JP2014221053A - 標的組込みのための線形ドナーコンストラクト - Google Patents
標的組込みのための線形ドナーコンストラクト Download PDFInfo
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Abstract
Description
1.50〜750塩基対の間のホモロジーアームと対象配列とを含み、ホモロジーアームは対象配列に隣接する線形ドナー核酸分子。
2.ホモロジーアームの長さが50〜100塩基対の間である、1の線形ドナー核酸。
3.ホモロジーアームの塩基対の1つ以上がホスホロチオエートホスホジエステル結合で連結されている、1の線形ドナー核酸。
4.ホスホロチオエートホスホジエステル結合がドナー核酸の5’および3’末端の第1、任意で、第2結合に配置される、3の線形ドナー核酸。
5.ホモロジーアーム間に2Aペプチドをコードする配列をさらに含む、1〜4のいずれかの線形ドナー核酸。
6.ホモロジーアーム間にSA部位を含む配列をさらに含む、1〜5のいずれかの線形ドナー核酸。
7.ホモロジーアーム間にIRES配列を含む配列をさらに含む、1〜6のいずれかの線形ドナー核酸。
8.対象配列がポリペプチドをコードしない、1〜7のいずれかの線形ドナー核酸。
9. 対象配列に作動可能に結合されたプロモーター配列をさらに含む、1〜7のいずれかの線形ドナー核酸。
10.対象配列がポリペプチドをコードする、1〜7または9のいずれかの線形ドナー核酸。
11.ポリペプチドが、抗体、抗原、酵素、成長因子、受容体(細胞表面または核内)、ホルモン、リンホカイン、サイトカイン、レポーター遺伝子、選択可能なマーカー、分泌因子、エピトープタグおよびそれらの機能性フラグメントならびにそれらの組み合わせからなる群より選択される、10による線形ドナー核酸。
12.配列が非コード核酸を含む、1〜7または9のいずれかの線形ドナー核酸。
13.非コード核酸がmiRNA、およびSH−RNA、またはsiRNAからなる群より選択される、請求項12記載の線形ドナー核酸。
14.(a)DNA−結合ドメインと切断ドメインまたは切断ハーフドメインを含み、DNA−結合ドメインが対象領域内の標的部位に結合するように操作されている融合タンパク質を細胞内で発現させることと、
(b)細胞を1〜11のいずれかのドナーポリヌクレオチドと接触させることと、
を含み、
標的部位への融合タンパク質の結合により、対象領域内の細胞ゲノムが切断され、これにより対象配列の細胞ゲノム内への相同性依存標的組込みが得られる、細胞のゲノム内の対象領域への対象配列の相同性依存標的組換えのための方法。
15.(a)第1のDNA−結合ドメインと第1の切断ハーフドメインを含み、第1のDNA−結合ドメインが細胞のゲノム内の対象領域内の第1の標的部位に結合するように操作されている第1の融合タンパク質を細胞内で発現させることと、
(b)第2のDNA−結合ドメインと第2の切断ハーフドメインを含む第2の融合タンパク質を細胞内で発現させることであって、第2のジンクフィンガー結合ドメインが細胞のゲノム内の対象領域内の第2の標的部位に結合し、第2の標的部位は第1の標的部位とは異なり、
(c)細胞を1〜11のいずれかによるドナー核酸を含むポリヌクレオチドと接触させることと、
を含み、
第1の標的部位への第1の融合タンパク質の結合により、および第2の標的部位への第2の融合タンパク質の結合により、細胞ゲノムが対象領域内で切断され、これによりドナー核酸の細胞ゲノムへの相同性依存組込みが得られるように切断ハーフドメインが配置される、細胞への対象配列の相同性依存標的組換えのための方法。
16.少なくとも1つのDNA−結合ドメインがジンクフィンガー結合ドメインである、14または15の方法。
17.少なくとも1つのDNA−結合ドメインがメガヌクレアーゼDNA−結合ドメインである、14〜16の方法。
18.組み込まれたドナー核酸由来の対象配列がポリペプチドを発現する、14または17の方法。
19.組み込まれたドナー由来の対象配列が非コード核酸配列を含む、14または17の方法。
20.切断ドメインがメガヌクレアーゼに由来する、14〜19の方法。
21.第1および第2の切断ハーフドメインがIIS型制限エンドヌクレアーゼに由来する、14〜19のいずれかによる方法。
22.IIS型制限エンドヌクレアーゼはFokIおよびStsIからなる群より選択される、21による方法。
23.細胞が細胞周期のG2期で停止される、14〜22のいずれかによる方法。
24.融合タンパク質の少なくとも1つが、切断ハーフドメインの二量体形成面のアミノ酸配列の変化を含む、14〜23のいずれかによる方法。
25.細胞が哺乳類細胞である、14〜24のいずれかによる方法。
26.細胞がヒト細胞である、25による方法。
27.細胞が植物細胞である、14〜24のいずれかによる方法。
