JP2021518760A - 対になったcrisprニッカーゼリボ核タンパク質を用いる免疫関連ゲノムの遺伝子座の改変 - Google Patents
対になったcrisprニッカーゼリボ核タンパク質を用いる免疫関連ゲノムの遺伝子座の改変 Download PDFInfo
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Abstract
Description
本願は、2018年4月13日出願の米国仮出願第62/657488号に対して優先権を主張するものであり、参照によりその全体を本願明細書に一体化させる。
本願は、EFS−Webを介してASCIIフォーマットで提出された配列表を含み、参照によりその全体を本願明細書に一体化させる。2019年4月10日に作成されたASCIIコピーはP18_061_SL.txtと命名され、19607バイトのサイズである。
本開示の1の態様は、免疫機能に関与しているゲノムの遺伝子座を標的とする対になったCRISPRニッカーゼリボ核タンパク質を提供する。対になったCRISPRニッカーゼRNPsは、対象とするゲノムの遺伝子座中の標的部位とハイブリダイズするように設計された少なくとも一対のオフセットガイドRNAを含んでおり、その結果、コーディネートされたニッカーゼのニッキングは当該ゲノムの遺伝子座に二本鎖の破壊を生じさせ、そのことは、細胞のDNA修復プロセスにより修復された場合に、当該ゲノムの遺伝子座の改変を生じさせる。
一般的に、免疫関連ゲノムの遺伝子座を標的とするように、対になったCRISPRニッカーゼRNPsを設計することができる。ゲノムの遺伝子座は、例えば、免疫細胞のエフェクター機能の喪失に関連したものであってもよく、有利には、免疫細胞活性化状態とは区別される、別個のまたはカップリングしていないものであり、あるいは免疫細胞活性化状態から独立したものである。あるいは、ゲノムの遺伝子座は、例えば、免疫細胞活性化に関連したものであってもよく、有利には、免疫細胞機能不全状態とは区別される、別個のまたはカップリングしていないものであり、あるいは免疫細胞機能不全状態から独立したものである。したがって、様々な具体例において、例えば、活性化遺伝子座をそのままにしておきながら機能不全遺伝子座を標的化してもよい。
CRISPRニッカーゼは、CRISPRヌクレアーゼのヌクレアーゼドメインの1つを不活性化することにより得られる。特別な具体例において、CRISPRニッカーゼは、II型CRISPRヌクレアーゼから得ることができる。例えば、II型CRISPRヌクレアーゼはCas9タンパク質であり得る。適切なCas9ヌクレアーゼは、Streptococcus pyogenes Cas9(SpCas9)、Francisella novicida Cas9(FnCas9)、Staphylococcus aureus(SaCas9)、Streptococcus thermophilus Cas9(StCas9)、Streptococcus pasteurianus(SpaCas9)、Campylobacter jejuni Cas9(CjCas9)、Neisseria meningitis Cas9(NmCas9)またはNeisseria cinerea Cas9(NcCas9)を包含する。他の具体例において、ニッカーゼは、Cpf1ヌクレアーゼのごときV型CRISPRヌクレアーゼから得ることができる。適切なCpf1ヌクレアーゼは、Francisella novicida Cpf1(FnCpf1)、Acidaminococcus sp. Cpf1(AsCpf1)、またはLachnospiraceae bacterium ND2006 Cpf1(LbCpf1)を包含する。さらにもう1つの具体例において、ニッッカーゼは、VI型CRISPRヌクレアーゼ、例えばLeptotrichia wadei Cas13a(LwaCas13a)またはLeptotrichia shahii Cas13a(LshCas13a)から得ることができる。
対になったCRISPRニッカーゼRNPsは、対象とするゲノムの遺伝子座の対向鎖(opposite strand)上の標的配列にハイブリダイズするように設計された少なくとも一対のオフセットガイドRNAを含む。ガイドRNAは、(i)CRISPR RNA(crRNA)および(ii)実行(transacting)crRNA(tracrRNA)を含む。crRNAは、対象とするゲノムの遺伝子座中の標的配列(すなわちプロトスペーサー(protospacer))とハイブリダイズするように設計された5’末端のガイド配列を含む。標的配列は、ゲノムの残りの部分と比較した場合にユニークなものであり、プロトスペーサー隣接モチーフ(protospacer adjacent motif)(PAM)に隣接している。tracrRNAは、CRISPRタンパク質およびPAM配列と相互作用する配列を含む。各crRNAのガイド配列が異なっていても(すなわち配列特異的であっても)、一般的には、tracrRNAの配列は、特定の細菌種由来のCRISPRタンパク質と複合体を形成するように設計されたガイドRNAs中では同じである。
