JP2014505464A - Nanogへの天然アンチセンス転写物の阻害によるnanog関連疾患の治療 - Google Patents
Nanogへの天然アンチセンス転写物の阻害によるnanog関連疾患の治療 Download PDFInfo
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Abstract
【選択図】図1
Description
配列番号1:ヒトNanog homeobox(NANOG)、mRNA(NCBI登録番号NM_024865);NANOGアンチセンス配列(AW006303)および配列番号3〜配列番号6:アンチセンスオリゴヌクレオチド。*はホスホチオアート結合を示す。
本明細書で使用される用語の選択は、特定の実施形態を説明する目的でされたものであり、本発明を限定することを意図するものではない。本明細書で使用される場合、単数形の「a」、「an」、及び「the」は文脈において明らかに別記されない限り、複数形の内容も含むものとする。さらに、用語「含む」、「含める」、「有する」、「もつ」またはその変化形は、本明細書および/または添付の請求項において使用される場合、用語「包含する」と同様に非排他的な意味で用いられるものとする。
標的:一実施形態において、該標的は、限定することなくNANOGに関連するセンスおよび/またはアンチセンスの非コードおよび/またはコード配列を含んだNANOGおよびその類似型の核酸配列を含む。
外来性核酸の宿主細胞または生体内への輸送は、細胞中または生体中の核酸を直接検出するステップによって評価され得る。そのような検出は、当技術分野において周知のいくつかの方法によって達成し得る。例えば、外来性核酸の存在は、サザンブロットまたは核酸に関連するヌクレオチド配列を特異的に増幅するプライマーを使用するポリメラーゼ連鎖反応(PCR)技術によって検出し得る。外来性核酸の発現も遺伝子発現分析を含む従来の方法を使用して測定し得る。例えば外来性核酸から生成されるmRNAはノーザンブロットおよび逆転写PCR(RT−PCR)を使用して検出および定量し得る。
本発明の化合物は、診断、治療および予防のためにならびに研究用試薬およびキットの構成要素として利用され得る。さらに、優れた特異性をもって遺伝子発現を阻害できるアンチセンスオリゴヌクレオチドは、当業者によって特定の遺伝子の機能を解明するため、または生物学的経路の種々のメンバー間の機能を区別するために使用されることが多い。
本発明のオリゴヌクレオチドの他の修飾は、オリゴヌクレオチドの活性、細胞分布または細胞への取り込みを増強する1以上の成分またはコンジュゲートへのオリゴヌクレオチドの化学的連結を含む。これらの成分またはコンジュゲートは、1級または2級ヒドロキシル基などの官能基に共有結合したコンジュゲート基を含み得る。本発明のコンジュゲート基は、干渉物質、レポーター分子、ポリアミン、ポリアミド、ポリエチレングリコール、ポリエーテル、オリゴマーの薬力学特性を増強する基、およびオリゴマーの薬物動態特性を増強する基を含む。典型的なコンジュゲート基は、コレステロール、脂質、リン脂質、ビオチン、フェナジン、葉酸、フェナントリジン、アントラキノン、アクリジン、フルオレセイン、ローダミン、クマリン、および色素を含む。本発明の文脈において薬力学特性を増強する基は、取り込みを改善し、分解への耐性を増強し、および/または標的核酸との配列特異的ハイブリダイゼーションを強化する基を含む。本発明の文脈において薬物動態特性を増強する基は、本発明の化合物の取り込み、分散、代謝または排出を改善する基を含む。代表的コンジュゲート基は、1992年10月23日出願の国際特許出願PCT/US92/09196および米国特許第6,287,860号、「Antisense inhibition of MEKK2 expression」において開示されており、これらはともに参照により本明細書に組み込まれる。コンジュゲート成分は、以下に限定されないが、コレステロール成分、コール酸、チオエーテル(例えばヘキシル−S−トリチルチオール)、チオコレステロール、脂肪族鎖(例えばドデカンジオールまたはウンデシル残基)、リン脂質(例えばジ−ヘキサデシル−rac−グリセロールまたはトリエチルアンモニウム1,2−ジ−O−ヘキサデシル−rac−グリセロ−3−H−ホスホネート)、ポリアミンまたはポリエチレングリコール鎖、あるいはアダマンタン酢酸、パルミチル成分、またはオクタデシルアミンもしくはヘキシルアミノ−カルボニル−オキシコレステロール成分などを含む。本発明のオリゴヌクレオチドは、活性原薬、例えばアスピリン、ワルファリン、フェニルブタゾン、イブプロフェン、スプロフェン、フェンブフェン、ケトプロフェン、(S)−(+)−プラノプロフェン、カプロフェン、ダンシルサルコシン、2,3,5−トリヨード安息香酸、フルフェナム酸、フォリン酸、ベンゾチアジアジド、クロロチアジド、ジアセピン、インドメチシン、バルビツール酸、セファロスポリン、サルファ剤、抗糖尿病薬、抗菌剤または抗生物質ともコンジュゲート形成され得る。
本発明の化合物は、取り込み、分散および/または吸収の補助ために、例えばリポソーム、受容体−標的分子、経口、直腸、局所または他の製剤として、他の分子、分子構造または化合物と、混合物と混合、封入、コンジュゲート化または他の方法で結合され得る。そのような取り込み、分散および/または吸収を補助する製剤の調製について記載した代表的米国特許としては、以下に限定されないが、米国特許第5,108,921号;第5,354,844号;第5,416,016号;第5,459,127号;第5,521,291号;第5,543,165号;第5,547,932号;第5,583,020号;第5,591,721号;第4,426,330号;第4,534,899号;第5,013,556号;第5,108,921号;第5,213,804号;第5,227,170号;第5,264,221号;第5,356,633号;第5,395,619号;第5,416,016号;第5,417,978号;第5,462,854号;第5,469,854号;第5,512,295号;第5,527,528号;第5,534,259号;第5,543,152号;第5,556,948号;第5,580,575号;および第5,595,756号が挙げられ、それぞれが本明細書に参照として組み込まれる。
治療用組成物の処方およびそれらの続く投与(投薬)は、当業者の技能の範囲内であると考えられる。投薬は、数日間から数カ月間継続する、または治療が効果的になるかもしくは病態の減退が達成されるまでの治療過程において、治療される病態の重症度および応答性に応じて決まる。最適な投薬レジメンは、患者の身体での薬剤蓄積の測定値から算出され得る。当業者であれば、最適投与量、投薬方法および反復頻度を容易に決定できる。最適な投与量は、個々のオリゴヌクレオチドの相対的効力に応じて変動し得、通常体外および生体内動物モデルにおいて効果的であると判明したEC50に基づいて推定され得る。通常投与量は、体重1kgあたり0.01μg〜約10mgであり、1日に、1週間に、1カ月にもしくは1年に1回もしくは複数回またはさらに2〜20年ごとに1回である場合がある。当業者であれば、測定された滞留時間および体液または組織における薬剤の濃度に基づいて投薬の反復頻度を容易に推定できる。治療の成功に続いて、病態の再発を予防するために患者に維持療法を受けさせることが望ましい場合があり、ここでオリゴヌクレオチドは維持投与において体重1kgあたり0.01μg〜約10mg、1日1回または複数回から2〜20年ごとに1回の範囲で投与される。
実施例
上記の通り用語「に特異的なオリゴヌクレオチド」または「オリゴヌクレオチド標的」は、(i)標的遺伝子の一部分と安定な複合体を形成できる配列、または(ii)標的遺伝子のmRNA転写物の一部分と安定な2重鎖を形成できる配列を有するオリゴヌクレオチドを指す。
実施例2において設計された実験を行うために、ATCC (cat# HB−8065)からのHepG2細胞を、増殖培地(MEM/EBSS(Hyclone cat#SH30024またはMediatech cat#MT−10−010−CV)+10%FBS(Mediatech cat#MT35−011−CV)+ペニシリン/ストレプトマイシン(Mediatech cat#MT30−002−CI))中、37℃、5%CO2で増殖させた。実験の1日前に、該細胞を6穴ブレートに0.5×104/mlの密度で再播種し、37℃、5%CO2で一晩インキュベートした。実験当日に6穴プレート中の培地を新鮮な増殖培地に交換した。
Claims (44)
- 生体系におけるNANOGポリヌクレオチドの機能および/または発現を調節する方法であって、
前記生体系を、5〜30個のヌクレオチドの長さの少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップであって、前記少なくとも1つのオリゴヌクレオチドが、NANOGポリヌクレオチドの天然のアンチセンスに対する逆相補配列と少なくとも50%の配列同一性を有する、接触させるステップを含み、
それによって前記NANOGポリヌクレオチドの機能/または発現を調節する、方法。 - 請求項1に記載の生体系におけるNANOGポリヌクレオチドの機能および/または発現を調節する方法であって、
前記生体系を、5〜30個のヌクレオチドの長さの少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップであって、前記少なくとも1つのオリゴヌクレオチドが、天然のアンチセンス転写物ヌクレオチドの配列番号2の1番目〜548番目の範囲内の5〜30個の連続したヌクレオチドを含むポリヌクレオチドの逆相補配列と少なくとも50%の配列同一性を有する、接触させるステップを含み、
それによって前記NANOGポリヌクレオチドの機が能および/または発現を調節する、請求項1に記載の方法。 - 生体内または体外で患者の細胞または組織におけるNANOGポリヌクレオチドの機能および/または発現を調節する方法であって、
前記細胞または組織を、5〜30個のヌクレオチドの長さの少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップであって、前記オリゴヌクレオチドが、NANOGポリヌクレオチドのアンチセンスオリゴヌクレオチドと少なくとも50%の配列同一性を有する、接触させるステップを含み、
それによって生体内または体外で患者の細胞または組織における前記NANOGポリヌクレオチドの機能および/または発現を調節する、方法。 - 請求項3に記載の患者の細胞または組織におけるNANOGポリヌクレオチドの機能および/または発現を調節する方法であって、
前記生体系を、5〜30個のヌクレオチドの長さの少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップであって、前記少なくとも1つのオリゴヌクレオチドが、天然のアンチセンス転写物ヌクレオチドの配列番号2の1番目〜548番目の範囲内の5〜30個の連続したヌクレオチドを含むポリヌクレオチドの逆相補配列と少なくとも50%の配列同一性を有する、接触させるステップを含み、
それによって前記NANOGポリヌクレオチドの機能および/または発現を調節する、請求項3に記載の方法。 - 生体系におけるNANOGの機能および/または発現を調節する方法であって、前記生体系を、NANOGポリヌクレオチドの天然のアンチセンスオリゴヌクレオチドの領域を標的にする少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップを含み、それによって前記NANOGポリヌクレオチドの機能および/または発現を調節する、方法。
- 前記NANOGの機能および/または発現が、対照と比較して生体内または体外で増加する、請求項5に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、NANOGポリヌクレオチドの天然のアンチセンス配列を標的とする、請求項5に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、NANOGポリヌクレオチドのコード核酸配列および/または非コード核酸配列を含む核酸配列を標的とする、請求項5に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、NANOGポリヌクレオチドの重複配列および/または非重複配列を標的とする、請求項5に記載の方法。
- 前記少なくとも1つのアンチセンスオリゴヌクレオチドが、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオチド間結合、少なくとも1つの修飾ヌクレオシド、およびそれらの組み合わせから選択された1以上の修飾を含む、請求項5に記載の方法。
- 前記1以上の修飾が、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された少なくとも1つの修飾糖部分を含む、請求項10に記載の方法。
- 前記1以上の修飾が、ホスホロチオエート、2’−O−メトキシエチル(MOE)、2’−フルオロ、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオシド間結合を含む、請求項10に記載の方法。
- 前記1以上の修飾が、ペプチド核酸(PNA)、ロックド核酸(LNA)、アラビノ核酸(FANA),類似体、誘導体、およびそれらの組み合わせから選択された少なくとも1つの修飾ヌクレオチドを含む、請求項10に記載の方法。
- 前記少なくとも1つのオリゴヌクレオチドが、配列番号3乃至配列番号6に記載するオリゴヌクレオチド配列を少なくとも1つ含む、請求項1に記載の方法。
- 生体内または体外で哺乳動物の細胞または組織におけるNANOG遺伝子の機能および/または発現を調節する方法であって、
前記細胞または組織を、5〜30個のヌクレオチドの長さの少なくとも1つの低分子干渉RNA(siRNA)オリゴヌクレオチドと接触させるステップであって、前記少なくとも1つのsiRNAオリゴヌクレオチドが、NANOGポリヌクレオチドのアンチセンスポリヌクレオチドに対して特異的であり、前記少なくとも1つのsiRNAオリゴヌクレオチドが、前記NANOGポリヌクレオチドのアンチセンス核酸分子および/またはセンス核酸分子の少なくとも約5個の連続した核酸の相補配列と少なくとも50%の配列同一性を有する、接触させるステップと、
生体内または体外で哺乳動物の細胞または組織におけるNANOGの機能および/または発現を調節するステップとを含む、方法。 - 前記オリゴヌクレオチドが、前記NANOGポリヌクレオチドの前記アンチセンス核酸分子および/またはセンス核酸分子に相補的な連続した少なくとも約5個の核酸の配列と少なくとも80%の配列同一性を有する、請求項15に記載の方法。
- 生体内または体外で哺乳動物の細胞または組織におけるNANOGの機能および/または発現を調節する方法であって、
前記細胞または組織を、NANOGポリヌクレオチドのセンス鎖および/または天然のアンチセンス鎖の非コード配列および/またはコード配列に対して特異的な、約5〜30個のヌクレオチドの長さの少なくとも1つのアンチセンスオリゴヌクレオチドと接触させるステップであって、前記少なくとも1つのアンチセンスオリゴヌクレオチドが、配列番号1および2に記載の少なくとも1つの核酸配列と少なくとも50%の配列同一性を有する、接触させるステップと、
生体内または体外で哺乳動物の細胞または組織における前記NANOGの機能および/または発現を調節するステップとを含む、方法。 - 合成された修飾オリゴヌクレオチドであって、少なくとも1つの修飾を含み、
前記少なくとも1つの修飾が、少なくとも1つの修飾糖部分、少なくとも1つの修飾ヌクレオチド間結合、少なくとも1つの修飾ヌクレオチド、およびそれらの組み合わせから選択され、
前記オリゴヌクレオチドが、生体内または体外でNANOG遺伝子にハイブリダイズし、通常の対照と比較してその機能および/または発現を調節するアンチセンス化合物であり、および
前記オリゴヌクレオチドが、前記NANOGポリヌクレオチドおよびアレル、ホモログ、アイソフォーム、変異型、誘導体、突然変異体、断片、またはそれらの組み合わせのアンチセンス核酸分子および/またはセンス核酸分子に相補的な少なくとも約5個の連続した核酸の配列と、少なくとも50%の配列同一性を有する、合成された修飾オリゴヌクレオチド。 - 前記オリゴヌクレオチドが、5〜30個のヌクレオチドの長さであり、かつNANOG遺伝子の天然のアンチセンス転写物内に5〜30個の連続したヌクレオチドの逆相補配列と少なくとも50%の配列同一性を有する、請求項18に記載のオリゴヌクレオチド。
- 前記少なくとも1つの修飾が、ホスホロチオエート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホルアミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせからなる群から選択されたヌクレオチド間結合を含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、少なくとも1つのホスホロチオエートヌクレオチド間結合を含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、ホスホロチオエートヌクレオチド間結合の骨格を含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが少なくとも1つの修飾されたヌクレオチドを含み、該修飾されたヌクレオチドは、ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組み合わせから選択されたものである、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが複数の修飾を含み、前記複数の修飾は、ホスホロチオエート、アルキルホスホナート、ホスホロジチオアート、アルキルホスホノチオアート、ホスホラミダート、カルバメート、炭酸塩、リン酸トリエステル、アセトアミダート、カルボキシメチルエステル、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが複数の修飾を含み、前記複数の修飾は、ペプチド核酸、ロックド核酸(LNA)、類似体、誘導体、およびそれらの組み合わせから選択された修飾ヌクレオチドを含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された少なくとも1つの修飾糖部分を含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが複数の修飾を含み、前記複数の修飾は、2’−O−メトキシエチル修飾糖部分、2’−メトキシ修飾糖部分、2’−O−アルキル修飾糖部分、二環糖部分、およびそれらの組み合わせから選択された修飾糖部分を含む、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、約5〜30個のヌクレオチドの長さであり、かつNANOGポリヌクレオチドのアンチセンス鎖および/またはセンス鎖にハイブリダイズし、
前記オリゴヌクレオチドが、NANOGポリヌクレオチドのアンチセンスおよび/またはセンスコード核酸配列および/または非コード核酸配列の少なくとも5個の連続した核酸の相補配列と少なくとも約60%の配列同一性を有する、請求項19に記載のオリゴヌクレオチド。 - 前記オリゴヌクレオチドが、NANOGポリヌクレオチドのアンチセンスおよび/またはセンスコード核酸配列および/または非コード核酸配列の連続した少なくとも5個の核酸の配列に相補的な配列に対して、少なくとも約80%配列同一性を有する、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、生体内または体外でNANOGポリヌクレオチドにハイブリダイズし、通常の対照と比較してその機能および/または発現を調節する、請求項19に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドが、配列番号3乃至配列番号6に記載する配列を含む、請求項19に記載のオリゴヌクレオチド。
- 医薬組成物であって、請求項18に記載の1以上のNANOGポリヌクレオチドに特異的な1以上のオリゴヌクレオチドと、医薬的に許容される賦形剤とを含む、医薬組成物。
- 前記オリゴヌクレオチドが、配列番号3乃至配列番号6に記載するヌクレオチド配列のいずれか1つと比較して、少なくとも約40%の配列同一性を有する、請求項32に記載の組成物。
- 前記オリゴヌクレオチドが、配列番号3乃至配列番号6に記載するヌクレオチド配列を含む、請求項32に記載の組成物。
- 配列番号3乃至配列番号6に記載する前記オリゴヌクレオチドが、1以上の修飾または置換を含む、請求項34に記載の組成物。
- 前記1以上の修飾が、ホスホロチオエート、メチルホスホナート、ペプチド核酸、ロックド核酸(LNA)分子、およびそれらの組み合わせから選択されたものである、請求項35に記載の組成物。
- 少なくとも1つのNANOGポリヌクレオチドおよび/または少なくとも1つのそのコードされた生成物に関連する疾患を予防または治療する方法であって、
少なくとも1つのNANOGポリヌクレオチドの天然のアンチセンス配列に結合し、かつ前記少なくとも1つのNANOGポリヌクレオチドの発現を調節する、少なくとも1つのアンチセンスオリゴヌクレオチドを治療上有効な用量を患者に投与するステップを含み、
それによって、前記少なくとも1つのNANOGポリヌクレオチドおよび/または少なくとも1つのそのコードされた生成物に関連する疾患を予防または治療する、方法。 - 前記少なくとも1つのNANOGポリヌクレオチドに関連する疾患が、NANOGの異常機能および/または発現に関連する疾患または障害、皮膚の交互変化(skin alternation)、熱傷、心血管疾患または障害、糖尿病、変形性関節症、リウマチ性関節炎、癌、遺伝性疾患または障害(例えば、デュシェンヌ型筋ジストロフィー)、神経性疾患または障害(例えば、パーキンソン病、ハンチントン病、ゴーシェ病)、多能性幹細胞から再生された新規の細胞/組織により交換することができる特定の細胞腫および組織の損失に関連する疾患または障害、障害のあるDNA修復に関連する疾患または障害、ゲノムの完全性に関連する疾患または障害、障害のあるリンパ球活性および/または増殖に関連する疾患または障害、障害のある内皮の血管新生に関連する疾患または障害、免疫系に関連する疾患または障害、障害のある胎児肝臓キナーゼ(FLK−1)転写に関連する疾患または障害、肝疾患または障害、幹細胞治療を必要とする障害または状態、先天性疾患または障害、代謝性疾患または障害(例えば、1型糖尿病)、外傷(脊髄損傷、熱傷など)、血流不全、および移植を必要とする他の血管、心臓、肝臓または腎臓の疾患から選択されたものである、請求項37に記載の方法。
- 生物学的な系におけるアポトーシスを誘導する方法であって、前記系にNANOGポリヌクレオチドに対する逆相補の天然のアンチセンス転写物内の5から30個の連続したヌクレオチドと少なくとも50%同一である、5から30個のヌクレオチドの長さのオリゴヌクレオチドを投与することを含む、方法。
- 前記天然のアンチセンス転写物が、配列番号2乃至配列番号6を有する、請求項39に記載の方法。
- 前記生物学的な系が、患者の細胞もしくは組織である、請求項39に記載の方法。
- 生物学的な系においてアポトーシスを誘導する方法であって、前記系に約5から30個のオリゴヌクレオチドを投与することを含み、前記オリゴヌクレオチドが、前記遺伝子の天然のアンチセンス転写物を標的とすることにより、標的遺伝子をアップレギュレートし、前記オリゴヌクレオチドが、アップレギュレートされた遺伝子の逆相補的な天然のアンチセンス転写物と少なくとも50%同一である、請求項39に記載の方法。
- 生体内投与のための選択された標的ポリヌクレオチドとして、NANOG遺伝子の天然のアンチセンス転写物に対して選択的な少なくとも1つのオリゴヌクレオチドを特定して、選択する方法であって、
前記選択された標的ポリヌクレオチドに対してアンチセンスであるポリヌクレオチドと少なくとも部分的に相補的な、少なくとも5個の連続したヌクレオチドを含む、少なくとも1つのオリゴヌクレオチドを特定するステップと、
ストリンジェントなハイブリダイゼーション条件下での、前記標的ポリヌクレオチドまたは前記選択された標的ポリヌクレオチドに対してアンチセンスであるポリヌクレオチドとアンチセンスオリゴヌクレオチドとのハイブリッドの熱融解温度を測定するステップと、
得られた情報に基づいて、生体内投与のための少なくとも1つのオリゴヌクレオチドを選択するステップとを含む、方法。 - 患者における障害のあるDNAを修復する方法であって、前記少なくとも1つのNANOGポリヌクレオチドの天然のアンチセンス配列と結合し、かつ前記少なくとも1つのNANOGポリヌクレオチドの発現を調節する少なくとも1つのアンチセンスオリゴヌクレオチドの治療上有効な用量を前記患者に投与し、それにより、前記患者の障害のあるDNAを修復することを含む、方法。
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EP2643463B1 (en) | 2017-09-27 |
RU2013123687A (ru) | 2014-12-27 |
RU2608493C2 (ru) | 2017-01-18 |
US20130261065A1 (en) | 2013-10-03 |
TW201300530A (zh) | 2013-01-01 |
US9809816B2 (en) | 2017-11-07 |
KR20140001225A (ko) | 2014-01-06 |
CA2818824A1 (en) | 2012-05-31 |
KR102010598B1 (ko) | 2019-08-13 |
US10053691B2 (en) | 2018-08-21 |
ES2657590T3 (es) | 2018-03-06 |
CN103459599B (zh) | 2017-06-16 |
EP2643463A4 (en) | 2014-04-09 |
WO2012071238A2 (en) | 2012-05-31 |
US20180037891A1 (en) | 2018-02-08 |
JP6071893B2 (ja) | 2017-02-01 |
TWI573871B (zh) | 2017-03-11 |
US20150166994A1 (en) | 2015-06-18 |
EP2643463A2 (en) | 2013-10-02 |
US8987225B2 (en) | 2015-03-24 |
CN103459599A (zh) | 2013-12-18 |
WO2012071238A3 (en) | 2012-10-04 |
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