JP7542595B2 - 配列操作のための系、方法および最適化ガイド組成物のエンジニアリング - Google Patents
配列操作のための系、方法および最適化ガイド組成物のエンジニアリング Download PDFInfo
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Description
本出願は、2013年6月17日に出願された米国仮特許出願第61/836,127号明細書、標題ENGINEERING OF SYSTEMS,METHODS AND OPTIMIZED COMPOSITIONS FOR SEQUENCE MANIPULATIONの優先権を主張する。本出願は、米国仮特許出願第61/758,468号明細書;同第61/769,046号明細書;同第61/802,174号明細書;同第61/806,375号明細書;同第61/814,263号明細書;同第61/819,803号明細書および同第61/828,130号明細書の優先権も主張し、それぞれ標題ENGINEERING AND OPTIMIZATION OF SYSTEMS,METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATIONであり、それぞれ2013年1月30日;2013年2月25日;2013年3月15日;2013年3月28日;2013年4月20日;2013年5月6日および2013年5月28日に出願されたものである。それぞれ2012年12月12日および2013年1月2日に出願された両方とも標題SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATIONの米国仮特許出願第61/736,527号明細書および同第61/748,427号明細書の優先権も主張される。それぞれ2013年3月15日および2013年6月17日に出願された両方とも標題BI-2011/008/44790.02.2003およびBI-2011/008/44790.03.2003の米国仮特許出願第61/791,409号明細書および同第61/835,931号明細書の優先権も主張される。
2013年6月17日にそれぞれ出願された米国仮特許出願第61/835,936号明細書、同第61/836,101号明細書、同第61/836,080号明細書、同第61/836,123号明細書および同第61/835,973号明細書も参照される。
本発明は、米国国立衛生研究所(National Institutes of Health)、NIHパイオニアアワードDP1MH100706により助成された政府支援によりなされた。米国政府は本発明において一定の権利を有する。
いて、Cas9酵素は、肺炎連鎖球菌(S.pneumoniae)、化膿性連鎖球菌(S.pyogenes)またはS.サーモフィラス(S.thermophilus)Cas9であり、それらの生物に由来する突然変異Cas9を含み得る。一部の実施形態において、CRISPR酵素は、真核細胞中の発現のためにコドン最適化されている。一部の実施形態において、CRISPR酵素は、標的配列の局在における1つまたは2つの鎖の開裂を指向する。一部の実施形態において、CRISPR酵素は、DNA鎖開裂活性を欠く。
または
I.CRISPR-Cas系キメラRNA(chiRNA)ポリヌクレオチド配列に作動可能に結合している第1の調節エレメント(ポリヌクレオチド配列は、(a)真核細胞中の1つ以上の標的配列にハイブリダイズし得る1つ以上のガイド配列、(b)tracrメイト配列、および(c)1つ以上のtracr配列を含む)、およびII.少なくとも1つ以上の核局在化配列を含むCRISPR酵素をコードする酵素コード配列に作動可能に結合している第2の調節エレメントを含み、(a)、(b)および(c)は、5'から3'配向で配置されており、成分IおよびIIは、系の同一または異なるベクター上にあり、転写されるとtracrメイト配列がtracr配列にハイブリダイズし、かつガイド配列が標的配列へのCRISPR複合体の配列特異的結合を指向し、CRISPR複合体は、(1)標的配列にハイブリダイズされるガイド配列、および(2)tracr配列にハイブリダイズされるtracrメイト配列と複合体形成しているCRISPR酵素含む1つ以上のベクターを含むベクター系によりコードされるCRISPR酵素系、またはI.