JP2020536551A - 一時的かつ一過性プラスミドベクター発現システムを用いる細胞のリプログラミング - Google Patents
一時的かつ一過性プラスミドベクター発現システムを用いる細胞のリプログラミング Download PDFInfo
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Abstract
Description
この出願は、2017年10月11日に出願された米国仮特許出願第62/571,105号の優先権を主張し、その開示はその全体が参照により本明細書に組み込まれる。
この出願は、この出願とともに提出されたASCIIテキスト形式の配列表のComupter Readable Form(CRF)を参照として組み込んでおり、タイトルは13601−187−228_SEQ_LISTING.txtで、2018年10月9日に作成され、サイズは9,600バイトである。
他に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、本発明が属する分野の当業者によって一般に理解されるのと同じ意味を有する。本発明の目的のために、以下の用語を下記に定義する。冠詞「a」、「an」、および「the」は、本明細書では、冠詞の文法的対象の1つまたは2つ以上(すなわち、少なくとも1つ)を指すために使用される。例として、「要素(an element)」とは、1つの要素または2つ以上の要素を意味する。
一般に、本開示は、非多能性細胞と少なくとも1つのリプログラミング因子とを、任意選択的にTGFβ受容体/ALK阻害剤、MEK阻害剤、GSK3阻害剤およびROCK阻害剤の組み合わせ(FRM、表1)の存在下で接触させることにより、開始されるリプログラミングプロセスを提供する。
本発明は、いくつかの実施形態において、本明細書に開示されるシステムおよび方法を使用して得られたiPSCに由来する非多能性細胞をさらに提供する。いくつかの実施形態では、由来非多能性細胞を生成するためのiPSCは、iPSCの標的編集を通じて、または部位特異的組み込みまたはインデルを有するゲノム操作した非多能性細胞のリプログラミングを通じて、ゲノム操作される。いくつかの実施形態では、iPSC由来非多能性細胞は、前駆細胞または完全に分化した細胞である。いくつかの実施形態では、ゲノム操作したiPSCに含まれる同じ標的編集を保持するiPSC由来細胞は、非天然の中胚葉細胞、CD34細胞、造血性内皮細胞、造血幹細胞または前駆細胞、造血多分化能前駆細胞、T細胞前駆細胞、NK細胞前駆細胞、T細胞、NKT細胞、NK細胞、B細胞、免疫制御性細胞、または任意の胚葉系統の任意の細胞である。いくつかの実施形態では、iPSC由来の非天然免疫制御性細胞は、骨髄由来サプレッサー細胞(MDSC)、制御性マクロファージ、制御性樹状細胞または間葉系間質細胞を含み、これらはNK、B、およびT細胞の強力な免疫調節因子である。
いくつかの実施形態では、本発明は、開示される方法および組成物を使用して、iPSCおよび/または前記iPSCに由来している免疫細胞の単離した集団または亜集団を含む組成物を提供する。いくつかの実施形態では、iPSCは、iPSC由来免疫細胞で保持可能な1つ以上の標的遺伝子編集を含み、遺伝子操作されたiPSCおよびその由来細胞は、細胞ベースの養子療法に適している。一実施形態では、遺伝子操作された免疫細胞の単離した集団または亜集団は、iPSC由来のHSC細胞を含む。一実施形態では、遺伝子操作された免疫細胞の単離した集団または亜集団は、iPSC由来のHSC細胞を含む。一実施形態では、遺伝子操作された免疫細胞の単離した集団または亜集団は、iPSC由来のproTまたはT細胞を含む。一実施形態では、遺伝子操作された免疫細胞の単離した集団または亜集団は、iPSC由来のproNKまたはNK細胞を含む。一実施形態において、遺伝子操作された免疫細胞の単離した集団または亜集団は、iPSC由来の免疫制御性細胞または骨髄由来のサプレッサー細胞(MDSC)を含む。いくつかの実施形態では、iPSC由来の遺伝子操作された免疫細胞は、改善された治療可能性のためにエクスビボでさらに調節される。一実施形態では、iPSCに由来している遺伝子操作された免疫細胞の単離した集団または亜集団は、増加した数または比率の、ナイーブT細胞、幹細胞メモリーT細胞、および/またはセントラルメモリーT細胞を含む。一実施形態では、iPSCに由来している遺伝子操作された免疫細胞の単離した集団または亜集団は、増加した数または比率のI型NKT細胞を含む。別の実施形態では、iPSCに由来している遺伝子操作された免疫細胞の単離した集団または亜集団は、増加した数または比率の適応NK細胞を含む。いくつかの実施形態では、iPSC由来の遺伝子操作されたCD34細胞、HSC細胞、T細胞、NK細胞、または骨髄由来サプレッサー細胞の、単離した集団または亜集団は、同種異系である。いくつかの他の実施形態では、iPSC由来の遺伝子操作されたCD34細胞、HSC細胞、T細胞、NK細胞、またはMDSCの単離した集団または亜集団は、自己由来である。
