JP6552965B2 - 配列操作のための改善された系、方法および酵素組成物のエンジニアリングおよび最適化 - Google Patents
配列操作のための改善された系、方法および酵素組成物のエンジニアリングおよび最適化 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61/836,101号明細書、標題ENGINEERING AND OPTIMIZATION OF IMPROVED SYSTEMS,METHODS AND ENZYME 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。本出願は、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し、両方とも標題SYSTEMS METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATIONであり、それぞれ2012年12月12日および2013年1月2日に出願されたものである。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。
それぞれ2013年6月17日に出願された米国仮特許出願第61/836,127号明細書、同第61/835,936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号明細書が参照される。
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(1DP1MH100706)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。
A)−I.CRISPR−Cas系キメラRNA(chiRNA)ポリヌクレオチド配列であって、
(a)真核細胞中の標的配列にハイブリダイズし得るガイド配列
(b)tracrメイト配列、および
(c)tracr配列
を含むポリヌクレオチド配列、および
II.少なくとも1つ以上の核局在化配列を含むCRISPR酵素をコードするポリヌクレオチド配列
を含み、
(a)、(b)および(c)は、5’から3’配向で配置されており、
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、CRISPR酵素をコードするポリヌクレオチド配列は、DNAまたはRNAである
天然に存在しないまたはエンジニアリングされた組成物
または
(B)I.ポリヌクレオチドであって、
(a)原核細胞中の標的配列にハイブリダイズし得るガイド配列、および
(b)少なくとも1つ以上のtracrメイト配列
を含むポリヌクレオチド、
II.CRISPR酵素をコードするポリヌクレオチド配列、および
III.tracr配列を含むポリヌクレオチド配列
を含み、
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複合体の配列特異標的結合を指向し、
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、CRISPR酵素をコードするポリヌクレオチド配列は、DNAまたはRNAであり、
CRISPR酵素は、コリネバクター属(Corynebacter)、ステレラ属(Sutterella)、レジオネラ属(Legionella)、トレポネーマ属(Treponema)、フィリファクター属(Filifactor)、ユーバクテリウム属(Eubacterium)、ストレプトコッカス属(Streptococcus)、ラクトバシラス属(Lactobacillus)、マイコプラズマ属(Mycoplasma)、バクテロイデス属(Bacteroides)、フラビイボラ属(Flaviivola)、フラボバクテリウム属(Flavobacterium)、スフェロケタ属(Sphaerochaeta)、アゾスピリラム属(Azospirillum)、グルコンアセトバクター属(Gluconacetobacter)、ネイセリア属(Neisseria)、ロゼブリア属(Roseburia)、パービバキュラム属(Parvibaculum)、スタフィロコッカス属(Staphylococcus)、ニトラティフラクター属(Nitratifractor)、マイコプラズマ属(Mycoplasma)およびカンピロバクター属(Campylobacter)からなる群に属する属のCas9オルソログである
天然に存在しないまたはエンジニアリングされた組成物に関する組成物および方法を提供する。