(a)細胞中の標的配列にハイブリダイズし得る1つ以上のガイド配列、および(b)少なくとも1つ以上のtracrメイト配列に作動可能に結合している第1の調節エレメント、II.CRISPR酵素をコードする酵素コード配列に作動可能に結合している第2の調節エレメント、ならびにIII.tracr配列に作動可能に結合している第3の調節エレメントを含み、成分I、IIおよびIIIは、系の同一または異なるベクター上にあり、転写されるとtracrメイト配列がtracr配列にハイブリダイズし、かつガイド配列が標的配列へのCRISPR複合体の配列特異的結合を指向し、CRISPR複合体は、(1)標的配列にハイブリダイズされるガイド配列、および(2)tracr配列にハイブリダイズされるtracrメイト配列と複合体形成しているCRISPR酵素を含み、多重化系において、複数のガイド配列および単一のtracr配列が使用される1つ以上のベクターを含むベクター系によりコードされる多重化CRISPR酵素系(ガイド、tracrおよびtracrメイト配列の1つ以上は、安定性を改善するように改変されている)を提供する。
のポリT配列の出現率の低減を含み得る。配列最適化は、tracrメイト配列とtracr配列との間のハイブリダイゼーションの領域の低減;例えば、tracr配列の長さの低減と組み合わせることができる。
ってもよく;Wは、AまたはTである)は、ゲノム中の単一発生を有する。ゲノム中のユニーク標的配列としては、フォームMMMMMMMMMNNNNNNNNNNNXXAGAAWのS.サーモフィラス(S.thermophilus)CRISPR1Cas9標的部位を挙げることができ、NNNNNNNNNNNXXAGAAW(Nは、A、G、T、またはCであり;Xは、いずれであってもよく;Wは、AまたはTである)は、ゲノム中の単一発生を有する。化膿性連鎖球菌(S.pyogenes)Cas9について、ゲノム中のユニーク標的配列としては、フォームMMMMMMMMNNNNNNNNNNNNXGGXGのCas9標的部位を挙げることができ、NNNNNNNNNNNNXGGXG(Nは、A、G、T、またはCであり;Xは、いずれであってもよい)は、ゲノム中の単一発生を有する。ゲノム中のユニーク標的配列としては、フォームMMMMMMMMMNNNNNNNNNNNXGGXGの化膿性連鎖球菌(S.pyogenes)Cas9標的部位を挙げることができ、NNNNNNNNNNNXGGXG(Nは、A、G、T、またはCであり;Xは、いずれであってもよい)は、ゲノム中の単一発生を有する。これらの配列のそれぞれにおいて、「M」は、A、G、T、またはCであり得、配列をユニークと同定するにあたり考慮する必要はない。
びパッケージングに十分であり、次いでそれを使用して治療遺伝子を標的細胞中にインテグレートして恒久的なトランス遺伝子発現を提供する。広く使用されるレトロウイルスベクターとしては、ネズミ白血病ウイルス(MuLV)、テナガザル白血病ウイルス(GaLV)、サル免疫不全ウイルス(SIV)、ヒト免疫不全ウイルス(HIV)をベースとするもの、またはそれらの組合せが挙げられる(例えば、Buchscher et al.,J.Virol.66:2731-2739(1992);Johann et al.,J.Virol.66:1635-1640(1992);Sommnerfelt et al.,Virol.176:58-59(1990);Wilson et al.,J.Virol.63:2374-2378(1989);Miller et al.,J.Virol.65:2220-2224(1991);PCT/US94/05700号明細書参照)。
々の資源から入手可能である(例えば、American Type Culture Collection(ATCC)(Manassus,Va.)参照)。一部の実施形態において、本明細書に記載の1つ以上のベクターにより形質移入された細胞を使用して1つ以上のベクター由来配列を含む新たな細胞系を樹立する。一部の実施形態において、本明細書に記載のCRISPR系の成分により一過的に形質移入され(例えば、1つ以上のベクターの一過的形質移入、またはRNAによる形質移入により)、CRISPR複合体の活性を通して改変された細胞を使用して改変を含有するがあらゆる他の外因性配列を欠く細胞を含む新たな細胞系を樹立する。一部の実施形態において、本明細書に記載の1つ以上のベクターにより一過的にまたは非一過的に形質移入された細胞、またはそのような細胞に由来する細胞系を、1つ以上の試験化合物の評価において使用する。