ある具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号31を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号32を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号33を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号34を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号33を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号32を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号39を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号40を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号41を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号42を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号43を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号44を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号45を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号46を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号47を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号48を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号49を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号50を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号51を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号52を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号53を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号54を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。他の具体例において、対になったCRISPRニッカーゼRNPsは、(i)配列番号55を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)および(ii)配列番号56を含むガイドRNAと複合体を形成しているCas9−D10A(+NLS)を含む。
本開示のさらなる態様は、上のセクション(I)で説明した対になったCRISPRニッカーゼRNPsを含むキットを提供する。いくつかの具体例において、CRISPRニッカーゼは、対になったガイドRNAのそれぞれと複合体を形成し、即使用可能なRNPsとして提供され得る。他の具体例において、CRISPRニッカーゼおよび対になったガイドRNAのそれぞれが、エンドユーザーに別々に提供され、使用前に複合体化されてRNPにされ得る。キットは、トランスフェクション試薬、細胞増殖培地、選択培地、反応バッファー等をさらに含み得る。いくつかの具体例において、キットは、対象とするゲノムの遺伝子座の遺伝子変換/修正のための1つまたはそれ以上のドナーポリヌクレオチドをさらに含み得る。一般的には、本発明により提供されるキットは、以下に説明する方法を実施するための説明書を含む。キットに含まれる説明書は包装材に付けられていてもよく、あるいは包装内に入れられていてもよい。典型的には説明書は手書きまたは印刷されたものであるが、そのようなものに限定されない。かかる説明書を保存し、それをエンドユーザーに届けることができる媒体はすべて本開示により企図される。かかる媒体は、限定するものではないが、電子的保存媒体(例えば、磁気ディスク、テープ、カートリッジ、チップ)、光学的媒体(例えば、CD ROM)等を包含する。本明細書の用語「説明書」は、説明書を提供するインターネットサイトのアドレスを包含し得る。
