JP2014532410A - Hprt遺伝子座を修飾するための方法および組成物 - Google Patents
Hprt遺伝子座を修飾するための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は、2011年10月27日出願の米国仮特許出願第61/552,309号、および2011年11月7日出願の米国仮特許出願第61/556,691号の利益を主張するものであり、これらの開示内容は、すべての目的のために参照によりこれらの全体が組み込まれる。
方法の実践、ならびに本明細書に開示の組成物の調製および使用は、別途示されない限り、分子生物学、生化学、クロマチン構造および分析、計算化学、細胞培養、組換えDNA、および当分野の技術の範囲内の関連分野における従来の技法を用いる。これらの技法は、文献内で十分に説明される。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 and periodic updates、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」という用語は、同義に使用され、線状または環状構造であり、かつ一本鎖または二本鎖形態のいずれかである、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ーを指す。本開示の目的のために、これらの用語は、ポリマーの長さに関して限定的であると解釈されるべきではない。これらの用語は、天然ヌクレオチドの既知の類似体、ならびに塩基部分、糖部分、および/またはリン酸部分において修飾されるヌクレオチド(例えば、ホスホロチオエート骨格)を包含することができる。概して、特定のヌクレオチドの類似体は、同一の塩基対合特異性を有し、すなわち、Aの類似体は、Tと塩基対合する。
組成物、具体的には、導入遺伝子の挿入のための遺伝子の標的化に有用なヌクレアーゼ、例えば、HPRTに特異的なヌクレアーゼが本明細書に記載される。ある実施形態において、ヌクレアーゼは、天然に存在する。他の実施形態では、ヌクレアーゼは天然には存在せず、すなわち、DNA結合ドメインおよび/または切断ドメインにおいて操作される。例えば、天然に存在するヌクレアーゼのDNA結合ドメインは、選択された標的部位(例えば、同族の結合部位とは異なる部位に結合するように操作されたメガヌクレアーゼ)に結合するように改変され得る。他の実施形態では、ヌクレアーゼは、異種のDNA結合ドメインおよび切断ドメイン(例えば、ジンクフィンガーヌクレアーゼ、TAL−エフェクターヌクレアーゼ、異種の切断ドメインを有するメガヌクレアーゼDNA結合ドメイン)を含む。
特定の実施形態において、ヌクレアーゼは、メガヌクレアーゼ(ホーミングエンドヌクレアーゼ)である。天然に存在するメガヌクレアーゼは、15〜40個の塩基対切断部位を認識し、一般に、4つのファミリー、すなわち、LAGLIDADGファミリー、GIY−YIGファミリー、His−Cystボックスファミリー、およびHNHファミリーに分類される。例示のホーミングエンドヌクレアーゼには、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が含まれる。これらの認識配列は既知である。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the New England Biolabsカタログも参照されたい。
