JP2018534922A - 基底状態の多能性の誘導及び維持に関するプラットフォーム - Google Patents
基底状態の多能性の誘導及び維持に関するプラットフォーム Download PDFInfo
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Abstract
【選択図】なし
Description
この出願は、2015年10月16日出願の米国仮出願第62/242,842号の優先権を主張し、その開示はその全体を参照することによりここに組み入れられたものとする。
多能性細胞の産生及び維持に関する既存の方法は、自然分化を含まず高分解能(high-resolution)/高クローン性の単一細胞継代及び大規模増殖に従う、フットプリントフリーである多能性細胞の均質培養を未だ実現できていない。基底状態の多能性細胞は、これら課題を解決する品質及び特性を与えることができる。しかしながら、今日まで、フィーダーフリー条件下での基底状態の多能性細胞を、高い生産性で産生する、信頼性があり頑健である方法は、存在してない。すなわち、この技術分野における既存の方法は、産業グレード又は臨床グレードの多能性細胞の産生に好適ではあり得なかった。本明細書で意図する発明では、基底状態の多能性の特性における又は該特性を伴う、安定な多能性細胞の頑健な産生の必要性に対処し、産業的使用及び臨床的使用に好適である安定な多能性細胞の作製における課題を解決する。
B.定義
C.細胞
D.自然分化を低減させ、基底状態の多能性を誘導する培養プラットフォーム
1.TGFΒ受容体/ALK5阻害剤
2.WNT経路アゴニスト
3.GSK−3β阻害剤
4.ERK/MEK阻害剤
5.ROCK阻害剤
7.培養基質
8.フィーダーフリー環境
9.解離
10.富化及び枯渇の戦略
E.細胞初期化培養プラットフォーム
F.多能性細胞の特性決定
G.ポリヌクレオチド
H.ポリペプチド
表2:例示的な2A部位は以下の配列を含む:
実施例1−IPSCを長期間維持及び増殖する培地プラットフォームの特定
概説
結果
実施例2−単一細胞の継代及びFFフォーマットでの導入遺伝子フリーのhiPSC作製に関するプラットフォーム
概説
結果
実施例3−FMM中での導入遺伝子フリーのhiPSC株の長期間継代及び増殖
概説
結果
実施例4−最小限の遺伝子によるエピソーマル初期化を可能とする多段階培地プラットフォーム
概説
結果
実施例5−基底状態の多能性を支持するFMMプラットフォーム
概説
結果
実施例6−小分子培養におけるhiPSCの維持
実施例7−小分子培養における最小限の遺伝子による初期化
表3:初期化因子の組み合わせ及び多能生表現型の発現
実施例8−初期化因子及びそれらの化学量論の影響
実施例9−実験手順
表4:FAM標識TaqManプローブ
表5:導入遺伝子特異的プライマーセット
実施例10−初期化因子として用いるために特定した遺伝子
表6−初期化因子として用いるために特定した遺伝子
表7:iPSC初期化に関する化学量論的因子を含有するコンストラクト
実施例11−センダイウイルスベクターを介した、化学量論的因子を用いた初期化
Claims (51)
- 非多能性細胞を初期化する方法であって、
a)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数のポリヌクレオチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数のポリヌクレオチドとを、前記非多能性細胞に導入すること、又は、
b)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドとを、前記非多能性細胞に接触させることを含む、方法。 - a)(i)及びa)(ii)の前記1つ又は複数のポリヌクレオチドは、1つ又は複数のベクターによって導入し、各ベクター内の前記1つ又は複数のポリヌクレオチドは、同一又は異なるポリペプチドをコードする、請求項1記載の方法。
- 1つ又は複数のポリヌクレオチドを前記非多能性細胞に導入することは、1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB、及びポリヌクレオチドをコードする少なくとも1つのNANOG、(vi)ポリヌクレオチドをコードする、CDH1、ZIC3及びHESRGのうちの少なくとも1つ、(vii)ポリヌクレオチドをコードする、L1TD1、DPPA4及びTDGF1のうちの少なくとも1つ、又は、(viii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターを導入することを含む、請求項1記載の方法。
- 1つ又は複数のポリヌクレオチドを前記非多能性細胞に導入することは、
(a)1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、又は、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、を含むものである前記1つ又は複数のベクターを導入することと、
(b)1つ又は複数のベクターであって、各ベクターが(1)ポリヌクレオチドをコードする少なくとも1つのCDH1、ポリヌクレオチドをコードする少なくとも1つのZIC3及びポリヌクレオチドをコードする少なくとも1つのHESRG、(ii)ポリヌクレオチドをコードする少なくとも1つのL1TD1、ポリヌクレオチドをコードする少なくとも1つのDPPA4及びポリヌクレオチドをコードする少なくとも1つのTDGF1、又は、(iii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターを導入することとを含む、請求項3記載の方法。 - 前記1つ又は複数のポリヌクレオチドは、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、を含むベクターのうちの少なくとも1つによって導入する、請求項1記載の方法。 - 前記1つ又は複数のポリヌクレオチドは、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとによって導入する、請求項5記載の方法。 - 前記1つ又は複数のベクターは、レトロウイルス、センダイウイルス、アデノウイルス、エピソーム、ミニサークル、発現カセットをもつベクター系又はmRNAによって導入する、請求項3記載の方法。
- ベクターのうちの少なくとも1つは、センダイウイルスによって導入する、請求項7記載の方法。
- 前記1つ又は複数のポリヌクレオチドは、少なくとも1つの自己切断(self-cleaving)ポリペプチドにより連結されている、請求項1記載の方法。
- 前記非多能性細胞を多能性細胞に初期化する、請求項1記載の方法。
- 前記非多能性細胞は体細胞である、請求項1記載の方法。
- 非多能性細胞を初期化することは、SOX2、Klf4及びc−Mycのうちの1つ又は複数の使用を除外する、請求項1記載の方法。
- 多能性細胞を産生する方法であって、
a)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数のポリヌクレオチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数のポリヌクレオチドとを、非多能性細胞に導入することと、又は、
b)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドとを、非多能性細胞に接触させることと、
それによって前記非多能性細胞を多能性細胞に初期化することとを含む、方法。 - a)(i)及びa)(ii)の前記1つ又は複数のポリヌクレオチドは、1つ又は複数のベクターによって導入し、各ベクター内の前記1つ又は複数のポリヌクレオチドは、同一又は異なるポリペプチドをコードする、請求項13記載の方法。
- 1つ又は複数のポリヌクレオチドを前記非多能性細胞に導入することは、1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、(vi)ポリヌクレオチドをコードする、CDH1、ZIC3及びHESRGのうちの少なくとも1つ、(vii)ポリヌクレオチドをコードする、L1TD1、DPPA4及びTDGF1のうちの少なくとも1つ、又は、(viii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターを導入することを含む、請求項13記載の方法。
- 1つ又は複数のポリヌクレオチドを前記非多能性細胞に導入することは、
(a)1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、又は、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、を含むものである前記1つ又は複数のベクターを導入することと、
(b)1つ又は複数のベクターであって、各ベクターが(1)ポリヌクレオチドをコードする少なくとも1つのCDH1、ポリヌクレオチドをコードする少なくとも1つのZIC3及びポリヌクレオチドをコードする少なくとも1つのHESRG、(ii)ポリヌクレオチドをコードする少なくとも1つのL1TD1、ポリヌクレオチドをコードする少なくとも1つのDPPA4及びポリヌクレオチドをコードする少なくとも1つのTDGF1、又は、(iii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターを導入することとを含む、請求項15記載の方法。 - 前記多能性細胞を産生することは、SOX2、Klf4及びc−Mycのうちの1つ又は複数の使用を除外する、請求項13記載の方法。
- 前記1つ又は複数のポリヌクレオチドは、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、を含むベクターのうちの少なくとも1つによって導入する、請求項13記載の方法。 - 前記1つ又は複数のポリヌクレオチドは、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとによって導入する、請求項13記載の方法。 - 前記1つ又は複数のベクターは、レトロウイルス、センダイウイルス、アデノウイルス、エピソーム、ミニサークル、発現カセットをもつベクター系又はmRNAによって導入する、請求項13記載の方法。
- ベクターのうちの少なくとも1つは、センダイウイルスによって導入する、請求項20記載の方法。
- 非多能性細胞を多能性細胞に初期化することに関する組成物であって、非多能性細胞の集団を含むものであり、前記非多能性細胞は、(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数の外因性ポリヌクレオチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数の外因性ポリヌクレオチドとを含む、組成物。
- 前記非多能性細胞は、OCT4、ESRRB、ECAT1、UTF1及びNANOGからなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数の外因性ポリヌクレオチドを含み、またCDH1、ZIC3、HESRG、L1TD1、DPPA4、TDGF1及びDNMT3Bからなる群から選択した1つ又は複数のポリペプチドをコードする1つ又は複数の外因性ポリヌクレオチドをさらに含む、請求項16記載の組成物。
- 前記非多能性細胞が、(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、(vi)ポリヌクレオチドをコードする、CDH1、ZIC3及びHESRGのうちの少なくとも1つ、(vii)ポリヌクレオチドをコードする、L1TD1、DPPA4及びTDGF1のうちの少なくとも1つ、ならびに/又は、(viii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものであって、前記ポリヌクレオチドは外因性である、請求項16記載の組成物。
- 前記非多能性細胞が、(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、ならびに/又は、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、を含むものであって、前記非多能性細胞は、SOX2、Klf4及びc−Mycのうちの1つ又は複数を含まない、請求項16記載の組成物。
- 前記非多能性細胞が、
(i)ポリヌクレオチドをコードする少なくとも1つのCDH1、ポリヌクレオチドをコードする少なくとも1つのZIC3及びポリヌクレオチドをコードする少なくとも1つのHESRG、(ii)ポリヌクレオチドをコードする少なくとも1つのL1TD1、ポリヌクレオチドをコードする少なくとも1つのDPPA4及びポリヌクレオチドをコードする少なくとも1つのTDGF1、ならびに/又は、(iii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、をさらに含む、請求項19記載の組成物。 - 多能性細胞を産生することに関するキットであって、
a)1つ又は複数のベクターであって、各ベクターがHESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のペプチドをコードする1つ又は複数のポリヌクレオチドを含むものである、前記1つ又は複数のベクター、又は、
b)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のポリペプチドを含む、キット。 - 1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、(vi)ポリヌクレオチドをコードする、CDH1、ZIC3及びHESRGのうちの少なくとも1つ、(vii)ポリヌクレオチドをコードする、L1TD1、DPPA4及びTDGF1のうちの少なくとも1つ、又は、(viii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターを含む、請求項27記載のキット。
- (a)1つ又は複数のベクターであって、各ベクターが(i)ポリヌクレオチドをコードする少なくとも2つのOCT4、(ii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのNANOG、(iii)ポリヌクレオチドをコードする少なくとも1つのOCT4及びポリヌクレオチドをコードする少なくとも1つのESRRB、(iv)ポリヌクレオチドをコードする少なくとも1つのECAT1及びポリヌクレオチドをコードする少なくとも1つのUTF1、又は、(v)ポリヌクレオチドをコードする少なくとも1つのOCT4、ポリヌクレオチドをコードする少なくとも1つのESRRB及びポリヌクレオチドをコードする少なくとも1つのNANOG、を含むものである前記1つ又は複数のベクターと、
(b)1つ又は複数のベクターであって、各ベクターが(1)ポリヌクレオチドをコードする少なくとも1つのCDH1、ポリヌクレオチドをコードする少なくとも1つのZIC3及びポリヌクレオチドをコードする少なくとも1つのHESRG、(ii)ポリヌクレオチドをコードする少なくとも1つのL1TD1、ポリヌクレオチドをコードする少なくとも1つのDPPA4及びポリヌクレオチドをコードする少なくとも1つのTDGF1、又は、(iii)ポリヌクレオチドをコードする少なくとも1つのDNMT3B、を含むものである前記1つ又は複数のベクターとを含む、請求項27記載のキット。 - ベクターが、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチドを含む、請求項27記載のキット。 - 前記キットが、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとを含む、請求項27記載のキット。 - ベクターは、レトロウイルス、センダイウイルス、アデノウイルス、プラスミド、ミニサークル、又はmRNAによって運ばれる、請求項27記載のキット。
- 前記ベクターは、センダイウイルスによって運ばれる、請求項27記載のキット。
- 初期化組成物であって、
(a)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のペプチドと、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1からなる群から選択した1つ又は複数のペプチドとをコードする、1つ又は複数のポリヌクレオチド、又は、
(b)(i)OCT4、SOX2、NANOG、KLF4、LIN28、C−MYC、ECAT1、UTF1、ESRRB、SV40LT、HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1と、(ii)HESRG、CDH1、TDGF1、DPPA4、DNMT3B、ZIC3及びL1TD1とからなる群から選択した1つ又は複数のポリペプチドを含む、初期化組成物。 - (a)OCT4、NANOG、ECAT1、ESRRB及びUTF1からなる群から選択した1つ又は複数のペプチドをコードする1つ又は複数のポリヌクレオチド、又は、
(b)OCT4、NANOG、ECAT1、ESRRB及びUTF1からなる群から選択した1つ又は複数のポリペプチドをさらに含む、請求項34記載の初期化組成物。 - 前記初期化組成物が、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、を含む少なくとも1つのベクターを含む、請求項34記載の初期化組成物。 - 前記初期化組成物が、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとを含む、請求項36記載の初期化組成物。 - ベクターは、レトロウイルス、センダイウイルス、アデノウイルス、プラスミド、ミニサークル、又はmRNAによって運ばれる、請求項36記載の初期化組成物。
- ベクターは、センダイウイルスによって運ばれる、請求項36記載の初期化組成物。
- 非多能性細胞を初期化する方法であって、
(a)Oct4と、任意にKlf、Sox2、Myc、Nanog及びESRRBのうちの1つ又は複数とをコードする1つ又は複数のポリヌクレオチドを、前記非多能性細胞に導入することと、
(b)ECAT1、UTF1、L1TD1、DPPA4、TDGF1、CDH1、ZIC3及びHESRGのうちの少なくとも1つをコードする1つ又は複数のポリヌクレオチドを、前記非多能性細胞に導入することと、
それによって多能性細胞を取得することとを含む、方法。 - (a)及び(b)の前記1つ又は複数のポリヌクレオチドは、1つ又は複数のベクターによって導入し、各ベクター内の前記1つ又は複数のポリヌクレオチドは、同一又は異なるポリペプチドをコードする、請求項40記載の方法。
- 1つ又は複数のベクターが、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、を含む少なくとも1つのコンストラクトを含む、請求項41記載の方法。 - 前記1つ又は複数のポリヌクレオチドは、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとを介して導入する、請求項40記載の方法。 - ベクターのうちの1つ又は複数は、レトロウイルス、センダイウイルス、アデノウイルス、プラスミド、ミニサークル、又はmRNAによって導入する、請求項40記載の方法。
- ベクターのうちの1つ又は複数は、センダイウイルスによって導入する、請求項40記載の方法。
- センダイウイルスを用いて非多能性細胞を初期化する方法であって、
(a)Oct4と、任意にKlf、Sox2、Myc、Nanog及びESRRBのうちの1つ又は複数とをコードする1つ又は複数のポリヌクレオチドを、前記非多能性細胞に導入することと、
(b)ECAT1、UTF1、L1TD1、DPPA4、TDGF1、CDH1、ZIC3及びHESRGのうちの少なくとも1つをコードする1つ又は複数のポリヌクレオチドを、前記非多能性細胞に導入することと、
それによって多能性細胞を取得することとを含む、方法。 - (a)及び(b)の前記1つ又は複数のポリヌクレオチドは、1つ又は複数のベクターによって導入し、前記1つ又は複数のポリヌクレオチドは、同一又は異なるポリペプチドをコードする、請求項46記載の方法。
- ベクターのうちの1つ又は複数が、
(a)Nanog、ESRRB及びOct4のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、
(b)ECAT1及びUTF1のうちの一方又は両方をコードする1つ又は複数のポリヌクレオチド、
(c)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードする1つ又は複数のポリヌクレオチド、又は、
(d)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードするポリヌクレオチドのうちの1つ又は複数、を含むコンストラクトを含む、請求項47記載の方法。 - 前記1つ又は複数のポリヌクレオチドは、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとを介して導入するものであって、
前記ベクターは、センダイウイルスによって運ばれる、請求項46記載の方法。 - センダイウイルスを用いて非多能性細胞を初期化する方法であって、
(a)Oct4と、任意にKlf、Sox2、Myc、Nanog及びESRRBのうちの1つ又は複数とをコードするポリヌクレオチドを、前記非多能性細胞に導入することと、
(b)
(i)ECAT1及びUTF1のうちの一方又は両方をコードするポリヌクレオチド、
(ii)L1TD1、DPPA4及びTDGF1のうちの1つ又は複数をコードするポリヌクレオチド、又は、
(iii)CDH1、ZIC3及びHESRGのうちの1つ又は複数をコードするポリヌクレオチド、を含むコンストラクトのうちの1つを前記非多能生細胞に導入することと、
それによって多能性細胞を取得することとを含む、方法。 - 前記1つ又は複数のポリヌクレオチドは、Oct4をコードする1つ又は複数のポリヌクレオチドを含むベクターと、
(a)Nanog、ESRRB及びOct4をコードするポリヌクレオチドを含むベクター、
(b)ECAT1及びUTF1をコードするポリヌクレオチドを含むベクター、
(c)L1TD1、DPPA4及びTDGF1をコードするポリヌクレオチドを含むベクター、ならびに、
(d)CDH1、ZIC3及びHESRGをコードするポリヌクレオチドを含むベクター、のうちの少なくとも1つとを介して導入するものであって、
前記ベクターは、センダイウイルスによって運ばれる、請求項50記載の方法。
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WO2017066634A1 (en) | 2017-04-20 |
EP3362570A1 (en) | 2018-08-22 |
SG11201802957PA (en) | 2018-05-30 |
CN108291237B (zh) | 2023-11-21 |
AU2016338680B2 (en) | 2022-11-17 |
CA3001917A1 (en) | 2017-04-20 |
JP2022036950A (ja) | 2022-03-08 |
AU2023200879A1 (en) | 2023-03-16 |
CN108291237A (zh) | 2018-07-17 |
JP7263005B2 (ja) | 2023-04-24 |
CN117737124A (zh) | 2024-03-22 |
KR20180055918A (ko) | 2018-05-25 |
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