本開示のもう1つの態様は、真核細胞におけるゲノムの遺伝子座を効率的に改変する方法に関する。該方法は、上のセクション(I)で説明した対になったCRISPRニッカーゼRNPsを細胞に導入することを含み、CRISPRニッカーゼは協働して標的ゲノムの遺伝子座に二本鎖破壊を導入し、その結果、細胞の二本鎖破壊の修復がゲノムの遺伝子座の改変をもたらす。
該方法は、対になったCas9ニッカーゼRNAsを細胞に導入することを含む。いくつかの具体例において、細胞にデリバリーする直前に、CRISPRニッカーゼおよび対になったガイドRNAのそれぞれを複合体化させてRNPとすることができる。他の具体例において、細胞にデリバリーする前数陣、数日間、数週間または数ヶ月の間、CRISPRニッカーゼおよび対になったガイドRNAのそれぞれを複合体化させる(そして適切に保存する)ことができる。
いくつかの具体例において、該方法は、対象とするゲノムの遺伝子座の標的領域と比較して少なくとも1つのヌクレオチド変化を有するドナー配列を含む少なくとも1つのドナーポリヌクレオチドを細胞に導入することをさらに含む。したがって、元のゲノム配列への組み込みまたは交換によって、改変されたゲノムの遺伝子座は少なくとも1つのヌクレオチド変化を有し、その結果、細胞は改変された遺伝子産物を生産する。
該方法は、対になったCRISPRニッカーゼRNPsを真核細胞に導入することを含む。真核細胞はヒト細胞または動物細胞であり得る。大部分の具体例において、真核細胞は免疫細胞であり得る。適切な免疫細胞は、T細胞(例えば、キラーT細胞、ヘルパーT細胞、ガンマデルタT細胞)、B細胞(例えば、プロB−細胞、メモリーB細胞、形質細胞)、ナチュラルキラー(NK)細胞のごときリンパ球、好中球、単球/マクロファージ、顆粒球、マスト細胞、および樹状細胞を包含する。いくつかの具体例において、細胞は非免疫細胞であり得る。真核細胞は、初代細胞または細胞株の細胞であり得る。特別な具体例において、細胞はヒト初代T細胞であり得る。
本明細書に開示された組成物および方法を、様々な治療、診断、工業および研究用途に使用し得る。いくつかの具体例において、本開示を用いて免疫腫瘍学、癌の免疫療法、免疫療法、免疫治療、免疫診断、または他の免疫に基づく処理を開発、試験、および/または実施することができる。例えば、特定のタイプの乳癌(例えば、ER−陽性、PR−陽性、トリプルネガティブ等)、前立腺癌、肺癌、皮膚癌等を標的とするように特別な組成物を設計することができる。
もう1つの態様において、対象の治療方法、例えば、対象中の過剰増殖の症状または疾患(例えば、癌)、例えば固形腫瘍、軟組織腫瘍、または転移性病変を軽減または改善方法が提供される。該方法は、本明細書に記載の方法に従って典型的にはエクスビボにて細胞を改変し、改変された細胞を単独または他の薬剤または治療モダリティーと組み合わせて治療を要する対象にデリバリーまたは投与することを含む。
特に定義しない限り、本明細書中のすべての技術用語および科学用語は、本発明が属する技術分野の当業者によって通常に理解されている意味を有する。以下の文献は、本発明にて使用される多くの用語の一般的定義を当業者に提供する:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd Ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991)。本明細書で使用される以下の用語は、特に断らない限り、それらに起因する意味を有する。
以下の実施例は、本開示の特定の態様を説明するものである。
細胞表面受容体であるプログラム細胞死(Programmed cell death)−1(PD−1またはPCD−1)を、癌の免疫療法のチェックポイントブロケード(blockade)の可能性のある標的とする。PD−1に対するCRISPR−ニッカーゼRNPs用に対になったcrRNAsのセットを設計した(表1)。対になったcrRNAsをPAM−out方向に配置した。