配列表
配列番号1
長さ:641
タイプ:PRT
生物:ヒトヘルペスウイルス4
MSDEGPGTGPGNGLGEKGDTSGPEGSGGSGPQRRGGDNHGRGRGRGRGRGGGRPGAPGGSGSGPRHRDGVRRPQKRPSCIGCKGTHGGTGAGAGAGGAGAGGAGAGGGAGAGGGAGGAGGAGGAGAGGGAGAGGGAGGAGGAGAGGGAGAGGGAGGAGAGGGAGGAGGAGAGGGAGAGGGAGGAGAGGGAGGAGGAGAGGGAGAGGAGGAGGAGAGGAGAGGGAGGAGGAGAGGAGAGGAGAGGAGAGGAGGAGAGGAGGAGAGGAGGAGAGGGAGGAGAGGGAGGAGAGGAGGAGAGGAGGAGAGGAGGAGAGGGAGAGGAGAGGGGRGRGGSGGRGRGGSGGRGRGGSGGRRGRGRERARGGSRERARGRGRGRGEKRPRSPSSQSSSSGSPPRRPPPGRRPFFHPVGEADYFEYHQEGGPDGEPDVPPGAIEQGPADDPGEGPSTGPRGQGDGGRRKKGGWFGKHRGQGGSNPKFENIAEGLRALLARSHVERTTDEGTWVAGVFVYGGSKTSLYNLRRGTALAIPQCRLTPLSRLPFGMAPGPGPQPGPLRESIVCYFMVFLQTHIFAEVLKDAIKDLVMTKPAPTCNIRVTVCSFDDGVDLPPWFPPMVEGAAAEGDDGDDGDEGGDGDEGEEGQE
配列番号2
長さ:422
タイプ:PRT
生物:ヒトヘルペスウイルス4
MSDEGPGTGPGNGLGEKGDTSGPEGSGGSGPQRRGGDNHGRGRGRGRGRGGGRPGAPGGSGSGPRHRDGVRRPQKRPSCIGCKGTHGGTGAGAGAGGAGAGGAGAGGGGRGRGGSGGRGRGGSGGRGRGGSGGRRGRGRERARGGSRERARGRGRGRGEKRPRSPSSQSSSSGSPPRRPPPGRRPFFHPVGEADYFEYHQEGGPDGEPDVPPGAIEQGPADDPGEGPSTGPRGQGDGGRRKKGGWFGKHRGQGGSNPKFENIAEGLRALLARSHVERTTDEGTWVAGVFVYGGSKTSLYNLRRGTALAIPQCRLTPLSRLPFGMAPGPGPQPGPLRESIVCYFMVFLQTHIFAEVLKDAIKDLVMTKPAPTCNIRVTVCSFDDGVDLPPWFPPMVEGAAAEGDDGDDGDEGGDGDEGEEGQE
単一細胞の解離 すべてのリプログラミング培養を、トランスフェクション後14日目にFMMに切り替えた。FMMに入ったら、すべてのリプログラミング培養を維持し、アキュターゼ(Accutase)を使用して分離した。次に、単一細胞をマトリゲルまたはビトロネクチンでコーティングした表面で継代した。次いで、単一細胞の解離細胞をFMMで増加させ、フローサイトメトリーによる選別まで維持した。
プラスミドベクターとエピソームベクターの両方は、非組み込み染色体外DNAである。標準プラスミドには、プロモーターと発現するポリヌクレオチド(複数可)のみを含有しており、自律的にまたは宿主細胞の染色体とともに複製することはできない。したがって、プラスミドによって媒介される導入遺伝子の発現は連続的でも安定的でもなく、むしろ一過性(細胞質)および一時的(短期)であり、トランスフェクション効率、コピー数、プラスミド損失率の影響を受けやすい、生き残ったインプットベクターDNAによって決まる。プラスミドベクターの毎日のトランスフェクションを繰り返すことによってのみ、リプログラミングがまだ許容できないほど低い効率で達成されたことが示されている(Okita et al.,Science(2008);322:949−953)。
表1−ベクター構築物