28.細胞がツメガエル細胞、昆虫細胞または線形動物細胞である、14〜24のいずれかによる方法。
本明細書で開示した方法の実行、ならびに組成物の調製および使用は、別記しない限り、分子生物学、生物化学、クロマチン構造および分析、コンピュータ化学、細胞培養、組換えDNAおよび当技術分野の技術の範囲内にある関連分野における従来の技術を使用する。これらの技術は文献で十分に説明されている。例えば、Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001、Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987および定期的更新、the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998、METHODS IN ENZYMOLOGY, Vol. 304, “Chromatin” (P.M. Wassarman and A. P. Wolffe, eds.), Academic Press, San Diego, 1999、およびMETHODS IN MOLECULAR BIOLOGY, Vol. 119, “Chromatin Protocols” (P.B. Becker, ed.) Humana Press, Totowa, 1999を参照されたい。
「核酸」、「ポリヌクレオチド」および「オリゴヌクレオチド」は同じ意味で使用され、線形または環状構造で、一本鎖または二本鎖形態のデオキシリボヌクレオチドまたはリボヌクレオチドポリマを示す。本開示のために、これらの用語は、ポリマ長さに関して制限するものと解釈すべきではない。用語は、天然ヌクレオチドの公知の類似体、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主鎖)において修飾されたヌクレオチドを含むことができる。一般に、特定のヌクレオチドの類似体は同じ塩基対特異性を有し、すなわち、Aの類似体はTと塩基対合する。
ゲノムに挿入するためのポリヌクレオチドが本明細書で記載されており、「外来」ポリヌクレオチドまたは「ドナー」ポリヌクレオチドとも呼ばれている。対象導入遺伝子に隣接する750bpホモロジーアームを、デザインされたジンクフィンガーヌクレアーゼ(ZFN)と組み合わせて有するプラスミドドナーは、標的遺伝子変化に使用することができることが示されている。例えば、Moehle et al. (2007) Proc. Nat’l. Acad. Sci. USA 104(9):3055−3060 および米国特許公開第20050064474号を参照されたい。長いホモロジーアームを有するそのようなプラスミドドナーポリヌクレオチドの構築は時間がかかる手順であり、対象座位の〜1.5フラグメントを増幅させるPCRプライマーのデザイン、所望のフラグメントを有し、PCRにより誘発された突然変異のない単一クローンの識別(増幅、クローニングおよび配列決定による)、そのフラグメントの中心への独特なRFLPの導入(典型的には、部位特異的変異誘発による)、対象のORFのそのフラグメントへのクローニング、所望の配向でORFを有するクローンの識別(典型的には制限消化による)および標的ゲノム変化において使用するために十分な量となるまでのプラスミドの増幅を含む。最良の状況下で、この過程は約2週間を要し、環状(プラスミド)ドナーポリヌクレオチドが得られる。
開示した方法および組成物は、切断ドメイン(または切断ハーフドメイン)およびジンクフィンガードメインを含む融合タンパク質を含み、ここで、ジンクフィンガードメインは、細胞ゲノム内の対象領域の配列に結合することにより、切断ドメイン(または切断ハーフドメイン)の活性を配列近くに移動させ、これにより、対象領域での切断(例えば、二本鎖切断)を誘導する。本開示のほかの場所で説明したように、ジンクフィンガードメインは、事実上、任意の所望の配列に結合するように操作することができる。したがって、1つ以上のジンクフィンガー結合ドメインは対象領域内の1つ以上の配列に結合するように操作することができる。ジンクフィンガー結合ドメインおよび切断ドメインを含む融合タンパク質(または、それぞれがジンクフィンガー結合ドメインおよび切断ハーフドメインを含む2つの融合タンパク質)の、細胞内での発現は、対象領域での切断を達成する。
本明細書で開示した方法では、任意のDNA結合ドメインを使用することができる。ある実施形態では、DNA結合ドメインはジンクフィンガータンパク質を含む。ジンクフィンガー結合ドメインは1つ以上のジンクフィンガーを含む。Miller et al. (1985) EMBO J. 4:1609−1614、Rhodes (1993) Scientific American Feb.:56−65、米国特許第6,453,242号。本明細書で記載したジンクフィンガー結合ドメインは一般に、2、3、4、5、6または実にそれ以上のジンクフィンガーを含む。