任意の好適な切断ドメインをDNA結合ドメインに作動可能に連結して、ヌクレアーゼを形成することができる。例えば、ZFP DNA結合ドメインをヌクレアーゼドメインに融合させてZFNを作成しており、これは、その操作された(ZFP)DNA結合ドメインを介してその目的とする核酸標的を認識し、かつヌクレアーゼ活性を介してZFP結合部位付近でのDNAの切断を引き起こすことができる機能的実体である。例えば、Kim et al.(1996)Proc Nat’l Acad Sci USA 93(3):1156−1160を参照されたい。TALEタンパク質は、ヌクレアーゼドメインに融合されて、部位特異的TALEヌクレアーゼ(TALEN)も作成し得る。ZFNおよびTALENは、様々な生物におけるゲノム修飾のために使用されている。例えば、米国特許公開第20030232410号、同第20050208489号、同第20050026157号、同第20050064474号、同第20060188987号、同第20060063231号、同第20110301073号、および国際公開第WO07/014275号を参照されたい。
上で詳述されるように、DNAドメインは、遺伝子座、例えば、HPRT遺伝子における任意の選択した配列に結合するように操作され得る。操作されたDNA結合ドメインは、天然に存在するDNA結合ドメインと比較して新規の結合特異性を有し得る。操作方法には、合理的設計および種々の種類の選択が含まれるが、これらに限定されない。合理的設計は、例えば、三重項(または四重項)ヌクレオチド配列および個々の(例えば、ジンクフィンガー)アミノ酸配列を含むデータベースの使用を含み、各三重項または四重項ヌクレオチド配列は、特定の三重項または四重項配列に結合するDNA結合ドメインの1つ以上のアミノ酸配列と会合している。例えば、参照によりそれらの全体が本明細書に組み込まれる、共同所有の米国特許第6,453,242号および同第6,534,261号を参照されたい。TALエフェクタードメインの合理的設計も実行され得る。例えば、米国特許公開第20110301073号を参照されたい。
上述のように、例えば、変異体遺伝子の修正または野生型遺伝子の発現の増大ための外因性配列(「ドナー配列」または「ドナー」または「導入遺伝子」とも称される)の挿入。ドナー配列は、典型的には、それが配置されるゲノム配列と同一ではないことは容易に明らかになる。ドナー配列は、目的とする位置で効率的なHDRを可能にするために、2つの相同性領域に隣接した非相同配列を含み得る。さらに、ドナー配列は、細胞染色体内の目的とする領域と相同ではない配列を含むベクター分子を含み得る。ドナー分子は、細胞染色体に対していくつかの不連続な相同性の領域を含み得る。例えば、通常は目的とする領域に存在しない配列の標的挿入の場合、この配列は、ドナー核酸分子に存在し得、目的とする領域内の配列に対して相同性の領域に隣接し得る。
ヌクレアーゼ、これらのヌクレアーゼをコードするポリヌクレオチド、ドナーポリヌクレオチド、ならびに本明細書に記載のタンパク質および/またはポリヌクレオチドを含む組成物は、任意の好適な手段によってインビボまたはエクスビボで送達され得る。
本発明の方法および組成物は、細胞におけるゲノム編集を行うことが所望されるといったいかなる場合でも使用され得る。編集は、所望の遺伝子または遺伝子座のノックアウトの形態であり得るか、または治療用導入遺伝子またはshRNA等の構造核酸をコードする核酸の標的組み込みを含み得る。本発明の方法および組成物を用いて、HPRT遺伝子座への標的組み込みを選択し、かつ/または例えば特異遺伝子もしくはセーフハーバー等の別の遺伝子座におけるヌクレアーゼ媒介修飾(例えば、挿入、欠失、不活性化)を選択することができるか、またはHPRTのノックアウトは、操作されたヌクレアーゼをコードする発現ベクター(複数可)の導入(形質導入)のマーカーおよび成功を収めるヌクレアーゼ活性のマーカーとして用いられ得る。所望の導入遺伝子は、HPRT遺伝子座に直接導入され得、実践者は、6−TGへのレシピエント細胞の曝露による組み込みを選択し得る。あるいは、HPRTを標的とするヌクレアーゼは、HPRTの切断およびノックアウトの成功が1つ以上のさらなる標的(非HPRT)遺伝子座での切断に成功した細胞のスクリーニングとして用いられ得るように、別の組の1つ以上の操作されたヌクレアーゼを有する細胞に導入され得る。同様に、標的組み込み用のドナーも1つ以上のヌクレアーゼによって導入され得、HPRTのノックアウトは、切断のために富化された細胞プールが特定されるように、ヌクレアーゼ活性に成功した細胞のスクリーンとして使用することができ、代替の(非HPRT)位置(複数可)での切断の可能性を増加させる。特定の遺伝子または遺伝子座のノックアウトは、多くの異なる科学技術に有益である。目的とする1つ以上の遺伝子は、表現型または他の効果の研究のために、細胞または動物モデルにおいてノックアウトされ得る。特定の位置での特定のドナーDNAの導入等の他のゲノム編集アプローチも細胞および動物モデルにおいて用いられ得る。
