JP2019517531A - 機能化ナノ粒子によるヒト体細胞の選択された(所定の)分化細胞への直接リプログラミング - Google Patents
機能化ナノ粒子によるヒト体細胞の選択された(所定の)分化細胞への直接リプログラミング Download PDFInfo
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Abstract
Description
本願は、2016年6月3日に出願された米国仮出願第62/345360号の利益を主張し、その開示全体が参照によって本明細書に組み込まれる。
本開示は、細胞リプログラミングのための、ならびにヒト体細胞から様々なヒト細胞種、例えば心臓細胞、肝細胞、血液細胞、神経細胞および他の細胞を発生させるための方法および組成物に関する。これらの新しく発生させた特殊化細胞(specialized cell)は、器官機能および/または組織再生(心臓、肝臓など)を改善するため、ならびに機能活性について薬物をスクリーニングするために有用である。
本発明は、米国立科学財団によって授与された小企業革新研究(SBIR)フェーズI IIP−1214943のもとの政府援助によりなされた。政府は本発明において一定の権利を有する。
正常に増殖し、遊走し、かつ様々な細胞種に分化する細胞の能力は、胚発生において、ならびに様々な遺伝性または後天性疾患における心血管系および/または造血系の細胞を含むが、これらに限定されない成熟細胞の機能において重要である。幹細胞および/またはより分化した特殊化細胞種のこの機能的能力は、様々な病理状態で変わるが、生物学的活性成分の細胞内導入によって、または代替的に、修復もしくは機能改善を必要とする特殊化細胞種への他の細胞種の分化転換により正常化することができる。例えば、異常な細胞機能、例えば骨髄幹細胞/前駆細胞の生存および/または好中球への分化の不全は、重度の命にかかわる感染を患う場合があり、かつ急性骨髄性白血病または他の悪性病変を発症するように進行し得る周期性または重度の先天性好中球減少症を有する患者において観察される(Carlssonら、Blood、103巻、3355頁(2004年);Carlssonら、Haematologica、(2006年))。別の例は、患者が、造血細胞の異常な生存および心筋症と呼ばれる心機能不全を有し得るバース症候群である(Makaryanら、Eur. J. Haematol.、(2012年))。
本発明は、一部の実施形態では、細胞機能を調節し、ヒト体細胞を、選択された(所定の)系統の機能細胞へ直接リプログラミングするための、タンパク質、ペプチドおよび/またはRNA分子を生体適合性ナノ粒子に連結する機能化方法を対象とする。かかる機能細胞は続いて、ヒトにおける細胞機能および/または器官機能を改善するための研究および開発、薬物スクリーニングならびに治療適用において使用することができる。選択された(所定の)細胞種の例として、誘導心臓細胞、肝細胞、神経細胞などが挙げられる。一部の実施形態では、本発明は、機能化生体適合性ナノ粒子それ自体を対象とする。
生物学的活性分子を細胞内に送達するために、本発明は、共有結合した生物学的活性分子を伴う細胞膜貫通ナノ粒子を含む組成物に基づく汎用プラットホームを提供する。この目標を達成するために、ナノ粒子へのタンパク質、ペプチドおよび/またはRNA(例えばマイクロRNA、転写因子をコードするRNA、siRNA、shRNAなど)分子の共有結合を確実にする機能化方法を、本明細書で示す。本発明の改変した細胞浸透性ナノ粒子は、一般的な細胞機能の調節および/または正常化のための生物学的活性分子の細胞内送達ならびにヒト体細胞の、選択された(所定の)系統の機能細胞への直接リプログラミングのための汎用機構を提供し、これは続いて、ヒトにおける細胞機能および/または器官/組織機能を改善するための研究および開発、薬物スクリーニングならびに治療適用において使用することができる。選択された(所定の)細胞種の例として、心臓細胞、肝細胞、神経細胞などが挙げられる。
ナノ粒子は、様々な長さのリンカーが結合している、X/Y官能基を有する生体適合性ポリマーコーティング(例えばデキストラン多糖)を伴う鉄または他の材料に基づいてもよく、そしてこれは次に、タンパク質、RNA(例えばマイクロRNA、転写因子をコードするRNA、siRNA、shRNAなど)分子および/またはペプチド(または他の小分子)にそのX/Y官能基を介して共有結合している。リンカー構造は、周知であり、開示する機能化ナノ粒子設計に慣用的に適用することができる。リンカーは、結合した生理活性化合物、例えばタンパク質またはポリヌクレオチドがその適切な三次元構造を維持し、その細胞内パートナーとより効率的に相互作用および結合するように回転することができるように、結合した生物活性化合物にコンフォメーション柔軟性を提供することができる。
