JP2011207893A - ジンクフィンガータンパク質を用いた、細胞における内因性遺伝子発現の調節 - Google Patents
ジンクフィンガータンパク質を用いた、細胞における内因性遺伝子発現の調節 Download PDFInfo
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Abstract
【解決手段】本発明は、組換えジンクフィンガータンパク質を用いることにより内因性細胞遺伝子の発現を調節するための方法を提供する。
【選択図】なし
Description
本願は、ZEPを使用して、その天然のクロマチン環境下に存在する内因性細胞遺伝子の発現を調節し得ることを初めて実証する。従って、本発明は、高い効率で内因性細胞遺伝子を特異的に認識するよう操作されたジンクフィンガーDNA結合タンパク質を提供する。本明細書に記載される実験により、約10nM未満の標的部位親和性を有する3つのフィンガーのZEP(VEGF1)を使用して、内因性遺伝子の活性化を効果的に活性化または抑制し得ることが実証される。さらに、6つのフィンガーのZEP(VEGF3a/1)もまた、内因性遺伝子の活性を効果的に抑制することが示された。最後に、3つのフィンガーのZEPを使用して、内因性のEPO(発生的に不活性な遺伝子)を活性化し得る。好ましくは、本発明のZFPは、約100nM未満の、好ましくは、約50nM未満の、最も好ましくは、約25nM以下未満のKdで、それらの標的部位に対する高い親和性を示す。
本明細書中で使用される場合、以下の用語は、他に特定されない限りそれらに示された意味を有する。
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7)セリン(S)、トレオニン(T);および8)システイン(C)、メチオニン(M)(例えば、Creighton,Proteins(1984)を参照のこと)。
本発明のZFPを、選択した内因性遺伝子において選択した標的部位を認識するように操作する。代表的には、任意の適切なC2H2ZFP(例えば、SP−1、SP−1CまたはZIF268)からの骨格を、操作されるZFPについての足場として使用する(例えば、Jacobs、EMBO J.11:4507(1992);DesjarlaisおよびBerg、PNAS 90:2256−2260(1993)を参照のこと)。次いで、多数の方法を使用して、その標的について高親和性を有するZFP(例えば、好ましくは、約25nM未満のKdを有する)を設計し、そして選択し得る。上記のように、ZFPは、高親和性を伴って、標的の内因性遺伝子における任意の適切な標的部位に結合するように設計または選択され得る。同時係属中の特許出願USSN09/229,007(1999年1月12日出願)は、選択された標的部位についてのZFPの設計、構築および発現のための方法を包括的に記載する。
ZFPポリペプチドおよび核酸は、組換え遺伝学の分野において慣用的な技術を用いて作製され得る。本発明における一般的使用法を開示する基本書は、Sambrookら、Molecular Cloning,A Laboratory Manual(第2版、1989),Kriegler,Gene Transfer and Expression:A Laboratory Manual(1990);およびCurrent Protocols inMolecular Biology(Ausubelら、編、1994)を含む。さらに、本質的に任意の核酸を、任意の種々の商業的供給元に特注することが可能である。同様に、ペプチドおよび抗体を、任意の種々の商業的供給元に特注することが可能である。