例示的なII型CRISPR系は、4つの遺伝子Cas9、Cas1、Cas2、およびCsn1のクラスター、ならびに2つの非コードRNAエレメント、tracrRNAおよび非反復配列の短いストレッチ(スペーサー、それぞれ約30bp)により間隔が空いている反復配列の特徴的アレイ(ダイレクトリピート)を含有する化膿性連鎖球菌(Streptococcus pyogenes)SF370からのII型CRISPR遺伝子座である。この系において、ターゲティングされるDNA二本鎖切断(DSB)を4つの連続ステップにおいて生成する(図2A)。第1に、2つの非コードRNA、プレcrRNAアレイおよびtracrRNAがCRISPR遺伝子座から転写される。第2に、tracrRNAがプレcrRNAのダイレクトリピートにハイブリダイズし、次いでそれが個々のスペーサー配列を含有する成熟crRNAにプロセシングされる。第3に、成熟crRNA:tracrRNA複合体がCas9を、crRNAのスペーサー領域とプロトスペーサーDNAとの間のヘテロ二本鎖形成を介してプロトスペーサーおよび対応するPAMからなるDNA標的に指向する。最後に、Cas9は、PAMの上流の標的DNAの開裂を媒介してプロトスペーサー内でDSBを創成する(図2A)。この例は、このRNAプログラマブルヌクレアーゼ系を適応させて真核細胞の核中のCRISPR複合体活性を指向する例示プロセスを記載する。
27%に達するインデル生成の効率で開裂された(図4および5)。
性を保持した(図4B)。PAMの他、SpCas9は、スペーサーの最後の12bp内の単一塩基特異性を有する。さらに、CRISPRは、同一EMX1プロトスペーサーをターゲティングするTALEヌクレアーゼ(TALEN)のペアと同程度に効率的にゲノム開裂を媒介し得る。図4Cは、EMX1をターゲティングするTALENの設計を示す模式図を提供し、図4Dは、TALENおよびCas9の効率を比較するSurveyorゲルを示す(n=3)。
配列特異的DNA開裂をプログラミングするためにRNAを使用する技能は、種々の研究および産業用途のための新たなクラスのゲノムエンジニアリングツールを定義する。CRISPR系のいくつかの態様は、CRISPRターゲティングの効率および多用途性を増加させるようにさらに改善することができる。最適なCas9活性は、哺乳動物核中に存在するものよりも高いレベルにおけるフリーMg2+の利用可能性に依存し得(例えば、Jinek et al.,2012,Science,337:816参照)、プロトスペーサーのすぐ下流のNGGモチーフについての優先性は、ヒトゲノム中で平均12bpごとでターゲティング能を制限する。これらの拘束の一部は、微生物メタゲノムにわたるCRISPR遺伝子座の多様性を利用することにより克服することができる(例えば、Makarova et al.,2011,Nat Rev Microbiol,9:467参照)。他のCRISPR遺伝子座を、実施例1に記載のものと同様の方法により哺乳動物細胞環境中に移植することができる。それぞれの標的部位における改変効率をRNA二次構造の下方に示す。この構造を生成するアルゴリズムは、それぞれの塩基を予測二次構造を仮定するその確率に従って着色する。RNAガイドスペーサー1および2は、それぞれ14%および6.4%を誘導した。これらの2つのプロトスペーサー部位における生物学的複製物にわたる開裂活性の統計的分析も図7に提供する。
規定のCRISPR酵素についての所望のガイド配列長およびCRISPRモチーフ配列(PAM)に基づきインプットDNA配列の両方の鎖上の候補CRISPR標的配列を同定するためのソフトウェアプログラムを設計する。例えば、化膿性連鎖球菌(S.pyogenes)からのCas9についての標的部位は、PAM配列NGGを用いて、インプット配列およびインプットの逆相補鎖の両方の上の5'-Nx-NGG-3'を探索することにより同定することができる。同様に、S.サーモフィラス(S.thermophilus)CRISPR1のCas9についての標的部位は、PAM配列NNAGAAWを用いて、インプット配列およびインプットの逆相補鎖の両方の上の5'-Nx-NNAGAAW-3'を探索することにより同定することができる。同様に、S.サーモフィラス(S.thermophilus)CRISPR3のCas9についての標的部位は、PAM配列NGGNGを用いて、インプット配列およびインプットの逆相補鎖の両方の上の5'-Nx-NGGNG-3'を探索することにより同定することができる。Nx中の値「x」は、プログラムにより固定し、または使用者により規定することができ、例えば、20である。