表2−リプログラミングのためのベクターの組み合わせ
2 :AP染色は、リプログラミング効率の推定において二重陽性よりも厳格でない
表3−STTRシステム媒介リプログラミングに適用可能な新規リプログラミング因子の組み合わせ
STTRリプログラミング組成物および方法は、市販の免疫療法のための再生可能かつ信頼性の高い細胞源として使用するためのクローンマスターiPSC系統を生成するために使用されている。ドナーが同意した線維芽細胞に、開示されているプラスミドの組み合わせをトランスフェクトした。リプログラミング細胞をクローン密度で96ウェルプレートに選別し、単一細胞由来のiPSCクローンを増加させ、多能性、リプログラミングプラスミドの喪失、ゲノム安定性、分化能などの望ましい属性についてスクリーニングした。選択されたクローンiPSC株は、厳格な製造およびプロセス品質管理の下で製造および凍結保存され、関連規制の下で必要とされる「マスターセルバンク」としての資格を得るために、株は広範な特性評価および試験を受けた。製造されたiPSCバンクは、現在の適正製造基準に従って、臨床的に適切な規模のナチュラルキラー(NK)細胞に分化された。由来細胞は、関連規制の下で必要とされる「原薬および医薬品」としての資格を得るために、さらに広範な特性評価および試験を受けた。iPSC由来のNK細胞を凍結保存して、単剤療法として、または免疫チェックポイント阻害剤と組み合わせて、血液がんおよび固形がんの養子細胞療法で使用するために、約1x108細胞/用量で多数の用量を生成した。通常、60kgの患者の場合、1x108細胞/用量は1.67x106細胞/kgに換算される。各適応症の剤形、投与経路、および投与計画は、インビトロおよびインビボの両方でのGLP(優良試験所基準)および非GLP研究からの前臨床データに従って設計および決定された。
Claims (65)
- 非多能性細胞をリプログラミングして多能性細胞、その細胞株または集団を生成する方法であって、
(a)第1の細胞であって、非多能性細胞である、第1の細胞に、
1つ以上の第1のプラスミドであって、前記第1のプラスミドは、複製起点、および1つ以上のリプログラミング因子をコードするがEBNAまたはその誘導体をコードしないポリヌクレオチドを含み、前記1つ以上の第1のプラスミドのうちの少なくとも1つが、OCT4をコードするポリヌクレオチドを含み、1つ以上の第1のプラスミドの導入が、リプログラミングプロセスを誘導する、1つ以上の第1のプラスミドと、任意選択的に、
(1)EBNAをコードするヌクレオチド配列を含む第2のプラスミドであって、複製起点、またはリプログラミング因子(複数可)をコードするポリヌクレオチド(複数可)を含まない、第2のプラスミド、(2)EBNA mRNAおよび(3)EBNAタンパク質、のうちの1つと、を導入することと、
(b)前記ステップ(a)からの細胞を培養して、第2の細胞を生成することであって、前記第2の細胞が、リプログラミング細胞であり、前記リプログラミング細胞は、前記第1の細胞からの形態学的変化を含みかつ本質的にEBNAを含まず、前記リプログラミング細胞は、
(1)多能性細胞形態と、
(2)内在性OCT4発現と、を含まない、第2の細胞を生成することと、
(c)多能性細胞を生成するのに十分な時間、ステップ(b)で得られた前記第2の細胞をさらに培養することと、を含む、方法。 - ステップ(a)が、EBNAをコードするヌクレオチド配列を含む第2のプラスミドを前記第1の細胞に導入することを含み、前記第2のプラスミドが、複製起点、またはリプログラミング因子(複数可)をコードするポリヌクレオチド(複数可)を含まない、請求項1に記載の方法。
- 前記多能性細胞を解離して、単一細胞の解離した多能性細胞を得ることをさらに含む、請求項1に記載の方法。
- 前記単一細胞の解離した多能性細胞を懸濁させることをさらに含む、請求項1〜3のいずれか一項に記載の方法。
- 1つ以上の多能性マーカーを発現する細胞を選択および単離して、前記マーカー(複数可)を発現する多能性細胞を濃縮することにより、前記単一細胞の解離した多能性細胞を選別することをさらに含む、請求項1〜4のいずれか一項に記載の方法。
- GSK3阻害剤、MEK阻害剤およびROCK阻害剤の存在下で前記多能性細胞を培養して、多能性を維持することをさらに含み、前記多能性細胞は少なくとも5、10、15、または20継代にわたって多能性を維持する、請求項1〜5のいずれか一項に記載の方法。