−規定のサイズを有するCRISPR酵素が選択され、少なくとも500アミノ酸、少なくとも800〜899アミノ酸、少なくとも900〜999アミノ酸、少なくとも1000〜1099アミノ酸、少なくとも1100〜1199アミノ酸、少なくとも1200〜1299アミノ酸、少なくとも1300〜1399アミノ酸、少なくとも1400〜1499アミノ酸、少なくとも1500〜1599アミノ酸、少なくとも1600〜1699アミノ酸または少なくとも2000アミノ酸の長さを有し;
−および/またはCRISPR酵素は、対応する野生型CRISPR酵素と比較してトランケートされており;
−および/またはCRISPR酵素は、標的配列の局在における両方の鎖の開裂を指向するヌクレアーゼであり、もしくはCRISPR酵素は、標的配列の局在における一方の鎖の開裂を指向するニッカーゼであり;
−および/またはガイド配列は、少なくとも10、少なくとも15または少なくとも20ヌクレオチドを含み;
−および/またはCRISPR酵素は、コドン最適化されており、もしくは真核細胞中の発現のためにコドン最適化されており;
−および/またはCRISPR酵素は、1つ以上の突然変異を含み;
−および/またはCRISPR酵素は、キメラCRISPR酵素を含み;
−および/またはCRISPR酵素は、本明細書において考察される1つ以上の他の特質を有する。
I.第1の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(第1のポリヌクレオチド配列は、
(i)生物の細胞中の第1のゲノム遺伝子座における第1の標的配列にハイブリダイズし得る第1のガイド配列
(ii)第1のtracrメイト配列、および
(iii)第1のtracr配列
を含む)、および
II.第2の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2の調節エレメント(第2のポリヌクレオチド配列は、
(i)生物の細胞中の第2のゲノム遺伝子座における第2の標的配列にハイブリダイズし得る第2のガイド配列、
(ii)第2のtracrメイト配列、および
(iii)第2のtracr配列
を含む)、および
III.少なくとも1つ以上の核局在化配列を含み、第1の機能ドメインに作動可能に結合している第1の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3の調節エレメント、
IV.少なくとも1つ以上の核局在化配列を含み、第2の機能ドメインに作動可能に結合している第2の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4の調節エレメント
を含み、IおよびIIの(i)、(ii)および(iii)は、5’から3’配向で配置されており、成分I、II、IIIおよびIVは、系の同一または異なるベクター上にあり、転写されるとそれぞれのtracrメイト配列gあgcr配列にハイブリダイズし、かつ第1および第2のガイド配列が第1および第2の標的配列への第1および第2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、CRISPR酵素の発現は、標的配列の操作を提供し、第1および第2のCRISPR酵素は、2つ以上の突然変異をそれぞれ含み、第1および第2のCRISPR酵素は、コリネバクター属(Corynebacter)、ステレラ属(Sutterella)、レジオネラ属(Legionella)、トレポネーマ属(Treponema)、フィリファクター属(Filifactor)、ユーバクテリウム属(Eubacterium)、ストレプトコッカス属(Streptococcus)、ラクトバシラス属(Lactobacillus)、マイコプラズマ属(Mycoplasma)、バクテロイデス属(Bacteroides)、フラビイボラ属(Flaviivola)、フラボバクテリウム属(Flavobacterium)、スフェロケタ属(Sphaerochaeta)、アゾスピリラム属(Azospirillum)、グルコンアセトバクター属(Gluconacetobacter)、ネイセリア属(Neisseria)、ロゼブリア属(Roseburia)、パービバキュラム属(Parvibaculum)、スタフィロコッカス属(Staphylococcus)、ニトラティフラクター属(Nitratifractor)、マイコプラズマ属(Mycoplasma)およびカンピロバクター属(Campylobacter)からなる群に属する属のCas9オルソログである1つ以上のベクターを含むベクター系を含む天然に存在しないまたはエンジニアリングされた組成物を送達することを含み、第1のゲノム遺伝子座を、第1の機能ドメインの活性によりモジュレートし、第2のゲノム遺伝子座を、第2の機能ドメインの活性によりモジュレートする方法を提供する。