SpCas9ヌクレアーゼRNPsおよびSpCas9ニッカーゼRNPsを実施例1で説明したようにして調製した。10%ヒトAB血清 (Sigma-Aldrich)、1x L-glutamine alternative (Gibco)、8ng/mL IL−2(Gibco)および50μMメルカプトエタノール(Sigma)を補充したT細胞拡大培地(Sigma-Aldrich)にてCD8+ヒト初代T細胞(AllCells, LLC)を維持した。ヌクレオフェクション(nucleofection)の7日前にT細胞拡大ビーズ(すなわち、DYNABEADSTM Human T-Expander CD3/CD28; Gibco)にて細胞を刺激した。1回のトランスフェクションあたりCD8+ヒト初代T細胞(約500x103個)を用い、実施例1で説明したようにしてヌクレオフェクションシステムを用いてトランスフェクションを行った。T細胞拡大ビーズの存在下で細胞を培養した。
NickFOR-ILLUMIPD1:
TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGNNNNNNGGACAACGCCACCTTCACCTG (配列番号:37)
NickREV-ILLUMIPD1: GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGNNNNNNCTACGACCCTGGAGCTCCTGAT (配列番号:38)
にてプライマーにタグを付した。
細胞毒性Tリンパ球タンパク質4(CTLA4)、T細胞免疫グロブリンおよびムチンドメイン含有−3(TIM-3; A型肝炎ウイスル細胞受容体2, HAVCR2とも呼ばれる)およびT細胞受容体アルファコンスタント(TRAC)は、癌の免疫療法における目立った標的またはゲノムの遺伝子座である。これらの標的に対するCRISPR−ニッカーゼRNPsのために対になったgRNAsのセットを設計した(表4)。化学的に修飾された単一のgRNAs(single gRNAs)(安定化のための2’−O−メチルおよびホスホロチオエート結合を含むmod-sgRNAs)を用いた。対になったmod−sgRNAをPAM−out方向に配置した。
K562細胞中の各標的に対する最も高い編集効率を有するSpCas9ニッカーゼRNPs(CTLA−4ペア#2、TIM−3ペア#3およびTRACペア#2)を、ヒト初代T細胞にて試験するために選択した。実施例3に記載したようにSpCas9ヌクレアーゼRNPsおよびSpCas9ニッカーゼRNPsを調製し;実施例2に記載したようにRNPsをヒト初代T細胞にデリバリーした。実施例3に記載したようにTIDE/ICEアッセイを用いることによりSpCas9ニッカーゼRNPsおよびSpCas9ヌクレアーゼRNPsの編集効率を測定した。結果を表6に示す。
真核細胞における標的化染色体の二本鎖の破壊(break)の特異性および頻度の両方を改善する対になったCRISPRニッカーゼRNPsの能力は、外来ドナーポリヌクレオチドの組み込み頻度を増加させるのにも有利であろう。外来ドナーポリヌクレオチドにてヒト体細胞免疫細胞のゲノムを遺伝学的に改変する能力は、様々な疾病(とりわけ癌、感染症)に対する免疫応答を改善するための多くの新たな選択肢を生じさせる。
Claims (32)
- 真核細胞中の免疫関連ゲノムの遺伝子座の改変方法であって、免疫関連ゲノムの遺伝子座における標的配列とハイブリダイズするように設計された一対のガイドRNAを含むClustered Regularly Interspaced Short Palindromic Repeats(CRISPR)ニッカーゼリボ核タンパク質(RNPs)を真核細胞に導入して、CRISPRニッカーゼRNPsによって作成された二本鎖の破壊の修復が該免疫関連ゲノムの遺伝子座の改変を引き起こすようにすることを含む、方法。
- 対になったガイドRNAsの標的配列が免疫関連ゲノムの遺伝子座の対向鎖(opposite strand)上にある、請求項1記載の方法。
- ガイドRNAの対が、標的配列の1つに隣接した各protospacer adjacent motif(PAM)配列が外向きになる(あるいは標的配列の遠位端に位置する)ように配置されている、請求項1または2記載の方法。
- PAM配列間の距離が約35塩基対ないし約120塩基対である、請求項3記載の方法。
- CRISPRニッカーゼRNPがCas9ニッカーゼ、Cpf1ニッカーゼまたはCas13aニッカーゼを含む、請求項1ないし4のいずれか1項記載の方法。
- CRISPRニッカーゼRNPがCas9ニッカーゼを含む、請求項1ないし5のいずれか1項記載の方法。