HPRTを標的としたジンクフィンガータンパク質を、本質的にUrnov et al.(2005)Nature 435(7042):646−651、Perez et al(2008)Nature Biotechnology 26(7):808−816に記載され、米国特許第6,534,261号に記載されるように設計し、プラスミド、AAV、またはアデノウイルスベクターに組み込んだ。表1は、例示のHPRT ZFPのDNA結合ドメイン内の認識ヘリックスを示し、表2は、これらのZFPの標的部位を示す(DNA標的部位は大文字で示され、非接触ヌクレオチドは小文字で示される)。ZFP認識ヘリックスに接触する標的部位におけるヌクレオチドは大文字で示され、非接触ヌクレオチドは小文字で示される。
マウスまたはヒトHPRT遺伝子を標的とするZFN対、ならびにヒトHPRT遺伝子およびマウスHPRT遺伝子の両方における保存配列を認識するように設計されたZFN対を用いて、これらのZFNがDSBを特異的標的部位で誘導する能力を試験した。具体的には、標的部位のPCR増幅後に、DSB頻度の下限推定値を提供するミスマッチ検出酵素Cel−I(Yang et al,(2000)Biochemistry 39,3533−3541)を用いた挿入および欠失(挿入欠失)の定量化が続く、Cel−Iミスマッチアッセイ(Surveyor(商標)、Transgenomics、Perez et al,(2008)Nat.Biotechnol.26:808−816およびGuschin et al,(2010)Methods Mol Biol.649:247−56)を用いた。Perez(同書)に記載されるようにZFN発現ベクターを標準の条件(37℃)でヒトK562細胞またはマウスNeuro2A細胞に導入した後、DNeasy(商標)キット(Qiagen)を用いてゲノムDNAを細胞から単離した。パーセント挿入欠失は、切断後のNHEJによって変化した対立遺伝子の割合を示す。
トランスフェクト細胞の6−TG選択後の標的修飾の頻度を試験するために、細胞を、HPRT特異的ZFN(SBS番号29251およびSBS番号29250、上の表1を参照のこと)ならびにCCR5特異的ZFN(SBS番号8196zおよびSBS番号8266、共同所有特許米国特許第7,951,925号を参照のこと)の組み合わせでトランスフェクトした。
6−TG選択を用いて、HPRT特異的ヌクレアーゼを導入した別のZFN対による第2の遺伝子座での修飾を富化することもできるという概念を次に試験した。我々は、第2のZFN対がHPRT ZFN対を超えて提供され、かつHPRT ZFN対の活性が第2のZFN対の活性よりも弱い場合に、そのような「共選択」が最も効率的であると推測し、それは、その対におけるHPRT ZFN DNA結合ドメインをより活性の低い偏性ヘテロ二量体性FokIヌクレアーゼドメイン変異体DDおよびRRに結合し、さらに第2の(非HPRT標的)ZFN対におけるDNA結合ドメインをELD KKR変異体対に結合することによって達成された(共同所有の米国特許公開第2011/0201055号および同第20110158957号を参照のこと)。この取り決めは、DD/RR変異体がより活性の高いヘテロ二量体性ELD/KKR FokI変異体に対してオルソロガスであるというさらなる利点を有し、これは、4つのZFNが細胞に同時に導入されたとしても、活性二量体ZFN対が2つの所望の組み合わせからのみ形成され得ることを意味する。