本実施例は、異なる長さの野生型tracrRNA配列を取り込むtracr配列を有するキメラRNA(chiRNA;ガイド配列、tracrメイト配列、およびtracr配列を単一転写物中で含む)について得られた結果を記載する。図18aは、キメラRNAおよびCas9のためのバイシストロニック発現ベクターの模式図を説明する。Cas9はCBhプロモーターによりドライブされ、キメラRNAはU6プロモーターによりドライブされる。キメラガイドRNAは、からなる。示される種々の位置においてトランケートされたtracr配列(下方の鎖の最初の「U」から転写物の末端に及ぶ)に結合している20bpのガイド配列(N)からなる。ガイドおよびtracr配列は、tracrメイト配列GUUUUAGAGCUAと、それに続くループ配列GAAAにより離隔している。ヒト遺伝子座EMX1およびPVALB遺伝子座におけるCas9媒介インデルについてのSURVEYORアッセイの結果を、それぞれ図18bおよび18cに説明する。矢印は、予測SURVEYOR断片を示す。chiRNAをそれらの「+n」表記により示し、crRNAは、ガイドおよびtracr配列が別個の転写物として発現されるハイブリッドRNAを指す。トリプリケートで実施されたこれらの結果の定量を、図11aおよび11bにヒストグラムにより示し、それぞれ図10bおよび10cに対応する(「N.D.」は、インデルが検出されなかったことを示す)。プロトスペーサーIDおよびそれらの対応するゲノム標的、プロトスペーサー配列、PAM配列、および鎖局在を表Dに提供する。ガイド配列は、ハイブリッド系における別個の転写物の場合、プロトスペーサー配列全体に相補的であるように、またはキメラRNAの場合、下線部にのみ相補的であるように設計した。
ヒト胚腎臓(HEK)細胞系293FT(Life Technologies)を、10%のウシ胎仔血清(HyClone)、2mMのGlutaMAX(Life Technologies)、100U/mLのペニシリン、および100μg/mLのストレプトマイシンが補給されたダルベッコ改変イーグル培地(DMEM)中で37℃において5%のCO2インキュベーションで維持した。293FT細胞を24ウェルプレート(Corning)上に、形質移入24時間前に1ウェル当たり150,000個の細胞の密度において播種した。Lipofectamine2000(Life Technologies)を製造業者の推奨プロトコルに従って使用して細胞を形質移入した。24ウェルプレートのそれぞれのウェルについて、合計500ngのプラスミドを使用した。
293FT細胞を上記プラスミドDNAにより形質移入した。細胞を37℃において形質移入後72時間インキュベートしてからゲノムDNAを抽出した。ゲノムDNAは、QuickExtract DNA Extraction Solution(Epicentre)を製造業者のプロトコルに従って使用して抽出した。手短に述べると、ペレット化細胞をQuickExtract溶液中で再懸濁させ、65℃において15分間および98℃において10分間インキュベートした。それぞれの遺伝子についてのCRISPR標的部位をフランキングするゲノム領域を、PCR増幅し(表Eに列記のプライマー)、QiaQuick Spin Column(Qiagen)を製造業者のプロトコルに従って使用して産物を精製した。合計400ngの精製PCR産物を2μlの10×Taq DNA Polymerase PCR緩衝液(Enzymatics)と混合し、超純水で20μlの最終容量とし、リアニーリングプロセスに供してヘテロ二本鎖形成を可能とした:95℃において10分間、-2℃/秒における傾斜で95℃から85℃、-0.25℃/秒における85℃から25℃、および25℃において1分間維持。リアニーリング後、産物をSURVEYORヌクレアーゼおよびSURVEYORエンハンサーS(Transgenomics)により製造業者の推奨プロトコルに従って処理し、4~20%のNovex TBEポリアクリルアミドゲル(Life Technologies)上で分析した。ゲルをSYBR Gold DNA染色(Life Technologies)により30分間染色し、Gel Docゲルイメージングシステム(Bio-rad)によりイメージングした。定量は、相対バンド強度に基づくものであった。
ヒト、マウス、ラット、ゼブラフィッシュ、ミバエ、および線虫(C.elegans)ゲノム中の化膿性連鎖球菌(S.pyogenes)SF370Cas9(SpCas9)酵素についてのユニーク標的部位を同定するため、本出願人らは、DNA配列の両方の鎖をスキャンし、考えられる全てのSpCas9標的部位を同定するためのソフトウェアパッケージを開発した。この実施例について、それぞれのSpCas9標的部位を20bp配列と、それに続くNGGプロトスペーサー隣接モチーフ(PAM)配列として操作上定義し、本出願人らは、全ての染色体上のこの5'-N20-NGG-3'定義を満たす全ての配列を同定した。