- Cas9ニッカーゼが、SpCas9ニッカーゼ、FnCas9ニッカーゼ、SaCas9ニッカーゼ、StCas9ニッカーゼ、SpaCas9ニッカーゼ、CjCas9ニッカーゼ、NmCas9ニッカーゼまたはNcCas9ニッカーゼを含む、請求項6記載の方法。
- Csa9ニッカーゼがSpCas9ニッカーゼ、FnCas9ニッカーゼまたはSaCas9ニッカーゼである、請求項6記載の方法。
- Cas9ニッカーゼがCas9−D10AニッカーゼまたはCas9−H840Aニッカーゼである、請求項6ないし8のいずれか1項記載の方法。
- Cas9ニッカーゼがCas9−D10Aニッカーゼである、請求項6ないし8のいずれか1項記載の方法。
- CRISPRニッカーゼが、少なくとも1つの核局在化シグナル、少なくとも1つの細胞透過ドメイン、少なくとも1つのクロマチン破壊ドメイン、またはそれらの組み合わせ
を含む、請求項1ないし10のいずれか1項記載の方法。 - CRISPRニッカーゼが少なくとも1つの核局在化シグナルを含む、請求項1ないし10のいずれか1項記載の方法。
- CRISPRニッカーゼに対するガイドRNAの対のモル比が約2:1ないし約10:1である、請求項1ないし12のいずれか1項記載の方法。
- CRISPRニッカーゼに対するガイドRNAの対のモル比が、0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4:1、4.5:1、5:1、5.5:1、6:1、6.5:1、7:1、7.5:1、8:1、8.5:1、9:1、9.5:1、または10:1である、請求項1ないし12のいずれか1項記載の方法。
- 真核細胞がヒト細胞または非ヒト哺乳動物細胞である、請求項1ないし14のいずれか1項記載の方法。
- 真核細胞が初代T細胞またはT細胞の集団である、請求項1ないし15のいずれか1項記載の方法。
- ガイドRNAの対が、(a)配列番号:31を含むガイドRNAおよび配列番号:32を含むガイドRNA、(b)配列番号:33を含むガイドRNAおよび配列番号:34を含むガイドRNA、(c)配列番号:33を含むガイドRNAおよび配列番号:32を含むガイドRNA、(d)配列番号:39を含むガイドRNAおよび配列番号:40を含むガイドRNA、(e)配列番号:41を含むガイドRNAおよび配列番号:42を含むガイドRNA、(f)配列番号:43を含むガイドRNAおよび配列番号:44を含むガイドRNA、(g)配列番号:45を含むガイドRNAおよび配列番号:46を含むガイドRNA、(h)配列番号:47を含むガイドRNAおよび配列番号:48を含むガイドRNA、(i)配列番号:49を含むガイドRNAおよび配列番号:50を含むガイドRNA、(j)配列番号:51を含むガイドRNAおよび配列番号:52を含むガイドRNA、(k)配列番号:53を含むガイドRNAおよび配列番号:54を含むガイドRNA、または(l)配列番号:55を含むガイドRNAおよび配列番号:56を含むガイドRNAから選択される、請求項1ないし16のいずれか1項記載の方法。
- 非相同末端結合(NHEJ)による二本鎖破壊の修復が、少なくとも1つのヌクレオチドの挿入、少なくとも1つのヌクレオチドの欠失、またはそれらの組み合わせを生じさせ、免疫関連ゲノムの遺伝子座を不活性化させる、請求項1ないし17のいずれか1項記載の方法。
- 免疫関連ゲノムの遺伝子座に関連した少なくとも1つのヌクレオチドの変化を有するドナー配列を含むドナーポリヌクレオチドを真核細胞に導入することを含み、相同性指向修復(HDR)による二本鎖破壊の修復が、免疫関連ゲノムの遺伝子座中へのドナー配列の組み込みまたは交換を生じさせ、その結果該免疫関連ゲノムの遺伝子座の改変が生じる、請求項1ないし17のいずれか1項記載の方法。
- 免疫関連ゲノムの遺伝子座が、2B4(CD244)、4−1BB(CD137)、A2aR、AAVS1、ACTB、ALB、B2M、B7.1、B7.2、B7−H2、B7−H3、B7−H4、B7−H6、BAFFR、BCL11A、BLAME(SLAMF8)、BTLA、ブチロフィリン、CCR5、CD100(SEMA4D)、CD103、CD11a、CD11b、CD11c、CD11d、CD150、IPO−3)、CD160、CD160(BY55)、CD18、CD19、CD2、CD27、CD28、CD29、CD30、CD4、CD40、CD47、CD48、CD49a、CD49D、CD49f、CD52、CD69、CD7、CD83、CD84、CD8アルファ、CD8ベータ、CD96(Tactile)、CDS、CEACAM1、CRTAM、CTLA4、CXCR4、DGK、DGKA、DGKB、DGKD、DGKE、DGKG、DGKI、DGKK、DGKQ、DGKZ、DHFR、DNAM1(CD226)、EP2/4受容体、A2ARを含むアデノシン受容体、FAS、FASLG、GADS、GITR、GM−CSF、gp49B、HHLA2、HLA−A、HLA−B、HLA−C、HLA−DPA1、HLA−DPB1、HIV−LTR(long