さらなる実施形態において、第1の機能ドメインは、転写アクチベーター、転写リプレッサー、リコンビナーゼ、トランスポーゼース、ヒストンリモデラー、DNAメチルトランスフェラーゼ、クリプトクロムおよび光誘導性/制御性ドメインまたは化学誘導性/制御性ドメインからなる群から選択される。さらなる実施形態において、第2の機能ドメインは、転写アクチベーター、転写リプレッサー、リコンビナーゼ、トランスポーゼース、ヒストンリモデラー、DNAメチルトランスフェラーゼ、クリプトクロムおよび光誘導性/制御性ドメインまたは化学誘導性/制御性ドメインからなる群から選択される。好ましい実施形態において、第1または第2のCRISPR酵素は、ステレラ・ウォズワーセンシス(Sutterella wadsworthensis)Cas9、フィリファクター・アロシス(Filifactor alocis)Cas9、ラクトバシラス・ジョンソニイ(Lactobacillus johnsonii)Cas9、カンピロバクター・ラリ(Campylobacter lari)Cas9、コリネバクター・ジフテリエ(Corynebacter diptheriae)Cas9、パービバキュラム・ラバメンティボランス(Parvibaculum lavamentivorans)Cas9、マイコプラズマ・ガリセプティカム(Mycoplasma gallisepticum)Cas9、黄色ブドウ球菌(Staphylococcus aureus subsubspecies Aureus)Cas9、レジオネラ・ニューモフィラ(Legionella pneumophila)Paris Cas9、トレポネーマ・デンティコラ(Treponema denticola)Cas9、スタフィロコッカス・シュードインターメディアス(Staphylococcus pseudintermedius)Cas9、ネイセリア・シネレア(Neisseria cinerea)Cas9である。
NHEJ媒介遺伝子ノックアウトを達成するため:
単一ウイルスベクター:
2つ以上の発現カセットを含有するベクター:
プロモーター−Cas9コード核酸分子−ターミネーター
プロモーター−gRNA1−ターミネーター
プロモーター−gRNA2−ターミネーター
プロモーター−gRNA(N)−ターミネーター(ベクターのサイズ限界まで)
二重ウイルスベクター:
Cas9の発現をドライブするための1つの発現カセットを含有するベクター1
プロモーター−Cas9コード核酸分子−ターミネーター
1つ以上のガイドRNAの発現をドライブするためのもう1つの発現カセットを含有するベクター2
プロモーター−gRNA1−ターミネーター
プロモーター−gRNA(N)−ターミネーター(ベクターのサイズ限界まで)
AAV ITRは、プロモーターとして機能し得:これは、追加のプロモーターエレメント(ベクター中のスペースを占め得る)の必要性の排除に有利である。追加スペースの制限解放を使用して追加のエレメント(gRNAなど)の発現をドライブすることができる。また、ITR活性は相対的に弱く、したがってそれを使用してCas9の過剰発現に起因する毒性を低減させることができる。
肝臓発現のため、アルブミンプロモーターを使用することができる。
肺発現のため、SP−Bを使用することができる。
内皮細胞のため、ICAMを使用することができる。
造血細胞のため、IFNベータまたはCD45を使用することができる。
骨芽細胞のため、OG−2を使用することができる。
ガイドRNAをドライブするために使用されるプロモーターは、以下を含み得る:
PolIIIプロモーター、例えば、U6またはH1
gRNAを発現させるためのPolIIプロモーターおよびイントロン性カセットの使用
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オルソログはかなり大きい。多くの公知のCas9オルソログは、巨大であり、1300を超えるアミノ酸を含有する。例えばSpCas9は約1368アミノ酸長であり、これは大き過ぎるため送達用のウイルスベクターへのパッケージングが容易でない。Cas9ホモログの長さ分布を表すグラフが図6に示される。グラフは、GenBankに寄託されている配列から作成される。配列の中には誤って注釈されているものもあり、従って各長さについての正確な度数は必ずしも正しいとは限らない。それでもなお、これによりCas9タンパク質の分布の概観が得られ、より短いCas9ホモログの存在が示唆される。