非特異的ゲノム編集を防止するため、全ての潜在的な部位を同定した後、全ての標的部位をそれらが関連参照ゲノム中で出現する回数に基づきフィルタリングした。例えば、PAM配列から5'側の約11~12bp配列であり得る「シード」配列により付与されるCas9活性の配列特異性を利用するため、5'-NNNNNNNNNN-NGG-3'配列を関連ゲノム中でユニークであると選択した。全てのゲノム配列をUCSCゲノムブラウザからダウンロードした(ヒトゲノムhg19、マウスゲノムmm9、ラットゲノムrn5、ゼブラフィッシュゲノムdanRer7、キイロショウジョウバエ(D.melanogaster)ゲノムdm4および線虫(C.elegans)ゲノムce10)。全探索結果は、UCSCゲノムブラウザ情報を使用して閲覧利用可能である。ヒトゲノム中の一部の標的部位の例示的可視化を図22に提供する。
本出願人らは、tracrRNAおよびダイレクトリピート配列を突然変異させ、またはキメラガイドRNAを突然変異させて細胞中のRNAを向上させた。
本出願人らは、図12に示されるガイドキメラRNAを設計した。
本出願人らは、小分子量を有するCas9についてメタゲノム検索を実施した。ほとんどのCas9ホモログはかなり大きい。例えば、SpCas9は、約1368aa長であり、送達のためのウイルスベクター中に容易にパッケージングされるには大きすぎる。配列の一部は誤ってアノテートされており、したがって、それぞれの長さについての正確な頻度は、必ずしも的確であるとは限らない。それにもかかわらず、これは、Cas9タンパク質の分布における徴候を提供し、より短いCas9ホモログが存在することを示唆する。
本出願人らは、最大開裂効率を有する最適なトランケートアーキテクチャーのためのSaCas9のための5つのsgRNAバリアントを設計した。さらに、天然ダイレクトリピート:tracr二本鎖系をsgRNAと並行して試験した。示される長さを有するガイドをSaCas9と同時形質移入し、HEK293FT細胞中で活性について試験した。合計100ngのsgRNA U6-PCRアンプリコン(または50ngのダイレクトリピートおよび50ngのtracrRNA)および400ngのSaCas9プラスミドを200,000個のHepa1-6マウス肝細胞中に同時形質移入し、SURVEYOR分析のために形質移入から72時間後にDNAを回収した。結果を図23に示す。
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Claims (26)
- CRISPR-Cas系キメラRNA(chiRNA)を含む組成物であって、
chiRNAは、5’から3’に、
(a)真核細胞の核内においてプロトスペーサー隣接モチーフ(PAM)に隣接する標的配列にハイブリダイズできるガイド配列、
(b)tracr配列にハイブリダイズできるtracrメイト配列、および
(c)少なくとも30ヌクレオチド長を含むtracr配列
を含み、
chiRNAは Cas9タンパク質とCRISPR-Cas複合体を形成することができ、真核細胞におけるPAMに隣接する標的配列へのCRISPR-Cas複合体の配列特異的結合を指向する、組成物。 - tracr配列が少なくとも40のヌクレオチド長を含む、請求項1に記載の組成物。
- tracr配列が少なくとも50のヌクレオチド長を含む、請求項1に記載の組成物。
- ガイド配列が15~25のヌクレオチド長を含む、請求項1~3の何れか一項に記載の組成物。
- ガイド配列が少なくとも20ヌクレオチド長を含む、請求項1~3の何れか一項に記載の組成物。
- キメラRNAが、
(a) NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuu;
(b) NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaagug;
(c) NNNNNNNNNNNNNNNNNNNNGUUUUAGAGCUAGAAAUagcaaguuaaaauaaggcuaguccguuauca:
から選択される、RNA配列を含む、請求項1~5の何れか一項に記載の組成物。 - キメラRNAが、
(a) NNNNNNNNNNNNNNNNNNNNgttttagagctaGAAAtagcaagttaaaataaggctagtccgttatcaacttgaaaaagtggcaccgagtcggtgcTTTTTT;
(b) NNNNNNNNNNNNNNNNNNNNgttttagagctaGAAATAGcaagttaaaataaggctagtccgttatcaacttgaaaaagtgTTTTTTT;