terminal repeat)、HLA−DQA1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−I、HVEM、HVEM、IA4、ICAM−1、ICOS、ICOS、ICOS(CD278)、IFN−アルファ/ベータ/ガンマ、IL−1ベータ、IL−12、IL−15、IL−18、IL−23、IL2Rベータ、IL2Rガンマ、IL2RA、IL−6、IL7Rアルファ、ILT−2、ILT−4、ITGA4、ITGA4、ITGA6、ITGAD、ITGAE、ITGAL、ITGAM、ITGAX、ITGB1、ITGB2、ITGB7、KIRファミリー受容体、KLRG1、LAIR−1、LAT、LIGHT、LTBR、Ly9(CD229)、MNK1/2、NKG2C、NKG2D、NKp30、NKp44、NKp46、NKp80(KLRF1)、OX2R、OX40、PAG/Cbp、PD−1、PD−L1、PD−L2、PGE2受容体、PIR−B、PPP1R12C、PSGL1、PTPN2、RANCE/RANKL、ROSA26、SELPLG(CD162)、SIRPアルファ(CD47)、SLAM(SLAMF1、SLAMF4(CD244、2B4)、SLAMF5、SLAMF6(NTB−A、Ly108)、SLAMF7、SLP−76、TGFBR2、TIGIT、TIM−1、TIM−3、TIM−4、TMIGD2、TRA、TRAC、TRB、TRD、TRG、TNF、TNF−アルファ、TNFR2、TUBA1、VISTA、VLA1、またはVLA−6から選択される、上記いずれかの請求項記載の方法。
- 免疫関連ゲノムの遺伝子座がPD−1、CTLA−4、TIM−3またはTRACである、上記いずれかの請求項記載の方法。
- CRISPRニッカーゼおよび免疫関連ゲノムの遺伝子座を標的とするように設計された一対のガイドRNAを含む組成物。
- CRISPRニッカーゼがCas9ニッカーゼ、Cpf1ニッカーゼまたはCas13aニッカーゼである、請求項23記載の組成物。
- CRISPRニッカーゼがCas9ニッカーゼである、請求項24記載の組成物。
- Cas9ニッカーゼが、SpCas9ニッカーゼ、FnCas9ニッカーゼ、SaCas9ニッカーゼ、StCas9ニッカーゼ、SpaCas9ニッカーゼ、CjCas9ニッカーゼ、NmCas9ニッカーゼまたはNcCas9ニッカーゼを含む、請求項25記載の組成物。
- Csa9ニッカーゼがSpCas9ニッカーゼ、FnCas9ニッカーゼまたはSaCas9ニッカーゼである、請求項24ないし26のいずれか1項記載の方法。
- Cas9ニッカーゼがCas9−D10AニッカーゼまたはCas9−H840Aニッカーゼである、請求項24ないし27のいずれか1項記載の方法。
- Cas9ニッカーゼがCas9−D10Aニッカーゼである、請求項24ないし28のいずれか1項記載の方法。
- ガイドRNAの対が、(a)配列番号:31を含むガイドRNAおよび配列番号:32を含むガイドRNA、(b)配列番号:33を含むガイドRNAおよび配列番号:34を含むガイドRNA、(c)配列番号:33を含むガイドRNAおよび配列番号:32を含むガイドRNA、(d)配列番号:39を含むガイドRNAおよび配列番号:40を含むガイドRNA、(e)配列番号:41を含むガイドRNAおよび配列番号:42を含むガイドRNA、(f)配列番号:43を含むガイドRNAおよび配列番号:44を含むガイドRNA、(g)配列番号:45を含むガイドRNAおよび配列番号:46を含むガイドRNA、(h)配列番号:47を含むガイドRNAおよび配列番号:48を含むガイドRNA、(i)配列番号:49を含むガイドRNAおよび配列番号:50を含むガイドRNA、(j)配列番号:51を含むガイドRNAおよび配列番号:52を含むガイドRNA、(k)配列番号:53を含むガイドRNAおよび配列番号:54を含むガイドRNA、または(l)配列番号:55を含むガイドRNAおよび配列番号:56を含むガイドRNAから選択される、請求項23ないし29のいずれか1項記載の方法。
- 対象における癌の治療方法であって、請求項1ないし22のいずれか1項記載の方法に従ってエクスビボにおいて真核細胞中の免疫関連ゲノムの遺伝子座を改変して、改変された真核細胞を該対象にデリバリーすることを含む、方法。
- 真核細胞がT細胞またはT細胞の集団である、請求項31記載の方法。
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