本明細書で開示した融合タンパク質の切断ドメイン部分は、任意のエンドヌクレアーゼまたはエキソヌクレアーゼから得ることができる。切断ドメインを誘導することができる例示的なエンドヌクレアーゼとしては、制限エンドヌクレアーゼおよびホーミングエンドヌクレアーゼが挙げられるが、これらに限定されない。例えば、2002−2003 Catalogue, New England Biolabs, Beverly, MA、およびBelfort et al. (1997) Nucleic Acids Res. 25:3379−3388を参照されたい。DNAを切断する追加の酵素が知られている(例えば、S1 ヌクレアーゼ、マングビーンヌクレアーゼ、膵臓DNase I、小球菌ヌクレアーゼ、酵母HOエンドヌクレアーゼ、Linn et al. (eds.) Nucleases, Cold Spring Harbor Laboratory Press,1993も参照されたい)。I−SceI、I−CeuI、PI−PspI、PI−Sce、I−SceIV、I−CsmI、I−PanI、I−SceII、I−PpoI、I−SceIII、I−CreI、I−TevI、I−TevIIおよびI−TevIIIなどのホーミングエンドヌクレアーゼおよびメガヌクレアーゼの非制限的例が知られている。米国特許第5,420,032号、米国特許第6,833,252号、Belfort et al. (1997) Nucleic Acids Res. 25:3379-3388、 Dujon et al. (1989) Gene 82:115-118、Perler et al. (1994) Nucleic Acids Res. 22, 1125-1127、Jasin (1996) Trends Genet. 12:224-228; Gimble et al. (1996) J. Mol. Biol. 263:163-180、Argast et al. (1998) J. Mol. Biol. 280:345-353 およびNew England Biolabsカタログもまた、参照されたい。これらの酵素(またはそれらの機能性フラグメント)の1つ以上を切断ドメインおよび切断ハーフドメインの起源として使用することができる。
融合タンパク質(および融合タンパク質をコードするポリヌクレオチド)のデザインおよび構築のための方法が当業者に公知である。例えば、ジンクフィンガータンパク質(およびこれをコードするポリヌクレオチド)を含む融合タンパク質のデザインおよび構築のための方法が、共に所有されている米国特許第6,453,242号および同第6,534,261号、ならびに国際公開公報第WO 2007/014275号において記載されている。ある実施形態では、そのような融合タンパク質をコードするポリヌクレオチドが構築される。これらのポリヌクレオチドは、ベクターに挿入することができ、ベクターは細胞に導入することができる(ポリヌクレオチドの細胞への導入のためのベクターおよび方法に関するさらなる開示については以下を参照されたい)。
開示した方法および組成物を使用し、細胞クロマチン内のDNAを切断することができ、これは本明細書で記載されるように外来配列(ドナーポリヌクレオチド)の標的組込みを促進する。「組込み」により、物理的挿入(例えば、宿主細胞のゲノム内への)および、さらに、核酸複製過程によるドナー配列の宿主細胞ゲノムへのコピーによる組込みの両方が意味される。
本明細書で記載した核酸(例えば、ZFNおよび/またはドナー配列をコードするポリヌクレオチド)は、任意の適した方法を用いて細胞内に導入し得る。
対象タンパク質をコードする配列に隣接する50、75または100塩基対のホモロジーアームを有する線形ドナーコンストラクトを、下記のようにデザインし、構築した。ドナーコンストラクトは、PPP1R12C座位(AAVS1またはp84部位とも呼ばれる)内、または内在IL2Rγ座位内に含まれるホモロジーアームを含んだ。PPP1R12C座位の説明については、2007年4月26日に出願された米国特許仮出願第60/926,322号(その全体が参照により本明細書に組み込まれる)を参照されたい。
短い(50〜100塩基対)ホモロジーアームを有する線形ドナーコンストラクトの標的組込みを評価するために、2007年4月26日に出願された米国特許仮出願第60/926,322号に記載され、表3(大文字で示されるDNA標的部位、小文字で示される非接触ヌクレオチド)に示されているような、線形ドナーおよびジンクフィンガータンパク質ヌクレアーゼ(ZFN)を含む一対の融合タンパク質を、表4に示すように、Amaxa(商標)Nucleofectionキットを用いてK562細胞にトランスフェクトさせた。
Claims (20)
- 50〜750塩基対の間のホモロジーアームと対象配列とを含み、ホモロジーアームは前記対象配列に隣接する線形ドナー核酸分子。