− NH2(例えばリジン、a−NH2);
− SH;
− COOH;
− NH−C(NH)(NH2);
炭水化物;
− ヒドロキシル(OH);および
リンカー上のアジド基の光化学による結合
が挙げられる。
架橋アミノ基およびチオール基のスルホスクシンイミジル誘導体である、スルホ−SMCCを含む、SMCC[スクシンイミジル4−(N−マレイミド−メチル)シクロヘキサン−1−カルボキシレート];
スルホ−LC−SMCCを含む、LC−SMCC(長鎖SMCC);
アミンと反応し、チオール基を提供する、スルホ−SPDPを含む、SPDP[N−スクシンイミジル−3−(ピプリジルジチオ(pypridyldithio))−プロピオネート];
スルホ−LC−SPDPを含む、LC−SPDP(長鎖SPDP);
−COOH基を−NH2基と連結するために使用する試薬であるEDC[1−エチルヒドロクロリド(Hydrocholride)−3−(3−ジメチルアミノプロピル)カルボジイミド];
スルホ−SM(PEG)n誘導体を含む、n=1、2、3、4...24グリコール単位であるSM(PEG)n;
スルホ−SPDP(PEG)n誘導体を含む、n=1、2、3、4...12グリコール単位であるSPDP(PEG)n;
カルボキシル基およびアミン基の両方を含有するPEG分子;ならびに
カルボキシル基およびスルフヒドリル基の両方を含有するPEG分子
が挙げられる。
NHに特異的なシトラコン酸無水物;
SHに特異的なエチルマレイミド;および
マレイミドに特異的なメルカプトエタノール
が挙げられる。
組込みを起こさないナノ粒子を、1組の心臓特異的転写因子(例えば、最近説明されたGata4、MEF2C、TBX5、MESP1およびMYOCDを含む組1(その全体を参照により本明細書に組み込むNamら、Proc. Natl. Acad. Sci. USA. 110巻、5588〜5593頁、(2010年)))で機能化する。簡単に説明すると、ヒト体細胞を、機能化ナノ粒子で1回または反復して(2回またはそれよりも多い回数)処理し、これは、処理した細胞の細胞質および核への心臓特異的因子の送達をもたらす。細胞を、適切な培養培地中で長期間維持し、ヒト体細胞の、機能的心臓細胞へのかかる直接リプログラミングの結果を、様々な分子生物学、生化学および細胞生物学技術を使用してモニターする。具体的には、心臓特異的トロポニンTまたはトロポミオシンの発現は、RNA単離および続くリアルタイムもしくは逆転写PCR、適切な抗体を使用する細胞の免疫染色により、または培養した細胞のフローサイトメトリー分析により決定することができる。
ヒト体細胞の直接リプログラミングのための心臓特異的因子の異なる組は、心臓特異的転写因子およびマイクロRNAで機能化したナノ粒子を含み得る。例えば、組2は、4つのタンパク質Gata4、Hand2、TBX5、MYOCDならびに2つのマイクロRNA miR−1およびmiR−133を含有する。ウイルスベクターを使用して細胞に導入したこの生物活性分子の組合せは、機能的に活性、かつ収縮性の心筋細胞様細胞の発生を伴うヒト線維芽細胞の直接リプログラミングにおいて効率的である(Wadaら、Proc. Natl. Acad. Sci. USA. 110巻、12667〜12672頁、(2013年))。ここで、ヒト線維芽細胞を、組換えタンパク質およびマイクロRNAの組2で機能化したナノ粒子で処理し、培養して、ヒトiCMの発生を誘導する。これらおよび/または他の組の心臓特異的因子の代替の組合せは共に、ヒト体細胞の、心臓細胞へのリプログラミングを誘発する。