本発明のZFPは、必要に応じて、遺伝子発現の調節のための調節ドメインと結合し得る。ZFPは、1つ以上の調節ドメイン、あるいは、同じドメインかまたは2つの異なるドメインの2つのコピーである2つ以上のドメインを有する、2つ以上の調節ドメインと共有的にかまたは非共有的に結合され得る。この調節ドメインは、ZFPへ共有的に連結され得る(例えば、アミノ酸リンカーを介して、融合タンパク質の一部として)。ZFPはまた、非共有的二量体化ドメインを介して調節ドメインと結合され得る(例えば、ロイシンジッパー、STATタンパク質N末端ドメイン、またはFK506結合タンパク質(例えば、O’Shea,Science 254:539(1991),Barahmand−Pourら、 Curr.Top.Microbiol.Immunol.211:121−128(1996);Klemmら、 Annu.Rev.Immunol.16:569−592(1998);Klemmら、 Annu.Rev.Immunol.16:569−592(1998);Hoら、Nature 382:822−826(1996);およびPomeranzら、Biochem.37:965(1998)を参照のこと))。調節ドメインは、ZFPの C末端またはN末端を含む、任意の適切な位置でZFPと結合され得る。
選択のZFPをコードする核酸は、代表的に、複製および/または発現のための(例えば、Kdを決定するための)原核生物細胞または真核生物細胞中に形質転換するための中間ベクター中にクローニングされる。中間ベクターは、代表的に、ZFPをコードする核酸またはタンパク質の産生の保存または操作のための原核生物ベクター(例えば、プラスミド)またはシャトルベクター、または昆虫ベクターである。ZFPをコードする核酸はまた、代表的には、植物細胞、動物細胞(好ましくは哺乳動物細胞またはヒト細胞)、真菌細胞、細菌細胞、または原生動物細胞へ投与するための発現ベクター中にクローニングされる。
種々のアッセイを使用して、ZFPによる遺伝子発現調節のレベルを決定し得る。特定のZFPの活性は、種々のインビトロアッセイおよびインビボアッセイを使用して、例えば、タンパク質レベルまたはmRNAレベル、産物レベル、酵素活性、腫瘍増殖;レポーター遺伝子の転写活性化または転写抑制;セカンドメッセンジャーレベル(例えば、cGMP、cAMP、IP3、DAG、Ca2+);サイトカインおよびホルモンの産生レベル;ならびに新生血管形成を測定することによって、例えば、イムノアッセイ(例えば、抗体を用いるELISAおよび免疫組織化学アッセイ)、ハイブリダイゼーションアッセイ(例えば、RNase保護、ノーザン、インサイチュハイブリダイゼーション、オリゴヌクレオチドアレイ研究)、比色定量アッセイ、増幅アッセイ、酵素活性アッセイ、腫瘍増殖アッセイ、表現型アッセイなどを使用して、評価され得る。
従来のウイルスおよび非ウイルスに基づく遺伝子移入方法は、哺乳動物細胞または標的組織に、操作されたZFPをコードする核酸を導入するために使用され得る。このような方法は、ZFPをコードする核酸をインビトロで細胞に投与するために使用され得る。好ましくは、ZFPをコードする核酸は、インビボまたはエキソビボでの遺伝子治療の使用のために投与される。非ウイルスベクター送達系は、DNAプラスミド、裸の核酸、および送達ビヒクル(例えば、リポソーム)と複合化した核酸を含む。ウイルスベクター送達系は、細胞への送達後にエピソームであるかまたはゲノムに組み込まれるかのいずれかである、DNAウイルスおよびRNAウイルスを含む。遺伝子治療の手順の概説については、Anderson、Science 256:808〜813(1992);NabelおよびFelgner、TIBTECH 11:211〜217(1993);MitaniおよびCaskey、TIBTECH 11:162〜166(1993);Dillon、TIBTECH 11:167〜175(1993);Miller、Nature 357:455〜460(1992);Van Brunt、Biotechnology 6(10);1149〜1154(1988);Vigne、Restorative Neurologyand Neuroscience 8:35〜36(1995);KremerおよびPerricaudet、British Medical Bulletin 51(1):31〜44(1995);Haddadaら、Current Topics in Microbiology and Immunology DoerflerおよびBohm(編)(1995);ならびにYuら、Gene Therapy 1:13〜26(1994)を参照のこと。