HPRT遺伝子座で導入されたドナーとの相同組換えを経た細胞を富化するために、29251/29250のHPRT ZFN対およびHPRT遺伝子座との相同性を有するドナー分子でトランスフェクトしたK562細胞における6−TG選択の使用も試験した。具体的には、HPRT遺伝子座に標的化されたBamHI制限部位を含むドナーを、上述のようにHPRT ZFNを用いて導入した。この実験において、制限部位を有するドナー分子を担持する3つの異なる種類のプラスミドをヌクレアーゼと共導入した:標的HPRT挿入部位との相同性を有する短い領域(アーム)(359ヌクレオチド長)を有するドナーDNA断片8μg、ドナープラスミドがエンハンサー要素を含んだこと以外同一のドナー8μg、および挿入部位との相同性を有する長いアーム(725ヌクレオチド長)を有するドナーDNA断片8μg。トランスフェクタントをあらゆる選択の不在下でトランスフェクション後に回復させ、その後、分割し、6−TGの存在下(+)または不在下(−)のいずれかで増殖させた。選択が完了した日(8〜11日目)にDNAを単離し、挿入部位を包囲する領域をPCRで増幅させた。その後、PCR産物をBamHI制限酵素消化に供した。
15512f:5’AGCCACTGGCCCAGTTTCTACAGTCTC 3’(配列番号58)
pgkr1:5’GACGTGCGGCTTCCGTTTGTC 3’(配列番号59)
r1−16078:5’GCCTCCCATCTCCTTCATCACAT 3’(配列番号60)
次に、我々は、β−グロビン標的ZFN、HPRT ZFNでの共トランスフェクションおよび6−TG選択後に、標的組み込みドナーを用いてヒトβ−グロビン遺伝子座の修飾を試験した。この実験において、細胞をHPRT ZFNおよび以下の表3に示されるβグロビン特異的ZFNでトランスフェクトした。
βグロビンF:CCAGAAGGTTTTAATCCAAATAAGGAGAAGATATG(配列番号56)
βグロビンR:AACGATCCTGAGACTTCCACACTGATGC(配列番号57)
図6に示されるように、6−TG選択細胞におけるβグロビン遺伝子座での遺伝子修正頻度の劇的な増加が観察され、HhaIでの切断が生じたことを示し、6−TG選択が67%の遺伝子修正を含む細胞プールをもたらすことができることを実証した。
HPRT ZFN発現プラスミドを末梢血動員造血幹細胞(男性ドナー由来のCD34+細胞、すなわち、これらの細胞は1細胞当たり1コピーのHPRT遺伝子のみを有した)にトランスフェクトした。手短に、200,000個の細胞を、Perez(同書)に記載されるようにAmaxaヌクレオフェクションを用いてトランスフェクトした。この実験において、2つの組のHPRT特異的ZFNを用い、2つの濃度の29251/29250対または30179/29250対のいずれかであり、1回のヌクレオフェクション当たりそれぞれ200(+)ngまたは400(++)ngのいずれかのZFN発現プラスミドであった。トランスフェクションからの回復後、細胞をプールに分け、6−TGの存在下または不在下で増殖させた。選択が完了した後、HPRT遺伝子座での修飾を実施例3に記載されるようにCel−Iミスマッチアッセイで分析した。
HPRT特異的TALENもK562細胞において試験した。これらの実験のために、10個の異なるTALENを、FokIドメインを+63C末端TALE変異形(米国特許出願第13/068,735号を参照のこと)に結合して構築した。各位置に用いた標的ヌクレオチドおよびRVDが以下の表4に示される。表中、R0および半反復の標的ヌクレオチドが各標的配列の脇に示されており、各反復単位における各RVDの正体(各組の2列目)が各標的ヌクレオチドの正体(各組の1列目)の下に示される(配列番号69〜78)。構築されたTALENは11〜16個の完全反復に及び、したがって、表4において、16個未満の反復を有するTALENは、必然的に15、14、13、または12位で(該当せず)を有する。
