JP7090775B2 - 遺伝子産物の発現を変更するためのCRISPR-Cas系および方法 - Google Patents
遺伝子産物の発現を変更するためのCRISPR-Cas系および方法 Download PDFInfo
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Description
本出願は、それぞれ2013年7月2日および2013年10月15日に出願された、それぞれBroad参照BI-2011/008Aを有する、標題CRISPR-CAS SYSTEMS AND METHODS FOR ALTERING EXPRESSION OF GENE PRODUCTSの米国仮特許出願第61/842,322号明細書および米国特許出願第14/054,414号明細書の優先権を主張する。それぞれBroad参照BI-2011/008/WSGR整理番号44063-701.101、BI-2011/008/WSGR整理番号44063-701.102、Broad参照BI-2011/008/VP整理番号44790.02.2003およびBI-2011/008/VP整理番号44790.03.2003を有する米国仮特許出願第61/736,527号明細書、同第61/748,427号明細書、同第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、これらは全て標題SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATIONであり、それぞれ2012年12月12日、2013年1月2日、2013年3月15日および2013年6月17日に出願されたものである。
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号明細書が参照され、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2013年6月17日に出願された米国仮特許出願第61/835,936号明細書、同第61/836,127号明細書、同第61/836,101号明細書、同第61/836,080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)により助成されたNIHパイオニアアワードDP1MH100706のもと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。
NA」、「単一ガイドRNA」および「合成ガイドRNA」は、互換的に使用され、ガイド配列、tracr配列およびtracrメイト配列を含むポリヌクレオチド配列を指す。用語「ガイド配列」は、標的部位を規定するガイドRNA内の約20bp配列を指し、用語「ガイド」または「スペーサー」と互換的に使用することができる。用語「tracrメイト配列」も、用語「ダイレクトリピート」と互換的に使用することができる。例示的なCRISPR-Cas系を図1に示す。
み得る。ハイブリダイゼーション反応は、より広範なプロセス、例えば、PCRの開始、または酵素によるポリヌクレオチドの開裂におけるステップを構成し得る。所与の配列とハイブリダイズし得る配列は、所与の配列の「相補鎖」と称される。
et al.,1985.Science 230:912-916)、および乳腺特異的プロモーター(例えば、乳清プロモーター;米国特許第4,873,316号明細書および欧州特許出願公開第264,166号明細書)が挙げられる。発生制御プロモーター、例えば、ネズミhoxプロモーター(Kessel and Gruss,1990.Science 249:374-379)およびα-フェトタンパク質プロモーター(Campes and Tilghman,1989.Genes Dev.3:537-546)も包含される。
因子C)、およびそれらの任意の組合せを挙げることができる。
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。
ヒト胚腎臓(HEK)細胞系HEK293FT(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。マウスneuro2A(N2A)細胞系(ATCC)を、5%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DMEMにより、37℃、5%のCO2で維持した。
HEK293FTまたはN2A細胞を、上記プラスミドDNAにより形質移入した。形質移入後、細胞を37℃において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、QuickExtractDNA抽出キット(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、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。抽出されたゲノムDNAを直ちに処理または-20℃において貯蔵した。