ポリペプチド化合物(例えば、ZFP)の投与における重要な因子は、このポリペプチドが細胞の形質膜、または核のような細胞内区画の膜を横切る能力を有することを確実にすることである。細胞膜は、非イオン性の脂溶性低分子に対して自由に透過性であり、かつ極性化合物、巨大分子、および治療剤または診断剤に対して固有に不透過性である、脂質タンパク質の二重層から構成される。しかし、細胞膜を横切るZFPのようなポリペプチドを輸送する能力を有する、タンパク質およびリポソームのような他の化合物が記載されている。
ZFPの治療的適用のために、本発明の状況において患者に投与される用量は、経時的に患者において有益な治療的応答をもたらすのに充分であるべきである。さらに、特定の投与レジメが、実験設定(例えば、機能的ゲノム研究における設定、および細胞または動物モデルにおける設定)における表現型の変化を決定するために有用であり得る。用量は、用いられる特定のZFPの効力およびKd、標的細胞の核の容量、および患者の状態、ならびに処置される患者の体重または表面積によって決定される。用量のサイズはまた、特定の患者における特定の化合物もしくはベクターの投与に伴う任意の有害な副作用の存在、性質、および程度によって決定される。
ZFPおよびZFPをコードする発現ベクターは、遺伝子発現の調節のために、そして治療的または予防的適用(例えば、癌、虚血、糖尿病性網膜症、黄斑変性、慢性関節リウマチ、乾癬、HIV感染、鎌状赤血球貧血、アルツハイマー病、筋ジストロフィー、神経変性疾患、血管疾患、嚢胞性線維症、発作など)のために、患者に直接的に投与され得る。ZFP遺伝子治療によって阻害され得る微生物の例は以下を含む:病原性細菌(例えば、クラミジア、リケッチア属細菌、ミコバクテリア、ブドウ球菌、連鎖球菌、肺炎球菌、髄膜炎菌およびconococci、クレブシエラ属、プロテウス属、セラチア属、シュードモナス属、レジオネラ属、ジフテリア菌、サルモネラ菌、バシラス属、コレラ菌、破傷風菌、ボツヌス菌、炭疽菌、ペスト菌、レプトスピラ菌、およびライム病細菌;感染性真菌(例えば、Aspergillus種、Candida種;胞子虫のような原生動物(例えば、Plasmodia)、根足虫(例えば、Entamoeba)および鞭毛動物(Trypanosoma、Leishmania、Trichomonas、Giardiaなど));ウイルス性疾患(例えば、肝炎(A型、B型、またはC型)、ヘルペスウイルス(例えば、VZV、HSV−1、HSV−6、HSV−II、CMV、およびEBV)、HIV、エボラ、アデノウイルス、インフルエンザウイルス、フラビウイルス、ECHOウイルス、ライノウイルス、コクサッキーウイルス、コロナウイルス(cornovirus)、RSウイルス、流行性耳下腺炎ウイルス、ロタウイルス、麻疹ウイルス、風疹ウイルス、パルボウイルス、ワクシニアウイルス、HTLVウイルス、デングウイルス、パピローマウイルス、ポリオウイルス、狂犬病ウイルス、ならびにアルボウイルス性脳炎ウイルスなど))。
ZFPは、例えば、病気に対する抵抗力の増加、構造的ポリサッカライドおよび貯蔵ポリサッカライドの改変、香り、タンパク質、および脂肪酸、果実成熟、収量、色、栄養的特性、貯蔵能の改善などのような形質について植物を操作するために使用され得る。特に、油脂産生の増強のための作物種の操作(例えば、脂肪種子において産生される脂肪酸の改変)が、目的のものである。
ZFPはまた、表現型の結果および遺伝子発現の機能を決定するためのアッセイについての使用を有する。分析技術における近年の進歩は、集中された大量の配列決定(focussed mass sequencing)の努力と合わせて、以前に利用可能であったものよりもずっと多い分子標的を同定および特徴付ける機会を作り出した。遺伝子およびそれらの機能に関するこの新しい情報は、基礎的な生物学的な理解とともに加速し、そして治療的介入のための多くの新しい標的を提供する。いくつかの場合において、分析の手段は、新しいデータの生成と歩調を合わせない。1つの例は、全体の示差的な遺伝子発現の測定における近年の進歩によって提供される。