- ステップ(b)における培養が、TGFβ阻害剤、GSK3阻害剤、MEK阻害剤およびROCK阻害剤のうちの少なくとも1つの存在下で培養することを含む、請求項1に記載の方法。
- 前記第1の細胞が体細胞、前駆細胞、または多分化能細胞である、請求項1に記載の方法。
- 前記第1の細胞が線維芽細胞であり、前記第2の細胞の前記形態学的変化がMET(間葉から上皮への転換)を含む、請求項1に記載の方法。
- 前記第2の細胞が、ステップ(a)のプラスミドを本質的に含まない、請求項1に記載の方法。
- 前記第2の細胞が、ステップ(a)における1つ以上の第1のプラスミドの前記導入後、約4〜10、12、14、21、25日、またはその間の任意の日数までのリプログラミング細胞を含む、請求項1に記載の方法。
- 前記多能性細胞は、多能性復帰または自発的分化が低減している、請求項1に記載の方法。
- 前記多能性細胞が、選択または前記多能性細胞の広範な継代を必要とせずに、前記ステップ(a)のプラスミドの前記ポリヌクレオチドを本質的に含まない、請求項1に記載の方法。
- 前記多能性細胞が、以下の特性
(1)高いクローン性、
(2)遺伝的安定性、および
(3)基底状態の多能性、のうちの少なくとも1つを有する、請求項1に記載の方法。 - 前記多能性細胞が、胚体外細胞に関連する再活性化遺伝子を含む、請求項1に記載の方法。
- 前記第2のプラスミドが、高い損失率を有し、かつ/またはEBNAの発現が一過性かつ一時的である、請求項2に記載の方法。
- 前記複製起点および/またはEBNAが、EBVベースである、請求項1または2に記載の方法。
- 前記細胞が、フィーダーフリー条件下にある、請求項1〜17のいずれか一項に記載の方法。
- 前記ROCK阻害剤が、チアゾビビンである、請求項1〜18のいずれか一項に記載の方法。
- 1つ以上の第1のプラスミドであって、前記第1のプラスミドが、複製起点、および1つ以上のリプログラミング因子をコードするがEBNAまたはその誘導体をコードしないポリヌクレオチドを含み、前記1つ以上の第1のプラスミドのうちの少なくとも1つが、OCT4をコードするポリヌクレオチドを含む、1つ以上の第1のプラスミドと、任意選択的に、
(1)EBNAをコードするヌクレオチド配列を含む第2のプラスミドであって、複製起点またはリプログラミング因子(複数可)をコードするポリヌクレオチド(複数可)を含まない、第2のプラスミド、
(2)EBNA mRNAおよび
(3)EBNAタンパク質、のうちの1つと、を非多能性細胞に導入した後に得られるリプログラミング細胞またはその集団であって、
前記リプログラミング細胞は、プラスミドの組み合わせの前記導入前の前記非多能性細胞からの形態学的変化を含み、本質的にEBNAまたはその誘導体を含まず、
前記リプログラミング細胞は、
(1)多能性細胞形態と、
(2)内在性OCT4発現を含まず、
前記リプログラミング細胞は、多能性細胞を生成するのに十分な時間を与えられると、安定したまたは自己持続的多能性を確立することができる、リプログラミング細胞またはその集団。 - 前記リプログラミング細胞が、1つ以上の第1のプラスミドの前記導入後、約4〜10、12、14、21、25日、またはその間の任意の日数までのものである、請求項20に記載のリプログラミング細胞またはその集団。
- 前記リプログラミング細胞が、TGFβ阻害剤、GSK3阻害剤、MEK阻害剤、およびROCK阻害剤のうちの少なくとも1つの存在下で培養される、請求項20または21に記載のリプログラミング細胞またはその集団。
- 前記非多能性細胞が線維芽細胞であり、前記リプログラミング細胞の前記形態学的変化がMET(間葉から上皮への転換)を含む、請求項20〜22のいずれか一項に記載のリプログラミング細胞またはその集団。
- 前記リプログラミング細胞が第1および/または第2のプラスミドを本質的に含まない、請求項20〜23のいずれか一項に記載のリプログラミング細胞またはその集団。
- 前記多能性細胞が、選択または前記多能性細胞の広範な継代を必要とせずに、前記プラスミドの前記ポリヌクレオチドを本質的に含まない、請求項20〜24のいずれか一項に記載のリプログラミング細胞またはその集団。
- 前記多能性細胞が、多能性復帰または自発的分化が低減している、請求項20〜25のいずれか一項に記載のリプログラミング細胞またはその集団。
- 前記多能性細胞が以下の特性
(1)高いクローン性、
(2)遺伝的安定性、および