野生型CRISPR−Cas系は、細菌および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−Cas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、ならびに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、真核細胞中の発現を向上させるためのコドン最適化Cas9オルソログを生成した。
本実施例において、本出願人らは、以下の突然変異がSpCas9をニック形成酵素に変換し得ることを示す:D10A、E762A、H840A、N854A、N863A、D986A。
機能向上または新たな機能の開発のため、本出願人らは、異なるCas9オルソログからの断片を組み合わせることによりキメラCas9タンパク質を生成した。
>St1(N)Sp(C)Cas9
a.毒性の低減
b.真核細胞中の発現の改善
c.特異性の向上
d.タンパク質の分子量の低減、異なるCas9ホモログからの最小ドメインを組み合わせることによるより小さいタンパク質の作製。
e.PAM配列要件の変更
インビボ送達−AAV法
AAVは、数個の理由について他のウイルスベクターと比べて有利である:
・毒性が低い(これは、免疫応答を活性化し得る細胞粒子の超遠心を要求しない精製法に起因し得る)
・それが宿主ゲノム中にインテグレートしないため、挿入突然変異導入を引き起こす確率が低い。
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(tools.invitrogen.com/content/sfs/manuals/geneart_chlamy_kits_man.pdfにおけるウェブサイト情報)からの標準的な推奨プロトコルに従う。
哺乳動物細胞中の機能ゲノムエンジニアリングツールとしての化膿性連鎖球菌(Streptococcus pyogenes)(Sp)およびストレプトコッカス・サーモフィラス(Streptococcus thermophiles)(St)CRISPR/Cas系の同定後に本出願人らがII型CRISPR/Cas系を多様性のさらなる利用を求めるため、このプロジェクトを開始した。
(1)より高い効率および/または特異性を有するCRISPR/Cas系
(2)より広い範囲のゲノム遺伝子座のターゲティングを可能とする異なるプロトスペーサー隣接モチーフ(PAM)を有するCRISPR/Cas系
(3)より小さいサイズを有するCRISPR/Cas系(したがって、本出願人らは、それらをインビボで単一ベクター中で、パッケージングサイズ限界(現行のSpまたはSt系は、4.7kbのこの限界を超過する)を有する哺乳動物ウイルス送達系、例えば、アデノ随伴ウイルス(AAV)ベクターにより送達することができる)
および他の所望の形質。
1.Cong,L.et al.Multiplex genome engineering using CRISPR/Cas systems.Science 339,819−823(2013)
2.Mali,P.et al.RNA−Guided Human Genome Engineering via Cas9.Science 339,823−826(2013).
3.Jinek,M.et al.RNA−programmed genome editing in human cells.eLife 2,e00471 (2013).
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Claims (28)
- 天然に存在しない又はエンジニアリングされた組成物であって、
I. CRISPR−Cas系キメラRNA(chiRNA)をコードするヌクレオチド配列に作動可能に結合している第1の調節エレメントであって、前記chiRNAが、
(a)真核細胞中の標的配列にハイブリダイズし得るガイド配列、
(b)tracr配列にハイブリダイズし得るtracrメイト配列、及び
(c)tracr配列
を含む、第1の調節エレメント、並びに
II. 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
を含む1つ以上のベクターを含むベクター系を含み、
(a)、(b)及び(c)は、5’〜3’配向で配置されており、
成分I及びIIは、前記系の同じ又は異なるベクター上に位置し、
前記CRISPR酵素が、黄色ブドウ球菌(Staphylococcus aureus)のCas9オルソログ(SaCas9)である、
組成物。 - 前記CRISPR酵素が、前記酵素のいずれかのドメインにおいて1つ以上の突然変異を有する、請求項1に記載の組成物。