HEK293FTおよびN2A細胞を、プラスミドDNAにより形質移入し、37℃において72時間インキュベートしてから上記のとおりゲノムDNAを抽出した。相同組換え(HR)テンプレートのホモロジーアーム外側のプライマーを使用して標的ゲノム領域をPCR増幅した。PCR産物を1%のアガロースゲル上で分離し、MinElute GelExtraction Kit(Qiagen)により抽出した。精製産物をHindIII(Fermentas)により消化し、6%のNovex TBEポリアクリルアミドゲル(Life Technologies)上で分析した。
RNA二次構造予測は、Institute for Theoretical Chemistry at the University of Viennaにおいて開発されたオンラインウェブサーバーRNAfoldを使用し、セントロイド構造予測アルゴリズムを使用して実施した(例えば、A.R.Gruber et al.,2008,Cell 106(1):23-24;およびPA Carr and GM Church,2009,Nature Biotechnology 27(12):1151-62参照)。
HEK293FT細胞を上記のとおり維持および形質移入した。細胞をトリプシン処理により回収し、次いでリン酸緩衝生理食塩水(PBS)中で洗浄した。トータル細胞RNAをTRI試薬(Sigma)により製造業者のプロトコルに従って抽出した。抽出されたトータルRNAをNaonodrop(Thermo Scientific)を使用して定量し、同一濃度に正規化した。
RNAを等容量の2×ローディング緩衝液(Ambion)と混合し、95℃に5分間加熱し、氷上で1分間冷蔵し、次いで8%の変性ポリアクリルアミドゲル(SequaGel,National Diagnostics)上に、少なくとも30分間のゲルのプレラン後にロードした。試料を40W限界において1.5時間電気泳動した。その後、RNAをHybond N+メンブレン(GE Healthcare)に300mAにおいてセミドライ転写装置(Bio-rad)中で室温において1.5時間転写した。Stratagene UV CrosslinkerのStratalinker(Stratagene)上のオートクロスリンクボタンを使用してRNAをメンブレンに架橋させた。メンブレンをULTRAhyb-オリゴハイブリダイゼーション緩衝液(Ambion)中で回転させながら42℃において30分間プレハイブリダイズさせ、次いでプローブを添加し、一晩ハイブリダイズさせた。プローブはIDTに発注し、T4ポリヌクレオチドキナーゼ(New England Biolabs)を用いて[ガンマ-32P]ATP(Perkin Elmer)により標識した。メンブレンを予備加温(42℃)された2×SSC、0.5%のSDSにより1分間1回洗浄し、次いで42℃において30分間2回洗浄した。メンブレンを蛍光スクリーンに室温において1時間または一晩曝露させ、次いでphosphorimager(Typhoon)によりスキャンした。
tracrRNA、Cas9、およびリーダーを含むCRISPR遺伝子座エレメントを、化膿性連鎖球菌(Streptococcus pyogenes)SF370ゲノムDNAから、ギブソン・アセンブリ(Gibson Assembly)のためのフランキングホモロジーアームを用いてPCR増幅した。2つのBsaI IIS型部位を2つのダイレクトリピート間に導入してスペーサーの容易な挿入を促進した(図8)。Gibson Assembly Master Mix(NEB)を使用してPCR産物をEcoRV消化pACYC184中にtetプロモーターの下流でクローニングした。Csn2の最後の50bpは除き、他の内因性CRISPR系エレメントは除外した。相補的オーバーハングを有するスペーサーをコードするオリゴ(Integrated DNA Technology)をBsaI消化ベクターpDC000(NEB)中にクローニングし、次いでT7リガーゼ(Enzymatics)によりライゲートしてpCRISPRプラスミドを生成した。哺乳動物細胞中のPAM発現を有するスペーサーを含有するチャレンジプラスミド(図6Aに説明される発現構築物、図6Bに示されるSurveyorアッセイの結果により決定された機能性を有する)。転写開始部位を+1として標識し、転写ターミネーターおよびノザンブロットによりプロ-ビングされる配列も示す。プロセシングされたtracrRNAの発現もノザンブロットにより確認した。図6Cは、長鎖または短鎖tracrRNA、ならびにSpCas9およびDR-EMX1(1)-DRを担持するU6発現構築物により形質移入された293FT細胞から抽出されたトータルRNAのノザンブロット分析の結果を示す。左および右側のパネルは、それぞれSpRNアーゼIIIを用いず、または用いて形質移入された293FT細胞からのものである。U6は、ヒトU6snRNAをターゲティングするプローブによりブロットされたローディング対照を示す。短鎖tracrRNA発現構築物の形質移入は、十分なレベルのプロセシング形態のtracrRNA(約75bp)をもたらした。極めて少量の長鎖tracrRNAがノザンブロット上で検出される。