次に、HPRT1特異的ヌクレアーゼ対をイヌ細胞においてインビトロで試験した。これらの実験において、リードヒトHPRT1 ZFNおよびTALENヌクレアーゼ対を使用し、ヌクレアーゼ標的部位を包囲するヒト配列およびイヌ(canine)(イヌ(dog))配列のアライメントが図9に示される。ヒト配列およびイヌ配列のアライメントを調べることで、標的部位での類似性が明らかになる。したがって、様々な量の対応するヌクレアーゼ発現ベクターのヌクレオフェクションによって、ヌクレアーゼ対をイヌ細胞株D17にトランスフェクトした。試験した対およびヌクレオフェクションで用いたDNAの量が以下の表6に示されており、レーンは図10と一致する。
リードヒト特異的ZFNおよびTALEN HPRT対の結合部位は、ヒトとアカゲザルとの間に保存される。したがって、我々は、アカゲザル細胞株LLC−MK2に対してこれらのヌクレアーゼを試験し、予想した通り、ヌクレアーゼが効率的な切断を示したことを見出した。
以下の表8に示されるZFN対を、製造業者のプロトコルに従ってBTX(登録商標)トランスフェクションを用いてmRNAとしてCD34+細胞(対A〜F)またはK562細胞(対A’)のいずれかにトランスフェクトした。各トランスフェクションについて、250,000個の細胞を用いた。DNAをトランスフェクションの3日後に標準の手順で回収した。
図13において、オリゴヌクレオチドドナーを示されるZFN mRNA対で共トランスフェクトした。表8に示されるオリゴヌクレオチドを用いてPCR産物を生成した。HPRTイントロンへの外因性DNA配列の組み込みを以下に示される制限酵素消化によってアッセイした。したがって、我々は、CD34+細胞におけるヒトHPRT遺伝子座の修飾を実証した。オリゴヌクレオチドドナーのDNA配列および標的組み込みの検出に用いた制限酵素が以下の表9に示される。アスタリスクは、ホスホロチオエート結合を示す。
5’のC切断部位に隣接するHPRT DNA(476bp)および3’の切断部位に隣接するHPRT DNA(354bp)を含有するプラスミドDNAドナーを構築した。これらの染色体相同性領域の間に強いスプライスアクセプター配列を配置した(DeKelver et al.(2010)Genome Research 20:1133−1142)。同様に、A切断部位の5’末端に429bpのHPRT相同性および3’末端に616bpのHPRT相同性を有するドナーを構築した。次に、HPRTを有するフレームに、ウイルス2A自己切断ペプチドをコードするDNA配列を配置し、その後、緑色蛍光タンパク質の遺伝子を配置した。ウシ成長ホルモン遺伝子からのポリアデニル化シグナルを導入遺伝子コード配列後に挿入した。このプラスミドを部位Cまたは部位AのZFN対をコードするmRNAを有するK562細胞に共トランスフェクトした。トランスフェクションの4日後に培養物を半分に分け、上述のように6−TG選択をその細胞の半分に適用した。培養物の生存率およびGFP陽性細胞の割合を6−TG選択の1週間後に製造業者のプロトコルに従ってGuavaに基づく細胞蛍光測定によってアッセイした。結果は、HPRTへの導入遺伝子の組み込みの成功およびHPRT陰性の導入遺伝子含有細胞の6−TG選択の成功を示す。
次に、部位Cの導入遺伝子ドナーをCD34+細胞中のHPRTに組み込んだ。細胞を、製造業者のプロトコルに従ってコードmRNAのAmaxaヌクレオフェクションによって部位CのZFNでトランスフェクトし、ドナーを上述のようにAAV2プラスミドを介して送達した。
Claims (20)
- 内因性ヒポキサンチングアニンホスホリボシルトランスフェラーゼ(HPRT)遺伝子に結合するジンクフィンガータンパク質および切断ドメインを含む非天然融合タンパク質であって、内因性HPRT遺伝子を修飾する、前記融合タンパク質。
- 前記ジンクフィンガータンパク質が、認識ヘリックス領域を含む4、5、または6個のジンクフィンガードメインを含み、前記ジンクフィンガータンパク質が、表1の単一列に示される順序で前記認識ヘリックス領域を含む、請求項2に記載の融合タンパク質。
- 請求項1または2に記載の1つ以上の融合タンパク質をコードするポリヌクレオチド。
- 請求項1に記載の1つ以上の融合タンパク質または請求項3に記載の1つ以上のポリヌクレオチドを含む単離細胞。