これらの方法は、遺伝子発現マイクロアレイ、示差的cDNAクローニング頻度、差引きハイブリダイゼーションおよびディファレンシャルディスプレイ法によって代表され、異なる組織でアップレギュレートされるか、またはダウンレギュレートされる遺伝子、あるいは特定の刺激に応答する遺伝子を非常に迅速に同定し得る。このような方法は、形質転換、腫瘍の進行、炎症応答、神経障害などのような生物学的プロセスを探索するためにますます使用されつつある。所定の生理学的な現象と相関する、示差的に発現された遺伝子の長いリストを今や非常に容易に生成し得るが、これは、個々の示差的に発現された遺伝子とその現象との間の原因となる関係が難しいということを実証する。今日まで、示差的に発現された遺伝子に機能を割り当てる簡単な方法は、示差的な遺伝子発現をモニタリングする能力と歩調を合わせてこなかった。
ZFP技術のさらなる適用は、トランスジェニック動物における遺伝子発現を操作することである。細胞株を用いる場合、内在性遺伝子の過剰発現または異種遺伝子のトランスジェニック動物(例えば、トランスジェニックマウス)への導入は、かなり直線的なプロセスである。ZFP技術は、これらの型の方法の改善である。なぜなら、研究対象の遺伝子の全長cDNAクローンを産生する必要性を回避し得るからである。
この第1の実施例は、ヒト血管内皮増殖因子(VEGF)遺伝子のプロモーターに含まれるDNA配列を認識するように設計されるZFPの構築を実証する。VEGFは、約46kDaの糖タンパク質であり、これは低酸素によって誘導される内皮細胞特異的マイトジェンである。VEGFは、癌、種々の網膜症、および他の重篤な疾患に関連する新脈管形成に関連している。選択されたDNA標的部位は、遺伝子の転写開始部位を取り囲む領域であった。選択された2つの9塩基対(bp)部位は、配列agcGGGGAGGATcGCGGAGGCTtgg(ここで、大文字は、実際の9bpの標的物を表す)内に見出される。9bp上流の標的物を標的化するタンパク質をVEGF1と示し、そして9bp下流の標的物を標的化するタンパク質をVEGF3aと示した。VEGFについての主な転写開始部位は、第1の9bp標的物の3’末端のTであり、これは上記配列の下線部である。
ZFP設計における重要な考慮は、DNA標的物の長さである。無作為のDNAについて、nヌクレオチドの配列は、0.5×4n塩基対毎に1回生じると期待される。従って、9bpのDNAのみを認識するように設計されたDNA結合ドメインは、130,000bp毎に部位が見出され、従って複雑なゲノムにおける複数の位置に結合し得る(ヒトゲノム中20,000部位のオーダーにおいて)。9bpの推定リプレレッサー結合配列は、5’UTR中のVEGFについて選択され、そしてこれらは直接転写を干渉し得る。しかし、細胞の内部で発現される場合、必要な親和性または特異性を欠失した9bp部位を認識するジンクフィンガードメインの場合において、より大きなドメインが、6フィンガータンパク質を形成するためのリンカー配列を有する別々の3つのフィンガードメインを結合させることによって、18塩基対を認識するために構築された。このことは、リプレッサーが、特に微量のリプレッサーのみが生成されている条件下で、特異的に適切な配列を標的化することを保証すべきである。VEGFにおける9bp標的部位を、ジンクフィンガーが18bp配列を認識するように連結され得るように、互いに隣接して選択した。VEGF1部位およびVEGF3a部位についての場合のように、1つのヌクレオチドギャップによって分離された2つの9bp部位へのZFPの結合を可能にするので、リンカーDGGGSを選択した(Liuら、PNAS 5525−5530(1997)もまた参照のこと)。
(1)GB19GCCATGCCGGTACCCATACCTGGCAAGAAGAAGCAGCAC)
(2)GB10CAGATCGGATCCACCCTTCTTATTCTGGTGGGTを用いて増幅し、上記のように改変されたpMAL−c2発現ベクターにクローニングするためのKpnIおよびBamHI部位を導入した。
この実施例は、哺乳動物細胞内のZFPの作製、それらの核への移行、およびZFPによって標的DNA配列に局在化される機能的ドメインを提供するための発現ベクターの開発を記載する。使用した機能的ドメインは、Kruppel−関連ボックス(KRAB)抑止ドメインおよび単純ヘルペスウイルス(HSV−1)VP16活性化ドメインである。
この実施例は、細胞におけるZFPリプレッサータンパク質の活性を測定するための、一過性の同時トランスフェクトション研究の使用を実証する。このような実験は、ZFP−KRAB発現(「エフェクター」)プラスミドと、VEGF標的部位を保有するレポータープラスミドとの同時トランスフェクションを含む。空ベクターコントロールに対するエフェクタープラスミドの存在下のレポーター遺伝子の発現の抑制によって、有効性を評価する。
この実施例は、細胞においてZFP転写アクチベーターの活性を測定するための一過性の同時トランスフェクション研究の使用を実証する。この実験の準備は、異なるトランスフェクション法、異なる細胞株、および異なるセットのレポータープラスミドおよびエフェクタープラスミドが使用されたことを除いて、実施例IVの準備と同様である。
この実施例は、設計したZFPが、天然の状況およびクロマチン構造にある内因性細胞遺伝子の発現を抑制し得ることを例証する。詳細には、KRAB抑制ドメインに融合されたVEGF ZFPを発現するエフェクタープラスミドを細胞に導入し、そしてVEGF遺伝子を下方制御することを示した。
この実施例は、設計したZFPは、天然の状況およびクロマチン構造にある遺伝子の発現を活性化し得ることを例証する。詳細には、VP16活性化ドメインに融合されたVEGF ZFPを発現するエフェクタープラスミドを細胞に導入し、そしてVEGF遺伝子を上方制御することを示した。
実施例VIおよびVIIの結果をさらに実証するために、リボヌクレアーゼ保護アッセイ(RPA)を行い、VEGFタンパク質の増加レベルをVEGF mRNAレベルの増加(実施例VII)と相関させ、そしてVEGFタンパク質の減少レベルをVEGF mRNAレベルの減少(実施例VI)と相関させた。
EPOは30.4kDの糖タンパク質ホルモンであり、赤血球産生の制御に重要な役割を果たす。EPO遺伝子は、通常、低酸素に応じて胎児肝臓および成体腎臓のみで発現される。EPOは、骨髄内の赤血球前駆体細胞上のEPOレセプターと相互作用することによって作用して、それらの細胞の増殖および成熟赤血球への分化を刺激する(Jelkmann,Physiological Reviews 72:449(1992);Semenza,Hematology/Oncology Clinics of North America8:863(1994);Ratcliffeら,J.Exp.Bio.(1991))。組換えヒトEPO遺伝子産物は、貧血および慢性腎不全を処置するために首尾良く使用されてきた(Egrie,Pharacotherapy 10:3S(1990))。
Claims (1)
- 細胞における内因性細胞遺伝子の発現を阻害する方法であって、該方法は、以下の工程:該内因性細胞遺伝子における第1の標的部位を、第1のジンクフィンガータンパク質と接触させる工程であって、ここで該ジンクフィンガータンパク質のKdは、約25nM未満である工程であって;これにより少なくとも約20%該内因性細胞遺伝子の発現を阻害する工程、を含む、方法。
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JP2001005820A Expired - Lifetime JP5490971B2 (ja) | 1999-01-12 | 2001-01-12 | ジンクフィンガータンパク質を用いた、細胞における、内因性遺伝子発現の調節 |
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AT (1) | ATE304792T1 (ja) |
AU (1) | AU745844B2 (ja) |
CA (1) | CA2323086C (ja) |
DE (2) | DE20023745U1 (ja) |
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