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(図9、ヒト染色体配列のプラスおよびマイナス鎖の両方を評価)。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。例えば、図10は、CRISPR媒介ゲノム編集を達成するための哺乳動物細胞中の異種発現のためのストレプトコッカス・サーモフィラス(Streptococcus thermophilus)LMD-9のCRISPR1からのII型CRISPR系の適応を説明する。図10Aは、S.サーモフィラス(S.thermophilus)LMD-9のCRISPR1の模式的説明を提供する。図10Bは、S.サーモフィラス(S.thermophilus)CRISPR系のための発現系の設計を説明する。ヒトコドン最適化hStCas9を、構成的EF1αプロモーターを使用して発現させる。tracrRNAおよびcrRNAの成熟バージョンを、U6プロモーターを使用して発現させて正確な転写開始を促進する。成熟crRNAおよびtracrRNAからの配列を説明する。crRNA配列中の小文字「a」により示される単一塩基を使用してRNApolIII転写ターミネーターとして機能するポリU配列を除去する。図10Cは、ヒトEMX1遺伝子座ターゲティングするガイド配列を示す模式図を提供する。図10Dは、Surveyorアッセイを使用する標的遺伝子座中のhStCas9媒介開裂の結果を示す。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分析も図5に提供する。図14は、ヒトEMX1遺伝子座中のS.サーモフィラス(S.thermophilus)CRISPR系の追加のプロトスペーサーおよび対応するPAM配列標的の模式図を提供する。2つのプロトスペーサー配列を強調し、NNAGAAWモチーフを満たすそれらの対応するPAM配列を対応する強調配列に対して3’側で下線を付けることにより示す。両方のプロトスペーサーは、アンチセンス鎖をターゲティングする。
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16a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(配列番号13)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16bおよび16c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17aおよび17bにヒストグラムにより示し、それぞれ図16bおよび16c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。
CRISPR-Cas系は、細菌から古細菌にわたる多様な種により用いられる侵入外因性DNAに対する適応免疫機序である。II型CRISPR-Cas9系は、CRISPR遺伝子座中への外来DNAの「獲得」を担うタンパク質をコードする遺伝子のセット、およびDNA開裂機序の「実行」をコードする遺伝子のセットからなり;これらは、DNAヌクレアーゼ(Cas9)、非コードトランス活性化crRNA(tracrRNA)、およびダイレクトリピートによりフランキングされている外来DNA由来スペーサーのアレイ(crRNA)を含む。Cas9による成熟時、tracRNAおよびcrRNA二本鎖は、Cas9ヌクレアーゼをスペーサーガイド配列により規定される標的DNA配列にガイドし、開裂に要求され、それぞれのCRISPR-Cas系に特異的な標的DNA中の短鎖配列モチーフ付近のDNAの二本鎖切断を媒介する。II型CRISPR-Cas系は、細菌界全体にわたり見出されており、Cas9タンパク質配列およびサイズ、tracrRNAおよびcrRNAダイレクトリピート配列、それらのエレメントのゲノム構成、および標的開裂のためのモチーフ要件は高度に多様である。ある種は、複数の区別されるCRISPR-Cas系を有し得る。
本出願人らは、Cas9オルソログを分析して関連PAM配列および対応するキメラガイドRNAを同定した。PAMの拡大セットを有することは、ゲノムにわたるより広いターゲティングを提供し、ユニーク標的部位の数も顕著に増加させ、ゲノム中の特異性の増加レベルを有する新規Cas9を同定する潜在性を提供する。
Cas9を送達する方法
Chlamydomonas Resource Centerからのコナミドリムシ(Chlamydomonas reinhardtii)株CC-124およびCC-125を、エレクトロポレーションに使用する。エレクトロポレーションプロトコルは、GeneArt Chlamydomonas Engineeringキットからの標準的な推奨プロトコルに従う。
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Claims (22)
- エンジニアリングされた天然に存在しないCRISPR-Cas系であって、
(a)触媒ドメインに少なくとも一つの変異を含み、一本のDNA鎖を切断する活性を欠くCas9ニッカーゼ(ここで、Cas9ニッカーゼは少なくとも2つの核局在化シグナル(NLS)に連結している)を含むタンパク質、又は前記タンパク質をコードするポリヌクレオチド;
(b)真核細胞の核における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し、CRISPR-Cas複合体の標的配列への配列特異的結合を指向することができるガイド配列と、tracr配列にハイブリダイズすることができるtracrメイト配列と、少なくとも30ヌクレオチド長を含むtracr配列とを含むCRISPR-Cas系キメラガイド;
を含む系。 - エンジニアリングされた天然に存在しないCRISPR-Casベクター系であって、
(a)触媒ドメインに少なくとも一つの変異を含み、一本のDNA鎖を切断する活性を欠くCas9ニッカーゼ(ここで、Cas9ニッカーゼは少なくとも2つの核局在化シグナル(NLS)に連結している)を含むタンパク質をコードするヌクレオチド配列に機能的に連結している第一の調節要素;
(b)真核細胞の核における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し、CRISPR-Cas複合体の標的配列への配列特異的結合を指向することができるガイド配列と、tracr配列にハイブリダイズすることができるtracrメイト配列と、少なくとも30ヌクレオチド長を含むtracr配列とを含むCRISPR-Cas系キメラガイドをコードするヌクレオチド配列に機能的に連結している第二の調節要素;
を含む、1以上のベクターを含み、成分(a)及び(b)が、系の同一又は異なるベクター上に位置している、系。 - ベクターがウイルスベクターである、請求項2に記載の系。
- ウイルスベクターがアデノ随伴ウイルスベクターである、請求項3に記載の系。
- 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から4の何れか一項に記載の系。
- 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から5の何れか一項に記載の系。
- ガイド配列が15~30のヌクレオチド長を含む、請求項1から6の何れか一項に記載の系。
- 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から7の何れか一項に記載の系。
- Cas9が、RuvCドメイン中に少なくとも1つの変異を含む、請求項1から8の何れか一項に記載の系。
- Cas9が、Streptococcus pyogenesのCas9のD10A、H840A、N854A、又はN863Aに対応する変異を含む、請求項1~9のいずれか一項に記載の系。
- Cas9が、S.pyogenesのCas9であり、PAMがNGGであるか、又はCas9が、S.thermophilusのCas9であり、PAMがNAGAAWである、請求項1~10のいずれか一項に記載の系。
- タンパク質が、Cas9に連結した少なくとも1つの異種タンパク質ドメインを含む、請求項1~10のいずれか一項に記載の系。
- 異種タンパク質ドメインが、以下の活性:即ち、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、転写リリース因子活性、ヒストン修飾活性、RNA切断活性および核酸結合活性、のうちの1つ以上を有する、請求項12に記載の系。
- 異種タンパク質ドメインが、GFPである、請求項12に記載の系。
- タンパク質が、Cas9に連結した少なくとも一つのSV40ウイルスラージT抗原NLS(PKKKRKV)を含む、請求項1~14のいずれか一項に記載の系。
- タンパク質が、少なくとも1つのN末端のNLSと、少なくとも1つのC末端のNLSとを含む、請求項1~15のいずれか一項に記載の系。
- タンパク質をコードするポリヌクレオチドが、哺乳動物細胞またはヒト細胞での発現用にコドン最適化されている、請求項1に記載の系。
- タンパク質をコードするポリヌクレオチドが、mRNAである、請求項1に記載の系。
- 系が、テンプレートポリヌクレオチドをさらに含み、テンプレートポリヌクレオチドは標的配列の少なくとも5ヌクレオチドと重複している、請求項1に記載の系。
- ゲノムエンジニアリングのための請求項1~19のいずれか一項に記載の系の使用であって、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、ヒト又は動物を処置するための方法ではない、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1~19のいずれか一項に記載の系の使用。
- 哺乳動物細胞中の1つ以上の遺伝子産物の発現をエクスビボで改変するための、請求項1~19のいずれか一項に記載の系の使用。
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