子操作する。
実施例1に記載されているように、sgRNAの設計は、種々の考慮、即ち(i)ZFNヘテロ二量体の認識配列を、関連ゲノム(ヒト、マウスまたは特定の植物種)の参照配列とアラインメントし、(ii)ZFN-ハーフ部位間のスペーサー領域を同定し、(iii)使用されているCas9タンパク質に関連し、スペーサー領域に最も近いPAMモチーフ(例えば、S.pyogenesのCas9を使用している場合のG[N17-20](G/A)G)の位置を同定し(1つよりも多いそのようなモチーフがスペーサーと重複する場合、スペーサーに対して中心にあるモチーフが選択された)、(iv)sgRNAのコアとしてそのモチーフを使用することを通して達成される。
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2015
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JP2019058193A (ja) | 2019-04-18 |
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US20160090607A1 (en) | 2016-03-31 |
US20180119175A1 (en) | 2018-05-03 |
US9873894B2 (en) | 2018-01-23 |
JP2020120690A (ja) | 2020-08-13 |
HK1223401A1 (zh) | 2017-07-28 |
CN116083487A (zh) | 2023-05-09 |
AU2014265331B2 (en) | 2019-12-05 |
EP2997146A2 (en) | 2016-03-23 |
US20180148740A1 (en) | 2018-05-31 |
JP2016521975A (ja) | 2016-07-28 |
JP6964103B2 (ja) | 2021-11-10 |
WO2014186585A2 (en) | 2014-11-20 |
CA2910489A1 (en) | 2014-11-20 |
CN105683376A (zh) | 2016-06-15 |
US10196652B2 (en) | 2019-02-05 |
WO2014186585A3 (en) | 2015-01-15 |
US9902974B2 (en) | 2018-02-27 |
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