- 前記CRISPR酵素が、触媒ドメインにおいて1つ以上の突然変異を有する、請求項2に記載の組成物。
- 前記1つ以上の突然変異が、前記CRISPR酵素のRuvC I、RuvC II、RuvC III又はHNHドメインに存在する、請求項2又は3に記載の組成物。
- 前記CRISPR酵素が、D10A、H840A、N854A又はN863AにおけるSpCas9の位置ナンバリングに対応する1つ以上の突然変異を含む、請求項3又は4に記載の組成物。
- 前記CRISPR酵素が、機能ドメインをさらに含む、請求項1〜5のいずれか一項に記載の組成物。
- 前記機能ドメインが、転写アクチベータードメインである、請求項6に記載の組成物。
- 前記転写アクチベータードメインが、VP64である、請求項7に記載の組成物。
- 前記機能ドメインが、転写リプレッサードメインである、請求項6に記載の組成物。
- 前記転写リプレッサードメインが、KRAB、SID又はSID4Xである、請求項9に記載の組成物。
- 前記機能ドメインが、リコンビナーゼ、トランスポーゼース、ヒストンリモデラー、DNAメチルトランスフェラーゼ、クリプトクロム及び光誘導性/制御性ドメイン又は化学誘導性/制御性ドメインである、請求項6に記載の組成物。
- 前記CRISPR酵素をコードするポリヌクレオチド配列が、真核細胞における発現のためにコドン最適化されている、請求項1〜11のいずれか一項に記載の組成物。
- 2つ以上のchiRNAを含む、請求項1〜12のいずれか一項に記載の組成物。
- 前記ベクター系が、単一ベクターを含み、前記成分I及びIIが前記単一ベクター上に位置する、請求項13に記載の組成物。
- 前記1つ以上のベクターが、1つ以上のウイルスベクターを含む、請求項13に記載の組成物。
- 前記1つ以上のウイルスベクターが、1つ以上のレトロウイルス、レンチウイルス、アデノウイルス、アデノ随伴ウイルス又は単純ヘルペスウイルスベクターを含む、請求項15に記載の組成物。
- ナノ粒子、リポソーム、エキソソーム、酵母系又はマイクロベシクルを含む、請求項1〜14のいずれか一項に記載の組成物。
- 前記ベクター系が、前記標的配列の開裂した鎖中への挿入のためのDNAを含み、前記CRISPR酵素が、前記標的配列を開裂し、挿入のための前記DNAが、前記標的配列の開裂した鎖中に挿入し、それによって、前記CRISPR−Cas系が、前記標的配列を有する真核細胞中に導入されると、媒介性ゲノムターゲティングをもたらす、請求項1〜17のいずれか一項に記載の組成物。
- 請求項1〜18のいずれか一項に記載の組成物を含む、エクスビボ又はインビトロ宿主細胞又は細胞系であって、前記宿主細胞又は細胞系が、ヒト生殖細胞系ではない、エクスビボ又はインビトロ宿主細胞又は細胞系。
- 幹細胞又は幹細胞系である、請求項19に記載のエクスビボ又はインビトロ宿主細胞又は細胞系。
- 目的のゲノム遺伝子座での1つ以上の標的配列の操作によって真核生物を改変する方法であって、請求項1〜18のいずれか一項に記載の組成物を前記真核生物に送達することを含み、前記真核生物が、非ヒト生物である、方法。
- 目的のゲノム遺伝子座での1つ以上の標的配列の操作によって細胞又は真核生物を改変するエクスビボ方法であって、請求項1〜18のいずれか一項に記載の組成物を前記細胞に送達することを含み、前記方法が、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ない、方法。
- 前記真核生物が、植物である、請求項21又は22に記載の方法。
- エクスビボ遺伝子又はゲノム編集における使用のための請求項1〜18のいずれか一項に記載の組成物。
- 医薬品の調製のための、請求項1〜18のいずれか一項に記載の組成物の使用。
- 遺伝子突然変異から生じる眼の異常の補正において使用するための、請求項1〜18のいずれか一項に記載の組成物。
- 天然に存在しない又はエンジニアリングされた組成物であって、
I.(a)真核細胞中の標的配列にハイブリダイズし得るガイド配列、
(b)tracr配列にハイブリダイズし得るtracrメイト配列、及び
(c)tracr配列
を含む、chiRNA、並びに
II.1つ以上の核局在化配列を含むCRISPR酵素
をコードするアデノ随伴ウイルス(AAV)ベクターを含み、
(a)、(b)及び(c)は、5’〜3’配向で配置されており、
前記CRISPR酵素が、黄色ブドウ球菌(Staphylococcus aureus)のCas9オルソログである、
組成物。 - 前記AAVベクターが2つ以上のchiRNAをコードする、請求項27に記載の組成物。
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