- 前記ホモロジーアームの長さが50〜100塩基対の間である、請求項1記載の線形ドナー核酸。
- 前記ホモロジーアームの塩基対の1つ以上がホスホロチオエートホスホジエステル結合で連結されている、請求項1記載の線形ドナー核酸。
- 前記ホスホロチオエートホスホジエステル結合が前記ドナー核酸の5’および3’末端の第1および、任意で、第2結合に配置される、請求項3記載の線形ドナー核酸。
- 前記ホモロジーアーム間に2Aペプチドをコードする配列、SA部位を含む配列およびIRES配列を含む配列からなる群より選択される配列をさらに含む、請求項1〜4のいずれかに記載の線形ドナー核酸。
- 前記対象配列がポリペプチドをコードしない、請求項1〜5のいずれかに記載の線形ドナー核酸。
- 前記対象配列がポリペプチドをコードする、請求項1〜5のいずれかに記載の線形ドナー核酸。
- 前記対象配列に作動可能に結合されたプロモーター配列をさらに含む、請求項7記載の線形ドナー核酸。
- 前記ポリペプチドが、抗体、抗原、酵素、成長因子、細胞表面受容体、核内受容体、ホルモン、リンホカイン、サイトカイン、レポーター遺伝子、選択可能なマーカー、分泌因子、エピトープタグおよびそれらの機能性フラグメントならびにそれらの組み合わせからなる群より選択される、請求項7または8に記載の線形ドナー核酸。
- 前記配列が非コード核酸を含む、請求項1〜4のいずれかに記載の線形ドナー核酸。
- 前記非コード核酸がmiRNA、およびSH−RNA、またはsiRNAからなる群より選択される、請求項10記載の線形ドナー核酸。
- (a)DNA−結合ドメインと切断ドメインまたは切断ハーフドメインを含み、DNA−結合ドメインが対象領域内の標的部位に結合するように操作されている融合タンパク質を細胞内で発現させることと、
(b)前記細胞を請求項1〜11のいずれかに記載のドナーポリヌクレオチドと接触させることと、
を含み、
前記標的部位への前記融合タンパク質の結合により、前記対象領域内の細胞ゲノムが切断され、これにより前記対象配列の前記細胞ゲノム内への相同性依存標的組込みが得られる、細胞のゲノム内の対象領域への対象配列の相同性依存標的組換えのための方法。 - (a)第1のDNA−結合ドメインと第1の切断ハーフドメインを含み、前記第1のDNA−結合ドメインが細胞のゲノム内の対象領域内の第1の標的部位に結合するように操作されている第1の融合タンパク質を細胞内で発現させることと、
(b)第2のDNA−ドメインと第2の切断ハーフドメインを含む第2の融合タンパク質を細胞内で発現させることであって、前記第2のジンクフィンガー結合ドメインが細胞のゲノム内の対象領域内の第2の標的部位に結合し、前記第2の標的部位は前記第1の標的部位とは異なる、工程と、
(c)前記細胞を請求項1〜11のいずれかに記載のドナー核酸を含むポリヌクレオチドと接触させることと、
を含み、
前記第1の標的部位への前記第1の融合タンパク質の結合により、および前記第2の標的部位への前記第2の融合タンパク質の結合により、細胞ゲノムが前記対象領域内で切断され、これにより前記ドナー核酸の前記細胞ゲノムへの相同性依存組込みが得られるように前記切断ハーフドメインが配置される、細胞への対象配列の相同性依存標的組換えのための方法。 - 少なくとも1つのDNA−結合ドメインがジンクフィンガー結合ドメインまたはメガヌクレアーゼDNA−結合ドメインである、請求項12または13に記載の方法。
- 前記切断配列がメガヌクレアーゼまたはIIS型制限エンドヌクレアーゼに由来する、請求項12〜14のいずれかに記載の方法。
- 前記IIS型制限エンドヌクレアーゼがFokIおよびStsIからなる群より選択される、請求項15に記載の方法。
- 前記融合タンパク質の少なくとも1つが、前記切断ハーフドメインの二量体形成面のアミノ酸配列の変化を含む、請求項12〜16のいずれかに記載の方法。
- 前記細胞が哺乳類細胞および植物細胞からなる群より選択される、請求項12〜17のいずれかに記載の方法。
- 前記哺乳類細胞がヒト細胞である、請求項18に記載の方法。
- 前記細胞が細胞周期のG2期で停止される、請求項12〜19のいずれかに記載の方法。
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AU2009238629B2 (en) | 2014-10-30 |
US9765360B2 (en) | 2017-09-19 |
JP6081963B2 (ja) | 2017-02-15 |
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JP2016208980A (ja) | 2016-12-15 |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |