JP2015506673A - 細胞に形質移入するための方法および製品 - Google Patents
細胞に形質移入するための方法および製品 Download PDFInfo
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- JP2015506673A JP2015506673A JP2014546024A JP2014546024A JP2015506673A JP 2015506673 A JP2015506673 A JP 2015506673A JP 2014546024 A JP2014546024 A JP 2014546024A JP 2014546024 A JP2014546024 A JP 2014546024A JP 2015506673 A JP2015506673 A JP 2015506673A
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Abstract
Description
本願は、2011年12月5日に出願された米国仮出願第61/566,948号、2011年12月12日に出願された米国仮出願第61/569,595号、2012年4月24日に出願された米国仮出願第61/637,570号、2012年5月7日に出願された米国出願第13/465,490号、および2012年6月26日に出願された米国仮出願第61/664,494号の優先権を主張し、それらは参照によりその全体が本明細書に援用される。
本明細書とともに電子的に提出されたテキストファイルの内容は、参照によりその全体が本明細書に援用される:配列表の機械可読フォーマットコピー(ファイル名:FABI_001_01WO_SeqList_ST25.txt;データ記録:2012年12月4日;ファイルサイズ:18KB)。
核酸は、核酸を、荷電された脂質、リピドイド、ペプチド、ポリマー、またはそれらの混合物と事前に複合体化することによって、in vitroおよびin vivoの双方で細胞へ送達することができる。そのような形質移入試薬は、市販されており、培養中の細胞に核酸を送達するために広く使用されている。形質移入試薬−核酸複合体に曝露された細胞は、エンドサイトーシスまたは他の手段によってこれらの複合体を中に取り入れることができる。細胞の中に入ると、核酸は、その意図される生物学的機能を実行することができる。タンパク質コード化RNAの場合、例えば、RNAは、細胞のリボソームによってタンパク質中へ翻訳されることができる。
ウシ胎仔血清(FBS)等の動物血清は一般的に、細胞培地内の補足物として多数の種類の細胞の成長を促進するために使用される。しかしながら、血清の不明確な性質は、この構成要素と接触する細胞を研究用途と治療用途との双方に対して望ましくないものにする。その結果、無血清細胞培地が、バッチ間変動、ならびに血清に関連付けられる毒性および/または病原性物質による汚染の危険性を排除するように開発されてきた。
細胞は、それらを、特定の細胞外キューに曝露することによって、および/または特異タンパク質、マイクロRNA等の異所性発現によって、再プログラミングすることができる。幾つかの再プログラミング方法がこれまでに説明されているが、異所性発現に依存する部分は外来性DNAの導入を必要とし、これは突然変異の危険性を伴う可能性がある。再プログラミングタンパク質の直接送達に基づくDNAを含まない再プログラミング方法は報告されているが、しかしながらこれらの方法は、商業的使用にはあまりに非効率的で信頼性がない。それに加えて、RNAに基づく再プログラミング方法が説明されているが、しかしながら、既存のRNAに基づく再プログラミング方法は、成体細胞において実施される場合に低速であり、信頼性が低く、また非効率的であり、多くの形質移入を必要とし(高額な費用およびエラーの起こる機会をもたらす)、限られた数の細胞種類しか再プログラミングすることができず、限られた数の細胞種類へしか細胞を再プログラミングすることができず、免疫抑制剤の使用を必要とし、また血液由来HSAおよびヒト線維芽細胞フィーダーを含む複数のヒト由来構成要素の使用を必要とする。これまでに開示された細胞再プログラミング方法の多数の欠点は、それらを研究上の使用と治療上の使用との双方に対して望ましくないものとする。
幾つかの自然発生的タンパク質は、特異的DNA配列、例えば、ジンクフィンガー(ZF)および転写活性化因子様エフェクター(TALE)を認識することができるDNA結合ドメインを含有する。1つ以上のDNA結合ドメインとヌクレアーゼの触媒ドメインとを含有する融合タンパク質は、細胞内のDNAの所望の領域において2本鎖切断を作成するために使用することができる。細胞のDNAに対する1つ以上の相同性の領域を含有するDNA鋳型と組み合わされると、遺伝子編集タンパク質は、DNA配列を挿入する、または別の方法で制御された手法で細胞のDNAの配列を変更するために使用することができる。しかしながら、細胞を遺伝子編集する最新の方法は、DNAに基づくベクターを使用して遺伝子編集タンパク質を発現させる。結果として、これらの遺伝子編集方法は、非効率的であり、制御されない突然変異誘発の危険性を伴い、それらを研究上の使用と治療上の使用との双方に対して望ましくないものにする。体細胞のDNAを含まない遺伝子編集のための方法は、これまでに探究されておらず、体細胞の同時または連続的遺伝子編集および再プログラミングのための方法も同様である。最後に、抗菌、抗ウイルス、または抗がん治療における遺伝子編集の使用は、これまでに探求されていない。
ノックアウトラットは、ジンクフィンガーヌクレアーゼおよびTALE−ヌクレアーゼ(TALEN)をコード化する核酸の胚微量注入によって生成されている。配列特異的突然変異(別称「ノックイン」)を導入するための遺伝子編集も、ジンクフィンガーヌクレアーゼをコード化する核酸を胚の中へ注入することによって、マウスおよびラットにおいて報告されている。遺伝子改変ラットは、胚性幹細胞を用いて生成されており、また生殖系列有能ラット多能性幹細胞は、体細胞再プログラミングによって生成されている。しかしながら、マウスおよびラットを含む遺伝子改変有機体を生成するための遺伝子編集された再プログラミング化細胞の使用は、これまでに探求されていない。当該技術分野において、細胞に形質移入するための改善された方法および産生物が必要とされる。
本発明は、添付の図面の図において、制限としてではなく、例として、例証される。
「分子」は、分子実体(分子、イオン、複合体等)を意味する。
ヒトタンパク質Oct4、Sox2、Klf4、c−Myc−2(T58A)、およびLin28をコード化し、また標準ヌクレオチドと非標準ヌクレオチドとの様々な組み合わせを含むRNAを、DNA鋳型から合成した(表1)。RNAの標本を、アガロースゲル電気泳動によって分析し、RNAの品質を評価した(図1)。RNAを次に、100ng/μL〜500ng/μLの間まで希釈した。特定の実験のために、RNase阻害剤(SuperaseIn(商標)、Life Technologies Corporation)を、RNAの1μL/100μgの濃度で添加した。RNA溶液を、4℃で保管した。RNA混合物に関する特定の実験のために、Oct4、Sox2、Klf4、c−Myc−2(T58A)、およびLin28をコード化するRNAを、3:1:1:1:1のモル比で混合した。
培地を、細胞の効率的な形質移入、再プログラミング、および遺伝子編集を支持するように開発した:
6ウェルプレート内での形質移入のために、はじめに2μgのRNAおよび6μLの形質移入試薬(Lipofectamine(商標)RNAiMAX、Life Technologies Corporation)を、複合体形成培地(Opti−MEM(登録商標)、Life Technologies Corporation)中で、それぞれ60μLの総容積まで別々に希釈した。希釈したRNAおよび形質移入試薬を次に、形質移入試薬製造者の説明書に従って、混合し、室温にて15分間インキュベートした。複合体を次に、培養中の細胞に添加した。30μL〜240μLの間の複合体を、1ウェルあたり2mLの形質移入培地を既に含有している6ウェルプレートの各ウェルに添加した。次にプレートをやさしく振盪して、ウェルの全体に複合体を分配した。培地を新鮮な形質移入培地(2mL/ウェル)と置換する前に、細胞を、2時間から一晩、複合体と共にインキュベートした。体積を、24ウェルおよび96ウェルプレート内の形質移入に関して計側した。Oct4に対する抗体を用いて、形質移入の20〜24時間後に細胞を固定および染色した(図2A)。核を染色および計数して、RNAの相対毒性を決定した(図2B)。
初代ヒト新生児線維芽細胞を、5mg/mLのHSAと共にまたは伴わずに培地中で培養した。Cohn画分V(A6784、Sigma−Aldrich Co.LLC.)および4つの異なる組み換えHSA調製物(A6608、A7736、A9731、およびA9986、全てSigma−Aldrich Co.LLC.による)を、スクリーニングした。細胞に、実施例1に従って合成されたRNAを、実施例3に従って形質移入した。非形質移入細胞は、任意のHSA調製物含有する培地中で良好に成長したのに対し、形質移入したウェルでは、それぞれのHSA調製物は、著しく異なる細胞形態および細胞密度を生み出し、またいずれも再プログラミングを示唆する形態学的変化をもたらさなかった。
HSAの10%溶液を、22mMの塩化ナトリウムおよび16mMのオクタン酸ナトリウム(Sigma−Aldrich Co.LLC.)と共に事前にインキュベートし、完全な培地の組み立て前に、37℃で3時間インキュベートした。
Pichia pastoris(A7736、Sigma−Aldrich Co.LLC.)内で産生した組み換えHSAの20%溶液を、10mLのヌクレアーゼを含まない水に2gのHSAを室温でやさしく攪拌しながら溶解することによって調製した。HSA溶液を次に、まず1gの混床脱イオン化樹脂(AG501−X8(D)、Bio−Rad Laboratories,Inc.)を添加し、また室温にて1時間揺動させることによって脱イオン化した。次にHSA溶液を、5gの新鮮な樹脂を含有するチューブにデカントし、室温にて4時間揺動させた。最後に、脱イオン化したHSA溶液を、デカントし、ヌクレアーゼを含まない水と共に10%の総タンパク質量に調節し、0.2μmPES−膜フィルタを用いて濾過殺菌し、4℃で保管した。
初代ヒト新生児線維芽細胞を、実施例4に従って処理された組み換えHSAを含有する、または処理された血液由来HSA(Bio−Pure HSA、Biological Industries)を含有する培地中で培養した。細胞に、0日目から開始して、実施例1に従って合成したRNAを実施例3に従って毎日形質移入した。画像を3日目に撮影した。間葉から上皮への移行に類似した形態学的変化を受けている細胞の幾つかの小さい領域が、オクタノエートを含有するウェル内で観察され、向上した形質移入効率を示した。間葉から上皮への移行に類似した形態学的変化の多数の広い領域が、処理された血液由来HSAを含有する標本内で観察された。どちらの場合においても、形態額的変化は、再プログラミングの特性であった。
初代ヒト新生児線維芽細胞を、線維芽細胞培地(DMEM+10%ウシ胎仔血清)中で、5000細胞/ウェルの密度で6ウェルプレートに蒔いた。6時間後、培地を、オクタノエートで処理されたHSAを含有する形質移入培地と置換した。細胞に、0日目から開始して、実施例1に従って合成したRNAを実施例3に従って毎日形質移入した。5日目までに、ウェルは、再プログラミングと一致する形態を示す細胞の幾つかの領域を含んだ。この実験は、フィーダーまたは免疫抑制剤の使用を含まなかった。
初代ヒト新生児線維芽細胞に、0日目から開始して、実施例1に従って合成したRNAを実施例3に従って形質移入した。画像を2日目に撮影した。非処理HSAを含有するウェル内の細胞は、処理された血液由来HSAまたはイオン交換樹脂で処理された組み換えHSAを含有するウェルのいずれかと比較して、低い生存率を示した。
初代ヒト新生児線維芽細胞を、線維芽細胞培地(DMEM+10%ウシ胎仔血清)中で、10,000細胞/ウェルの密度でフィーダー上の6ウェルプレート内に蒔いた。細胞に、0日目から開始して、実施例1に従って合成したRNAを実施例3に従って毎日形質移入した。1:20の分割比を伴う継代を、4日目に実施した。画像を10日目に撮影した。ウェルは、再プログラミングと一致する形態を示す細胞の多数の大きいコロニーを含んだ。非処理HSAを含有する細胞培地に曝露されたウェル内には、コロニーは観察されなかった。
初代ヒト線維芽細胞を、線維芽細胞培地(DMEM+10%ウシ胎仔血清)中で、20,000細胞/ウェルの密度で6ウェルプレート内に蒔いた。6時間後、培地を、処理されたHSAを含有し、免疫抑制剤を含有しない形質移入培地と置換し、細胞に、実施例1に従って合成したRNAを、RNAの用量が1μg/ウェルに低減されたことおよび合計で5回の形質移入が実施されたこととを除いて実施例3に従って毎日形質移入した。画像を7日目に撮影した。再プログラミングと一致する形態を示す細胞の小コロニーを、早くも5日目に見ることができた。7日目に、培地を、DMEM/F12+20%Knockout(商標)Serum Replacement(Life Technologies Corporation)+1X非必須アミノ酸+2mMのL−グルタミンと置換し、照射したマウス胚性線維芽細胞上で24時間条件化し、次に20ng/mLのbFGFおよび10μΜのY−27632で補充した。再プログラミングされた形態を有する大コロニーを、早くも8日目に見ることができた。コロニーを、10日目に採集し、基底膜抽出物(Cultrex(登録商標)Human BME Pathclear(登録商標)、Trevigen Inc.)でコーティングされたウェル内に蒔いた(図3A)。細胞は迅速に成長し、継代されて株を樹立した。樹立された株を、多能性幹細胞マーカーOct4およびSSEA4に対して陽性に染色した(図3B)。プロトコル全体を反復し、同様の結果が観察された(図3C)。
全層皮膚パンチ生検を、認可されたプロトコルに従って、健康な31歳の有志者に実施した。簡単に、左上腕の皮膚領域を2.5%リドカインの局所塗布によって麻酔した。該領域を70%のイソプロパノールで消毒し、1.5mm直径のパンチを用いて全層皮膚生検を実施した(図4A)。組織をリン酸緩衝食塩水(PBS)内ですすぎ、250μLのTrypLE(商標)Select CTS(商標)(Life Technologies Corporation)を含有する1.5mLのチューブ内に蒔き、37℃で30分間インキュベートした。次に組織を、250μLのDMEM/F12−CTS(商標)(Life Technologies Corporation)+5mg/mLのコラゲナーゼを含有する1.5mLチューブへ移し、37℃で2時間インキュベートした(図4B)。鉗子を用いて上皮を除去し、組織を機械的に解離させた。細胞を、DMEM/F12−CTS(商標)中で2回すすぎ、24ウェルおよび96ウェルプレートのフィブロネクチンでコーティングされたウェルに蒔いた。静脈切開術も、同一の有志者に実施し、静脈血をVacutainer(登録商標)SST(商標)チューブ(Becton、Dickinson and Company)内に収集した。製造者プロトコルに従って、血清を単離した。同遺伝子型プレート培地を、DMEM/F12−CTS(商標)+2mMのL−アラニル−L−グルタミン(Sigma−Aldrich Co.LLC.)+20%のヒト血清を混合することによって調製した。皮膚組織標本からの細胞を、形質移入培地中または同遺伝子型プレート培地中のいずれかに蒔いた。2日後、ウェルをすすぎ、培地を形質移入培地と置換した。線維芽細胞形態を有する多数の細胞が、2日目までに付着し広がり始めた(図4C)。細胞に、2日目から開始して、実施例1に従って合成したRNAを実施例3に従って形質移入し、全体積はより小さいウェルに適応するように計測した。5日目までに、再プログラミングと一致する形態を有する細胞の領域が観察された。
初代ヒト線維芽細胞を、形質移入培地中において20,000細胞/ウェルの密度で、組み換えヒトフィブロネクチンおよび組み換えヒトビトロネクチン(それぞれ、DMEM/F12中で1μg/mL、1mL/ウェルの濃度に希釈され、室温で1時間インキュベートされた)でコーティングされた6ウェルプレート内に蒔いた。翌日、細胞に、実施例1に従って合成したRNAを、RNAの用量が1日目は0.5μg/ウェル、2日目は0.5μg/ウェル、および3日目は2μg/ウェルであることを除いて実施例3に従って形質移入した。画像を4日目に撮影した。再プログラミングと一致する形態を示す細胞の小コロニーを、4日目に見ることができた。
初代ヒト線維芽細胞を、形質移入培地中において20,000細胞/ウェルの密度で、組み換えヒトフィブロネクチンおよび組み換えヒトビトロネクチン(それぞれ、DMEM/F12中で1μg/mL、1mL/ウェルの濃度に希釈され、室温で1時間インキュベートされた)でコーティングされた6ウェルプレート内に蒔いた。翌日、細胞に、実施例1に従って合成したRNAを、RNAの用量が1日目は0.5μg/ウェル、2日目は0.5μg/ウェル、3日目は2μg/ウェル、4日目は2μg/ウェル、および5日目は4μg/ウェルであることを除いて実施例3に従って形質移入した。再プログラミングと一致する形態を示す細胞の小コロニーを、早くも5日目に見ることができた。7日目に、培地を、DMEM/F12+20%のKnockout(商標)Serum Replacement(Life Technologies Corporation)+1X非必須アミノ酸+2mMのL−グルタミンで置換し、照射したマウス胚性線維芽細胞上で24時間条件化し、次に20ng/mLのbFGFおよび10μΜのY−27632で補充した。再プログラミングされた形態を有する大コロニーを、早くも8日目に見ることができた。コロニーを、10日目に採集し、基底膜抽出物(Cultrex(登録商標)Human BME Pathclear(登録商標)、Trevigen Inc.)でコーティングされたウェル内に蒔いた。細胞は迅速に成長し、継代されて株を樹立した。
細胞を、実施例11または実施例12に従って再プログラミングし、次にDMEM/F12+0.2%HSA+0.5X N2補充物+0.5X B27補充物+100ng/mLのアクチビンA+1μΜのウォルトマンニン中で4日間、その後1:1F12/IMDM+0.5%HSA+0.5%ITS補充物+0.5X B27補充物+2μΜのレチノイン酸+20ng/mLのFGF7+50ng/mLのNOGGIN中で4日間、その後DMEM+0.5%HSA+1%ITS補充物+1X N2補充物+50ng/mLのEGF中で5日間、その後DMEM/F12+1%ITS補充物+10ng/mLのbFGF+10mMのニコチンアミド+50ng/mLのエキセンジン−4+10ng/mLのBMP4中で7〜9日間培養して、グルコース応答性インスリン産生細胞を生成する。別の方法として、細胞を、実施例11または実施例12に従って再プログラミングし、次に1:1F12/IMDM+0.5%HSA+0.5%ITS補充物+0.5X B27補充物+2μΜのレチノイン酸+20ng/mLのFGF7+50ng/mLのNOGGIN中で4日間、その後DMEM+0.5%HSA+1%ITS補充物+1X N2補充物+50ng/mLのEGF中で5日間、その後DMEM/F12+1%ITS補充物+10ng/mLのbFGF+10mMのニコチンアミド+50ng/mLのエキセンジン−4+10ng/mLのBMP4中で7〜9日間培養して、決定的な内胚葉細胞を生成することなくグルコース応答性インスリン産生細胞を生成する。別の方法として、細胞を、実施例11または実施例12に従って再プログラミングし、次に1:1F12/IMDM+0.5%HSA+0.5%ITS補充物+0.5X B27補充物+2μΜのレチノイン酸+20ng/mLのFGF7+50ng/mLのNOGGIN中で4日間、その後DMEM/F12+1%ITS補充物+10ng/mLのbFGF+10mMのニコチンアミド+50ng/mLのエキセンジン−4+10ng/mLのBMP4中で7〜9日間培養して、決定的な内胚葉細胞を生成することなく、また前駆細胞を増殖することなく、グルコース応答性インスリン産生細胞を生成する。内胚葉細胞またはインスリン産生細胞は、培養中に存在する他の細胞から単離されることができるが、この方法は、十分に高いパーセンテージのそのような単離が通常必要とされないグルコース応答性インスリン産生細胞を生成する。得られた細胞は次に、糖尿病の研究のため、または糖尿病に関する治療法の開発のために、生理活性分子をスクリーニングするためにin vitroまたはin vivoで使用することができる。
細胞を、実施例11に従って再プログラミングし、次にDMEM/F12、100ng/mlのアクチビンA、25ng/mlのWnt3a、0.01%組み換えHSA、1X ITSE中で1日間、その後DMEM/F12、100ng/mlのアクチビンA、0.01%組み換えHSA、1X ITSE中で2日間、その後DMEM/F12、50ng/mlのFGF10、0.25μΜのKAAD−シクロパミン、0.01%組み換えHSA、1X ITSE中で3日間、その後DMEM/F12、1%B27、2μΜのオールトランスレチノイン酸、50ng/mlのFGF10、0.25μΜのKAAD−シクロパミン中で4日間、その後DMEM/F12、1%B27、1μΜのγ−セクレターゼ阻害剤DAPT、50ng/mlのエキセンジン−4、10nMのベタセルリン、10mMのニコチンアミド中で2日間、その後DMEM/F12、50mg/Lのアスコルビン酸−2−ホスフェート、1%B27、1μΜのγ−セクレターゼ阻害剤DAPT、50ng/mlのエキセンジン−4、50ng/mlのIGF−1、50ng/mlのHGF、10nMのベタセルリン、10mMのニコチンアミド中で6日間培養して、グルコース応答性インスリン産生細胞を生成した(図5A)。得られた細胞は、糖尿病の研究のため、または糖尿病に関する治療法の開発のために、生理活性分子をスクリーニングするためにin vitroまたはin vivoで使用することができる。
患者の皮膚細胞を、実施例12および実施例14に従って、グルコース応答性インスリン産生細胞へと再プログラミングする。細胞を次に、細胞容器から酵素的に解離させ、約1X106〜約1X107個の間の細胞を、腹腔内空間または門脈内へ注射する。腹腔内注射の場合、細胞を、過剰な移動を防止するために細胞外マトリックスタンパク質と事前に混合する。細胞は移植され、インスリンを産生し始める。インスリン/C−ペプチドを観察し、必要に応じて追加の注射を実施する。
20bpマッチングTALENをコード化するRNAを、実施例1に従ってDNA鋳型から合成した(図6A〜Cおよび図7)(表2)。得られたRNAを、アガロースゲル電気泳動によって分析し、RNAの品質を評価した。RNAを次に、200ng/μLに希釈し、RNase阻害剤(SuperaseIn(商標)、Life Technologies Corporation)を、RNAの1μL/100μgの濃度で添加した。RNA溶液を、4℃で保管した。TALEN対の各半分をコード化するRNAを、1:1のモル比で混合した。
TALEN L1:TCATTTTCCATACAGTCAGT、L2:TTTTCCATACAGTCAGTATC、R1:TGACTATCTTTAATGTCTGG、およびR2:TATCTTTAATGTCTGGAAATをコード化するRNAを、実施例18に従って合成した。これらのTALENは、センス鎖(L1およびL2)上またはアンチセンス鎖(R1およびR2)上でCCR5遺伝子内の20−bp部位を標的とする。次のTALEN対を調製した:L1&R1、L1&R2、L2&R1、およびL2&R2
初代ヒト線維芽細胞を、形質移入培地中において10,000細胞/ウェルの密度で、組み換えヒトフィブロネクチンおよび組み換えヒトビトロネクチン(それぞれ、DMEM/F12中で1μg/mL、1mL/ウェルの濃度に希釈され、室温で1時間インキュベートされた)でコーティングされた6ウェルプレート内に蒔いた。翌日、細胞に、RNAの用量が0.5μg/ウェルであること、およびRNAが実施例19に従って合成されたことを除いて、実施例3に従って形質移入した。翌日から開始して、細胞を実施例11に従って再プログラミングした。再プログラミングの形態特性を有する細胞の大コロニーが、実施例11の通りに見ることができるようになった。画像を9日目に撮影した(図8)。
はじめに、標的とされる2本鎖切断位置の500bp上流から標的とされる2本鎖切断位置の500bp下流にわたる1001bp領域を含有する0.5ugRNA+0.5ugDNAおよび、6μLの形質移入試薬(Lipofectamine(商標)2000、Life Technologies Corporation)を、複合体形成培地(Opti−MEM(登録商標))中で、それぞれ60μLの総容積まで別々に希釈する。次に、希釈したRNA+DNAおよび形質移入試薬を形質移入試薬の製造者の説明書に従って、混合し、室温で15分間インキュベートする。次に、複合体を培養中の細胞に添加する。60μL〜120μLの間で、1ウェルあたり2mLの形質移入培地を既に含有している6ウェルプレートの各ウェルに添加する。プレートを次にやさしく振盪して、ウェル全体に複合体を分配する。培地を新鮮な形質移入培地(2mL/ウェル)と置換する前に、細胞を、2時間から一晩、複合体と共にインキュベートする。
初代ヒト線維芽細胞を、線維芽細胞培地(DMEM+10%ウシ胎仔血清)中において10,000細胞/ウェルの密度で、6ウェルプレート内に蒔く。6時間後、培地を、処理されたHSAを含有し免疫抑制剤を含有しない形質移入培地と置換し、実施例21に従って細胞に形質移入する。翌日から開始して、細胞を、最初の蒔くことおよび培地変更ステップを省略したことを除いて、実施例11または実施例12に従って再プログラミングする。
細胞を、実施例11に従って再プログラミングし、次にIMDM+0.5%HSA+1x ITS補充物+450μΜのモノチオグリセロール+2mMのL−グルタミン+1Xの非必須アミノ酸+50ng/mLのBMP4+50ng/mLのVEGF+50ng/mLのbFGF中で6日間培養して、造血細胞を生成した(図5B)。別の方法として、細胞を、実施例11または実施例12または実施例20または実施例22に従って再プログラミングし、次にIMDM+0.5%HSA+1x ITS補充物+450μΜのモノチオグリセロール+2mMのL−グルタミン+1Xの非必須アミノ酸+50ng/mLのBMP4+50ng/mLのVEGF+50ng/mLのbFGF中で6日間、その後IMDM+0.5%HSA+1x ITS補充物+0.1mMの2−メルカプトエタノール+5U/mLのヘパリン+10ng/mLのTPO+25ng/mLのSCF+25ng/mLのFLT3L+10ng/mLのIL−3+10ng/mLのIL−6中で8日間培養して、造血細胞を生成する。別の方法として、細胞を、実施例11または実施例12または実施例20または実施例22に従って再プログラミングし、次にコラーゲンIV上に再び蒔き、IMDM+0.5%HSA+1x ITS補充物+450μΜのモノチオグリセロール+2mMのL−グルタミン+1Xの非必須アミノ酸+50ng/mLのBMP4+50ng/mLのVEGF+50ng/mLのbFGF中で6日間、その後IMDM+0.5%HSA+1x ITS補充物+0.1mMの2−メルカプトエタノール+5U/mLのヘパリン+10ng/mLのTPO+25ng/mLのSCF+25ng/mLのFLT3L+10ng/mLのIL−3+10ng/mLのIL−6中で8日間培養して、造血細胞を生成する。別の方法として、細胞を、実施例11または実施例12または実施例20または実施例22に従って再プログラミングし、次に1:1F12/IMDM+0.5%HSA+1x ITS補充物+4.5μg/mLのコレステロール+10μg/mLのタラ肝油脂肪酸+25μg/mLのポリオキシエチレンソルビタンモノオレエート+2μg/mLのD−a−酢酸トコフェロール+450μΜのモノチオグリセロール+2mMのL−グルタミン+25ng/mLのBMP4+25ng/mLのVEGF+25ng/mLのbFGF+20ng/mLのSCF中で10日間培養して、造血細胞を生成する。
患者の皮膚細胞を、実施例23に従って造血細胞へと再プログラミングする。細胞を次に、培養容器から放出し、患者の体重1kgあたり約1X106〜約1X107個の間の細胞を、数時間にわたって大動脈内へ注入する。
患者の皮膚細胞を、実施例23に従って、造血細胞へと遺伝子編集および再プログラミングする。細胞を次に、培養容器から酵素的に解離させ、患者の体重1kgあたり約1X106〜約1X107個の間の細胞を、数時間にわたって大動脈内へ注入する。造血幹細胞は、髄腔へと戻り、移植される。別の方法として、患者の皮膚細胞を、実施例23に従って、造血細胞へと遺伝子編集および再プログラミングし、細胞を次に、培養容器から酵素的に解離させ、CD34+/CD90+/Lin−またはCD34+/CD49f+/Lin−細胞を単離する。約1X103〜約1X105個の間の細胞を、患者の大動脈内に注入する。造血幹細胞は、髄腔へと戻り、移植される。
細胞を、実施例11に従って再プログラミングし、次にDMEM/F12+0.2%HSA+0.5X N2補充物+0.5X B27補充物+100ng/mLのアクチビンA+1μΜのウォルトマンニン中で4日間、その後1:1F12/IMDM+0.5%HSA+0.5%ITS補充物+0.5X B27補充物+2μΜのレチノイン酸+20ng/mLのFGF7+50ng/mLのNOGGIN中で4日間、その後DMEM/F12+1%ITS補充物+10ng/mLのbFGF+10mMのニコチンアミド+50ng/mLのエキセンジン−4+10ng/mLのBMP4中で7〜9日間培養して、心細胞を生成した(図5C)。別の方法として、細胞を、実施例12に従って再プログラミングする。心細胞は、培養中に存在する他の細胞から単離されることができるが、この方法は、十分に高いパーセンテージのそのような単離が通常必要とされない心細胞を生成する。得られた細胞は、心疾患の研究のため、または心疾患に関する治療法の開発のために、生理活性分子をスクリーニングするためにin vitroまたはin vivoで使用することができる。得られた細胞はまた、心毒性スクリーニングのために使用することもできる。
患者の皮膚細胞を、実施例26に従って心細胞へと再プログラミングする。細胞を次に、培養容器から酵素的に解離させ、約1X106〜約1X107個の間の細胞を心膜内に注射する、または約1X103〜約1X105個の間の細胞を1つ以上の冠状動脈内に注射する。細胞を移植し、また追加の注射を必要に応じて実施する。
細胞を、実施例11または実施例12に従って再プログラミングし、次にDMEM/F12+0.2% HSA+0.5X N2補充物+0.5X B27補充物中で7日間培養して、網膜細胞を生成する。得られた細胞は、網膜疾患の研究のため、または網膜疾患に関する治療法の開発のために、生理活性分子をスクリーニングするためにin vitroまたはin vivoで使用することができる。
患者皮膚細胞を、実施例28に従って網膜細胞へと再プログラミングする。細胞を次に、培養容器から酵素的に解離させ、約1X104〜約1X105個の間の細胞を、網膜内または網膜下に注射する。細胞を移植し、また追加の注射を必要に応じて実施する。
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Claims (61)
- 合成RNA分子であって、ピリミジン位置2C、ピリミジン位置4C、ピリミジン位置5C、プリン位置6C、プリン位置7N、およびプリン位置8Cからの1つ以上の置換をそれぞれが含む3つ以上の非標準ヌクレオチドを含む、合成RNA分子。
- 前記合成RNA分子は、in vitro転写によって産生される、請求項1に記載の合成RNA分子。
- 前記合成RNA分子は、5’−キャップ、5’−キャップ1構造、および3’−ポリ(A)テイルのうちの少なくとも1つを更に含む、請求項1に記載の合成RNA分子。
- 前記非標準ヌクレオチドのうちの少なくとも2つは、ピリミジンである、請求項1に記載の合成RNA分子。
- 前記非標準ヌクレオチドは、プソイドウリジン、2−チオウリジン、4−チオウリジン、5−アザウリジン、5−ヒドロキシウリジン、5−アミノウリジン、5−メチルウリジン、2−チオプソイドウリジン、4−チオプソイドウリジン、5−ヒドロキシプソイドウリジン、5−メチルプソイドウリジン、5−アミノプソイドウリジン、プソイドイソシチジン、5−メチルシチジン、N4−メチルシチジン、2−チオシチジン、5−アザシチジン、5−ヒドロキシシチジン、5−アミノシチジン、N4−メチルプソイドイソシチジン、2−チオプソイドイソシチジン、5−ヒドロキシプソイドイソシチジン、5−アミノプソイドイソシチジン、5−メチルプソイドイソシチジン、N6−メチルアデノシン、7−デアザアデノシン、6−チオグアノシン、7−デアザグアノシン、8−アザグアノシン、6−チオ−7−デアザグアノシン、6−チオ−8−アザグアノシン、7−デアザ−8−アザグアノシン、および6−チオ−7−デアザ−8−アザグアノシンのうちの少なくとも1つを含む、請求項1に記載の合成RNA分子。
- 前記非標準ヌクレオチドのうちの少なくとも2つは、前記合成RNA分子の20%未満をそれぞれ構成する、請求項1に記載の合成RNA分子。
- 前記非標準ヌクレオチドは、
a.プソイドウリジン、2−チオウリジン、4−チオウリジン、5−アザウリジン、5−ヒドロキシウリジン、5−アミノウリジン、5−メチルウリジン、2−チオプソイドウリジン、4−チオプソイドウリジン、5−ヒドロキシプソイドウリジン、5−メチルプソイドウリジン、および5−アミノプソイドウリジンのうちの少なくとも1つと、
b.プソイドイソシチジン、5−メチルシチジン、N4−メチルシチジン、2−チオシチジン、5−アザシチジン、5−ヒドロキシシチジン、5−アミノシチジン、N4−メチルプソイドイソシチジン、2−チオプソイドイソシチジン、5−ヒドロキシプソイドイソシチジン、5−アミノプソイドイソシチジン、および5−メチルプソイドイソシチジンのうちの少なくとも1つと、を含む、請求項1に記載の合成RNA分子。 - 前記非標準ヌクレオチドは、N6−メチルアデノシン、7−デアザアデノシン、6−チオグアノシン、7−デアザグアノシン、8−アザグアノシン、6−チオ−7−デアザグアノシン、6−チオ−8−アザグアノシン、7−デアザ−8−アザグアノシン、および6−チオ−7−デアザ−8−アザグアノシンのうちの少なくとも1つを更に含む、請求項7に記載の合成RNA分子。
- 合成RNA分子であって、
a.非標準ヌクレオチドを含む、および
b.遺伝子編集タンパク質をコード化する、
合成RNA分子。 - 請求項1から9のいずれか一項に記載の合成RNA分子を含む、治療用組成物。
- 遺伝子編集タンパク質をコード化する合成RNA分子と、形質移入試薬とを含む、治療用組成物。
- 細胞に核酸を形質移入するための方法であって、前記細胞を請求項1から9のいずれか一項に記載の合成RNA分子と接触させることを含む、方法。
- 哺乳類細胞を、関心のタンパク質を発現するように誘導するための方法であって、前記細胞を請求項1から9のいずれか一項に記載の合成RNA分子と接触させることを含む、方法。
- 細胞を再プログラミングするための方法であって、前記細胞を請求項1から9のいずれか一項に記載の合成RNA分子と接触させることを含む、方法。
- 細胞を遺伝子編集するための方法であって、前記細胞を請求項1から9のいずれか一項に記載の合成RNA分子と接触させることを含む、方法。
- 細胞に核酸を形質移入するための方法であって、
a.前記細胞を、ヒドロコルチゾンおよび/またはアルブミンを含有する培地と接触させることであって、前記アルブミンは、イオン交換樹脂または炭で処理される、ことと、
b.前記細胞を前記核酸と接触させることと、
を含む、方法。 - 前記アルブミンは、短鎖脂肪酸で処理される、請求項16に記載の方法。
- 前記アルブミンは、少なくとも40℃の温度に昇温される、請求項16に記載の方法。
- 前記細胞を形質移入試薬と接触させることを更に含む、請求項16に記載の方法。
- 前記細胞は、哺乳類細胞であり、また前記哺乳類細胞は、関心のタンパク質を発現するように誘導される、請求項16に記載の方法。
- ステップ(b)を、連続した5日間の間に少なくとも2回繰り返すことを更に含む、請求項16に記載の方法。
- 前記核酸は、再プログラミングタンパク質をコード化する、請求項16に記載の方法。
- 前記細胞は、再プログラミングされる、請求項16に記載の方法。
- 前記細胞は、皮膚細胞であり、前記皮膚細胞を、皮膚細胞、多能性幹細胞、グルコース応答性インスリン産生細胞、造血細胞、心細胞、および網膜細胞のうちの少なくとも1つの成長を支持する条件下で培養することを更に含み、前記皮膚細胞は、皮膚細胞、多能性幹細胞、グルコース応答性インスリン産生細胞、造血細胞、心細胞、および網膜細胞から選択される細胞へ再プログラミングされる、請求項23に記載の方法。
- 前記核酸は、Oct4タンパク質をコード化する、請求項16に記載の方法。
- 前記細胞を、Sox2タンパク質、Klf4タンパク質、およびc−Mycタンパク質のうちの少なくとも1つをコード化する核酸と接触させることを更に含む、請求項25に記載の方法。
- 前記細胞を、Sox2タンパク質、Klf4タンパク質、およびc−Mycタンパク質をコード化する1つ以上の核酸と接触させることを更に含む、請求項25に記載の方法。
- 前記核酸は、遺伝子編集タンパク質をコード化する、請求項16に記載の方法。
- 前記細胞は、遺伝子編集される、請求項16に記載の方法。
- 前記核酸は、単独で、または1つ以上の他の分子との組み合わせで作用して、DNA分子中に1本鎖または2本鎖切断を作成する、タンパク質をコード化する、請求項16に記載の方法。
- 前記1本鎖または2本鎖切断は、CCR5、CXCR4、GAD1、GAD2、CFTR、HBA1、HBA2、HBB、HBD、FANCA、XPA、XPB、XPC、ERCC2、POLH、HTT、DMD、SOD1、APOE、APP、LRRK2、PRNP、BRCA1、およびBRCA2、またはそれらの類似体、変異体、もしくはファミリーメンバーから選択される遺伝子の転写開始部位の約5,000,000塩基以内にある、請求項30に記載の方法。
- 前記細胞を、ポリ−L−リジン、ポリ−L−オルニチン、RGDペプチド、フィブロネクチン、ビトロネクチン、コラーゲン、およびラミニン、またはそれらの生物学的に活性な断片、機能変異体、もしくはファミリーメンバーのうちの少なくとも1つと接触させることを更に含む、請求項16に記載の方法。
- 前記核酸は、合成RNA分子である、請求項16に記載の方法。
- 前記合成RNA分子は、プソイドウリジン、5−メチルプソイドウリジン、および5−メチルシチジンのうちの少なくとも1つを含有する、請求項33に記載の方法。
- 前記細胞を、分化因子と接触させることを更に含む、請求項16に記載の方法。
- 前記細胞を、患者から採取することを更に含む、請求項16に記載の方法。
- 前記細胞を、患者に送達することを更に含む、請求項16に記載の方法。
- アルブミンを含む培地であって、前記アルブミンは、
a.組み換え体である、および
b.イオン交換樹脂または炭で処理される、
培地。 - 緩衝食塩水とアミノ酸とを更に含む、請求項38に記載の培地。
- インスリン、トランスフェリン、およびセレニウムのうちの1つ以上を更に含む、請求項38に記載の培地。
- コレステロールを更に含む、請求項38に記載の培地。
- ステロイドを更に含む、請求項38に記載の培地。
- 前記ステロイドは、ヒドロコルチゾンである、請求項41に記載の培地。
- 免疫抑制剤を更に含む、請求項38に記載の培地。
- 前記免疫抑制剤は、B18Rである、請求項38に記載の培地。
- キットであって、
a.ヒドロコルチゾンおよび/またはアルブミンであって、前記アルブミンは、イオン交換樹脂または炭で処理される、ヒドロコルチゾンおよび/またはアルブミンと、
b.合成RNA分子と、
を含む、キット。 - 前記合成RNA分子は、Oct4タンパク質、Sox2タンパク質、Klf4タンパク質、c−Mycタンパク質、Nanogタンパク質、Lin28タンパク質、およびUtflタンパク質のうちの少なくとも1つをコード化する、請求項46に記載のキット。
- 形質移入試薬を更に含む、請求項46に記載のキット。
- 請求項1から9のいずれか一項に記載の合成RNA分子を含む、キット。
- 前記キットは、再プログラミングキットである、請求項49に記載のキット。
- 前記キットは、遺伝子編集キットである、請求項49に記載のキット。
- 核酸と形質移入試薬とを含む核酸形質移入試薬複合体であって、前記核酸形質移入試薬複合体は、冷却によって固化される、核酸形質移入試薬複合体。
- 前記核酸形質移入試薬複合体は、前記核酸形質移入試薬複合体を、液相および/または気相中で液体窒素と接触させることによって固化される、請求項52に記載の核酸形質移入試薬複合体。
- 細胞に形質移入するための方法であって、前記細胞を、請求項52の核酸形質移入試薬複合体と接触させることを含む、方法。
- 細胞に形質移入するためのシステムであって、細胞を形質移入培地と接触させるための手段と、前記細胞を核酸形質移入試薬複合体と接触させるための手段と、を備える、システム。
- 前記細胞の周囲雰囲気は、約5%の二酸化炭素を含有する、請求項54に記載のシステム。
- 前記細胞の周囲雰囲気は、約5%の酸素を含有する、請求項54に記載のシステム。
- 請求項12から37または54のいずれか一項に記載の方法によって産生される、細胞。
- 請求項12から37または54のいずれか一項に記載の方法によって産生される、有機体。
- 請求項12から37または54のいずれか一項に記載の方法によって産生される細胞を含む、治療用組成物。
- 請求項12から37または54のいずれか一項に記載の方法によって産生される、治療用組成物。
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WO2019240255A1 (ja) * | 2018-06-15 | 2019-12-19 | 扶桑薬品工業株式会社 | 生殖補助医療用培地 |
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