(3)基底状態の多能性、のうちの少なくとも1つを有する、請求項20〜26のいずれか一項に記載の方法。 - 前記多能性細胞が、胚体外細胞に関連する再活性化遺伝子を含む、請求項20〜27のいずれか一項に記載のリプログラミング細胞またはその集団。
- 請求項20〜28のいずれか一項に記載のリプログラミング細胞またはその集団を含む組成物。
- TGFβ阻害剤、GSK3阻害剤、MEK阻害剤およびROCK阻害剤を含む培地をさらに含む、請求項29に記載の組成物。
- 前記ROCK阻害剤が、チアゾビビンである、請求項29に記載の組成物。
- 前記培地が、フィーダーフリーである、請求項30または31に記載の組成物。
- 請求項1〜19のいずれか一項に記載の方法により産生された場合の、単離した多能性細胞または多能性細胞株。
- 請求項1〜19のいずれか一項に記載の方法により産生された前記単離した多能性細胞または細胞株を使用して、ゲノム操作した多能性細胞またはその細胞株。
- 請求項33に記載の単離した多能性細胞もしくは細胞株から、または請求項34に記載のゲノム操作した多能性細胞もしくは細胞株から再分化した由来非天然細胞(derived non−natural cell)。
- 前記細胞が免疫細胞様であり、前記細胞がCD34細胞、造血性内皮細胞、造血幹細胞もしくは前駆細胞、造血多分化能前駆細胞、T細胞前駆細胞、NK細胞前駆細胞、T細胞、NKT細胞、NK細胞、B細胞、または免疫制御性細胞を含む、請求項35に記載の由来非天然細胞。
- 前記細胞が、その天然の細胞対応物と比較して、以下の特性:ヘテロクロマチンの全体的増加、ミトコンドリア機能の改善、DNA損傷応答の増加、テロメアの伸長および短いテロメアの割合の減少、老化細胞の割合の減少、ならびに増殖、生存、持続、または記憶様機能に対するより高い可能性、のうちの少なくとも1つを含む若返り細胞(rejuvenated cell)である、請求項35または36に記載の由来非天然細胞。
- 請求項1〜19のいずれか一項に記載の方法により得られた多能性細胞と、任意選択的に1つ以上の追加の治療薬とを含む、治療的使用のための組成物。
- 請求項34に記載のゲノム操作した多能性細胞または請求項35〜37に記載の由来非天然細胞と、任意選択的に1つ以上の追加の治療薬とを含む、治療的使用のための組成物。
- 治療が必要な対象の治療に使用するための請求項38または39に記載の組成物。
- 細胞ベースの治療に適用するための多能性細胞の製造に使用するための組成物であって、請求項1〜19のいずれか一項に記載の方法により産生された多能性細胞を含む、組成物。
- 前記多能性細胞が同種異系または自己である、請求項41に記載の組成物。
- 請求項1〜19のいずれか一項に記載の方法により得られた多能性細胞を含む、医薬使用のためのキット。
- 請求項34に記載のゲノム操作した多能性細胞または請求項35〜37に記載の由来非天然細胞を含む医薬使用のためのキット。
- 非多能性細胞でリプログラミングを開始するためのインビトロシステムであって、前記システムが、
1つ以上の第1のプラスミドであって、前記第1のプラスミドは、複製起点、および1つ以上のリプログラミング因子をコードするがEBNAまたはその誘導体をコードしないポリヌクレオチドを含み、前記1つ以上の第1のプラスミドのうちの少なくとも1つが、OCT4をコードするポリヌクレオチドを含む、1つ以上の第1のプラスミドと、任意選択的に、
(1)EBNAをコードするヌクレオチド配列を含む第2のプラスミドであって、複製起点またはリプログラミング因子(複数可)をコードするポリヌクレオチド(複数可)を含まない、第2のプラスミド、
(2)EBNA mRNAおよび
(3)EBNAタンパク質、のうちの1つと、を含む、インビトロシステム。 - 前記第2のプラスミドが、高い損失率を有し、前記EBNAの発現は一過性かつ一時的である、請求項44に記載のシステム。
- 前記システムが、核内でEBNA複製および/または連続発現を提供しない、請求項45または46に記載のシステム。
- 前記システムが、短期間、かつ多能性細胞形態の出現および内在性多能性遺伝子の誘導発現の前に、EBNAの一過性/細胞質発現を可能にする、請求項45〜47のいずれか一項に記載のシステム。
- 前記システムが、短期間、かつ多能性細胞形態の出現および内在性多能性遺伝子の誘導発現の前に、第1のプラスミド(複数可)に含まれる1つ以上のリプログラミング因子の一過性/細胞質発現を可能にする、請求項45〜48のいずれか一項に記載のシステム。
- 前記複製起点が、Polyomavirinaeウイルス、Papillomavirinaeウイルス、およびGammaherpesvirinaeウイルスからなる群より選択される、請求項45〜49のいずれか一項に記載のシステム。
- 前記複製起点が、SV40、BKウイルス(BKV)、ウシパピローマウイルス(BPV)、またはエプスタインバーウイルス(EBV)からなる群から選択されるものである、請求項45〜50のいずれか一項に記載のシステム。
- 前記複製起点が、EBVの野生型複製起点に対応するか、または由来する、請求項45〜51のいずれか一項に記載のシステム。
- 前記EBNAが、EBVベースである、請求項45〜52のいずれか一項に記載のシステム。
- 前記1つ以上の第1のプラスミドが、OCT4、SOX2、NANOG、KLF、LIN28、c−MYC、ECAT1、UTF1、ESRRB、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3、およびL1TD1のうちの1つ以上を含むリプログラミング因子(複数可)をコードするポリヌクレオチドを集合的に含む、請求項45〜53のいずれか一項に記載のシステム。
- リプログラミング因子をコードする前記ポリヌクレオチドが、ポリシストロン性構築物または非ポリシストロン性構築物に含まれる、請求項45〜54のいずれか一項に記載のシステム。
- 前記ポリシストロン性構築物が、単一のオープンリーディングフレームまたは複数のオープンリーディングフレームを含む、請求項45〜55のいずれか一項に記載のシステム。
- 前記システムが、2つ以上の第1のプラスミドを含み、各第1のプラスミドがポリヌクレオチドの少なくとも1つのコピーによりコードされる同じまたは異なるリプログラミング因子を含む、請求項45〜56のいずれか一項に記載のシステム。
- 2つ以上の第1のプラスミドを含む前記システムが、リプログラミング因子の化学量論の制御を提供する、請求項56に記載のシステム。
- 前記第1のプラスミドが、リプログラミング因子をコードする2つ以上のポリヌクレオチドを含み、隣接するポリヌクレオチドが自己切断性ペプチドまたはIRESをコードするリンカー配列により作動可能に連結される、請求項45〜58のいずれか一項に記載のシステム。
- 前記自己切断性ペプチドが、F2A、E2A、P2A、およびT2Aを含む群から選択される2Aペプチドである、請求項45〜59のいずれか一項に記載のシステム。
- 第1のプラスミド構築物に含まれる前記2Aペプチドが、同じであっても異なっていてもよい、請求項45〜60のいずれか一項に記載のシステム。
- 隣接する位置にある2つの2Aペプチドが異なる、請求項45〜61のいずれか一項に記載のシステム。
- 前記第1および前記第2のプラスミドがそれぞれ、リプログラミング因子およびEBNAの発現のための1つ以上のプロモーターを含み、かつ前記1つ以上のプロモーターがCMV、EF1α、PGK、CAG、UBC、および構成的、誘導的、内因的に調節された、または時間特異的、組織特異的もしくは細胞型特異的な他の適切なプロモーターのうちの少なくとも1つを含む、請求項45〜62のいずれか一項に記載のシステム。
- 前記第1および前記第2のプラスミドがそれぞれ、CAGプロモーターを含む、請求項45〜63のいずれか一項に記載のシステム。
- 請求項45〜64のいずれか一項に記載のシステムを含むキット。
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WO2019075057A1 (en) | 2019-04-18 |
SG11202002625YA (en) | 2020-04-29 |
BR112020007228A2 (pt) | 2020-10-13 |
IL273864A (en) | 2020-05-31 |
AU2018348142A1 (en) | 2020-04-02 |
JP2024099655A (ja) | 2024-07-25 |
CN111278967A (zh) | 2020-06-12 |
CA3078734A1 (en) | 2019-04-18 |
JP7554670B2 (ja) | 2024-09-20 |
MX2020003739A (es) | 2020-11-06 |
EP3694986A4 (en) | 2021-07-14 |
US20200270581A1 (en) | 2020-08-27 |
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