(c) NNNNNNNNNNNNNNNNNNNNgttttagagctagAAATAGcaagttaaaataaggctagtccgttatcaTTTTTTTT
から選択されるDNA配列によってコードされる、請求項1~5の何れか一項に記載の組成物。 - chiRNAが、メチル化ヌクレオチドまたはヌクレオチドアナログを含む、請求項1~7のいずれか一項記載の組成物。
- chiRNAが、2’-O-メチルアナログ、2’-デオキシアナログ、2’-フルオロアナログ、2-アミノプリン、5-ブロモ-ウリジン、シュードウリジン、イノシン、7-メチルグアノシン、ホスホロチオエート骨格、またはそれらの組み合わせから選択される化学修飾を含む、請求項1~7のいずれか一項に記載の組成物。
- Cas9タンパク質またはCas9タンパク質をコードするポリヌクレオチドをさらに含む、請求項1~9のいずれか一項に記載の組成物。
- Cas9タンパク質が少なくとも1つのNLSに融合されている、請求項10に記載の組成物。
- Cas9タンパク質が少なくとも2つのNLSに融合されている、請求項11に記載の組成物。
- 少なくとも1つのNLSがCas9タンパク質のアミノ末端またはその付近に存在し、少なくとも1つのNLSがCas9タンパク質のカルボキシ末端またはその付近に存在している、請求項12に記載の組成物。
- NLSが、PKKKRKV、KRPAATKKAGQAKKKK、PAAKRVKLD、RQRRNELKRSP、NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY、RMRIZFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV、VSRKRPRP、PPKKARED、POPKKKPL、SALIKKKKKMAP、DRLRR、PKQKKRK、RKLKKKIKKL、REKKKFLKRR、KRKGDEVDGVDEVAKKKSKK、およびRKCLQAGMNLEARKTKKから独立して選択される、請求項11~13のいずれか一項に記載の組成物。
- Cas9タンパク質が、PKKKRKVに融合されている、請求項14に記載の組成物。
- Cas9タンパク質が、両DNA鎖を切断することができるヌクレアーゼである、請求項10~15のいずれか一項に記載の組成物。
- Cas9タンパク質が、S.pyogenes Cas9のD10A、H840A、N854A、またはN863Aに対応する変異を含み、Cas9タンパク質が、1本のDNA鎖を切断する能力を欠くニッカーゼである、請求項10~15のいずれか一項に記載の組成物。
- Cas9タンパク質が、S.pyogenes Cas9のD10Aに対応する変異、およびS.pyogenes Cas9のH840A、N854A、またはN863Aに対応する変異を含み、Cas9タンパク質が全てのDNA切断活性を実質的に欠いている、請求項10~15のいずれか一項に記載の組成物。
- Cas9タンパク質が異種タンパク質ドメインに融合している、請求項10~18のいずれか一項に記載の組成物。
- 異種タンパク質ドメインが、メチラーゼ活性、デメチラーゼ活性、転写活性化活性、転写抑制活性、転写放出因子活性、ヒストン修飾活性、RNA切断活性及び核酸結合活性のうちの1つ以上の活性を有する、請求項19に記載の組成物。
- Cas9タンパク質をコードするポリヌクレオチドが、哺乳動物細胞又はヒト細胞における発現のためにコドン最適化されているmRNAを含む、請求項10~20のいずれか一項に記載の組成物。
- Cas9タンパク質がS.pyogenes Cas9であり、PAMがNGGであるか、またはCas9タンパク質がS.thermophilus Cas9であり、PAMがNAGAAWである、請求項1~21のいずれか一項に記載の組成物。
- 組成物が、複数の異なる標的配列を標的とする複数のchiRNAを含む、請求項1~22のいずれか一項に記載の組成物。
- テンプレートポリヌクレオチドをさらに含み、前記テンプレートポリヌクレオチドが標的配列の少なくとも5ヌクレオチドと重複する、請求項1~23のいずれか一項に記載の組成物。
- ゲノムエンジニアリングのための請求項1~24のいずれか一項に記載の組成物の使用であって、前記使用は、人間の生殖系列の遺伝的同一性を改変するためのプロセスを含まず、前記使用は、手術又は治療により人又は動物の体を処置する方法ではない、使用。
- 非ヒトトランスジェニック動物またはトランスジェニック植物の製造における、請求項1~24のいずれか一項に記載の組成物の使用。
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