- 前記細胞が、T細胞、B細胞、または幹細胞からなる群から選択される、請求項3に記載の細胞。
- 前記幹細胞が、胚幹細胞(ESC)、人工多能性幹細胞(iPSC)、CD34+造血幹細胞、および肝幹細胞からなる群から選択される、請求項5に記載の細胞。
- 請求項1または請求項2に記載の融合タンパク質または請求項3に記載のポリヌクレオチドを含むキット。
- 細胞中の内因性HPRT遺伝子を切断する方法であって、
前記1つ以上の融合タンパク質が発現され、かつ前記HPRT遺伝子が切断されるような条件下で、前記細胞に、請求項3に記載の1つ以上のポリヌクレオチドを導入することを含む、前記方法。 - 前記細胞が、T細胞、B細胞、または幹細胞からなる群から選択される、請求項8に記載の方法。
- 前記幹細胞が、胚幹細胞(ESC)、人工多能性幹細胞(iPSC)、CD34+造血幹細胞、および肝幹細胞からなる群から選択される、請求項9に記載の細胞。
- 導入遺伝子を前記細胞のゲノムに組み込むことをさらに含む、請求項8〜10のいずれかに記載の方法。
- 前記導入遺伝子が前記HPRT遺伝子座に組み込まれる、請求項11に記載の方法。
- 前記導入遺伝子が、CCR5遺伝子、CXCR4遺伝子、アルブミン遺伝子、AAVS1遺伝子、Rosa遺伝子、またはβ−グロビン遺伝子に組み込まれる、請求項11に記載の方法。
- 前記導入遺伝子が内因性プロモーターの制御下にある、請求項12または請求項13に記載の方法。
- 前記導入遺伝子が外因性プロモーターの制御下にある、請求項12または請求項13に記載の方法。
- 内因性遺伝子座でヌクレアーゼによって修飾された細胞を富化する方法であって、
請求項8〜15のいずれかに記載の方法に従って細胞中の内因性HPRT遺伝子を切断することと、
前記細胞に、前記内因性遺伝子座で前記細胞の前記ゲノムを切断するヌクレアーゼをコードする1つ以上のポリヌクレオチドを導入することと、
前記細胞を6−TG選択に供し、それによって前記細胞を前記内因性遺伝子座が修飾された細胞に富化することと、を含む、前記方法。 - 前記内因性遺伝子座が不活性化される、請求項16に記載の方法。
- 前記内因性遺伝子座が、HPRT、AAVS1、アルブミン、β−グロビン、およびRosa26からなる群から選択される、請求項16または請求項17に記載の方法。
- 前記細胞が、T細胞、B細胞、または幹細胞からなる群から選択される、請求項16〜18のいずれかに記載の方法。
- 前記幹細胞が、胚幹細胞(ESC)、人工多能性幹細胞(iPSC)、CD34+造血幹細胞、および肝幹細胞からなる群から選択される、請求項19に記載の方法。
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HK1200696A1 (en) | 2015-08-14 |
WO2013063315A3 (en) | 2013-06-20 |
US8895264B2 (en) | 2014-11-25 |
CA3099582A1 (en) | 2013-05-02 |
US20130137104A1 (en) | 2013-05-30 |
CA2852955A1 (en) | 2013-05-02 |
JP6188703B2 (ja) | 2017-08-30 |
WO2013063315A2 (en) | 2013-05-02 |
AU2012328682B2 (en) | 2017-09-21 |
EP2771457A2 (en) | 2014-09-03 |
US20130122591A1 (en) | 2013-05-16 |
EP2771457B1 (en) | 2017-11-22 |
US9222105B2 (en) | 2015-12-29 |
CA2852955C (en) | 2021-02-16 |
EP2771457A4 (en) | 2015-04-08 |
AU2012328682A1 (en) | 2014-05-01 |
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