組込みを起こさないナノ粒子を、例として、最近説明されたFOXA3、HNF1AおよびHNF4Aを含む1組の肝細胞リプログラミング転写因子で機能化する(その全体を参照により本明細書に組み込むHuangら、Cell Stem Cell.、14巻、370〜384頁、(2014年))。簡単に説明すると、ヒト体細胞を、機能化ナノ粒子で1回または反復して(2回またはそれよりも多い回数)処理し、これは、処理した細胞の細胞質および核への肝臓特異的因子の送達をもたらす。細胞を、適切な培養培地中で長期間維持し、ヒト体細胞の、機能的肝細胞へのかかる直接リプログラミングの結果を、様々な分子生物学、生化学および細胞生物学技術を使用してモニターする。具体的には、アルブミン(ALB)、a−1−アンチトリプシン(AAT)およびシトクロムP450(CYP)酵素の発現は、RNA単離および続くリアルタイムもしくは逆転写PCR、適切な抗体を使用する細胞の免疫染色により、または培養した細胞のフローサイトメトリー分析により決定することができる。さらに、また、新しく発生した肝細胞の機能性を、液体クロマトグラフィー・タンデム質量分析法を使用して誘導CYP酵素の代謝活性を評価することにより確認することができる。これらの種類の肝細胞は、レンチウイルスベクターを使用してリプログラミングしても、急性肝不全の動物モデルにおいて肝機能の復元を示す(Huangら、Cell Stem Cell.、14巻、370〜384頁(2014年))。
組込みを起こさないナノ粒子を、最近説明された1組の神経リプログラミング転写因子PAX6および/またはSOX2で機能化する(その全体を参照により本明細書に組み込むConnor、Protocol Exchange doi:10.1038/protex.2015.034(2015年))。簡単に説明すると、ヒト体細胞を、機能化ナノ粒子で1回または反復して(2回またはそれよりも多い回数)処理し、これは、処理した細胞の細胞質および核へのリプログラミング因子の送達をもたらす。細胞を、適切な培養培地中で長期間維持し、ヒト体細胞の、神経前駆細胞へのかかる直接リプログラミングの結果を、様々な分子生物学、生化学および細胞生物学技術を使用してモニターする。具体的には、新しく発生させた神経細胞におけるニューロン特異的TUJ1、MAP2またはNSE表現型マーカーと共にチロシンヒドロキシラーゼ(TH)、vGlut1、GAD65/67およびDARPP32の発現は、RNA単離および続くリアルタイムもしくは逆転写PCRならびに/もしくは適切な抗体を使用する細胞の免疫染色により、またはヒト線維芽細胞から直接的にリプログラミングした培養した神経細胞のフローサイトメトリー分析により決定することができる。
人々が、医薬に対して様々に反応することは十分に確立されている。細胞は、個体の中で細胞の遺伝子型またはバリアント発達歴に基づいて医薬に対して様々に反応するので、これらの差は、細胞レベルで現れ得る(その全体を参照により本明細書に組み込むTurner RMら、Parsing interindividual drug variability: an emerging role for systems pharmacology. Rev Syst Biol Med. 2015年 7巻(4号)、221〜41頁)。生殖細胞系バリアントは、遺伝性の変異であり、多くの場合、薬物動態ならびに最終的には薬物有効性および/または毒性を含む、薬物の薬力学的挙動と関連付けられ、一方で、体細胞変異は多くの場合、薬物への薬力学的応答を予測することにおいて有用である。薬理民族性(Pharmacoethnicity)または薬物応答もしくは毒性の民族多様性は、薬物応答の個人間変異を説明する、益々認識されている因子である。薬理民族性は多くの場合、生殖細胞系薬理ゲノミクス因子および様々な集団にわたる単一のヌクレオチド多型の分布により決定される(その全体を参照により本明細書に組み込むPatel JN、Cancer pharmacogenomics: implications on ethnic diversity and drug response. Pharmacogenet Genomics. 2015年 25巻(5号)、223〜30頁)。
前記誘導特殊化細胞を前記候補医薬組成物と接触させることと、
前記誘導特殊化細胞を活性の徴候について観察することと
を含む方法。
Claims (38)
- 中心ナノ粒子にコンジュゲートした少なくとも1つの特殊化細胞種誘導剤を含む、体細胞の、目的の特殊化細胞種への分化を誘導する組成物。
- 前記少なくとも1つの特殊化細胞種誘導剤が、前記ナノ粒子上の第1の機能化基を介して前記中心ナノ粒子にコンジュゲートされる、請求項1に記載の組成物。
- 前記特殊化細胞種が、心筋細胞様細胞(iCM)、肝細胞、神経、ベータ細胞、血液前駆細胞、筋細胞、骨芽細胞または他の細胞種である、請求項1に記載の組成物。
- 前記少なくとも1つの特殊化細胞種誘導剤が、表1に列挙する剤またはその機能ドメインのうちの少なくとも1つを含む、請求項1に記載の組成物。
- 前記少なくとも1つの特殊化細胞種誘導剤が、表1に列挙する分子またはそれらの機能ドメインのうちの2つ、3つ、4つ、5つもしくはそれよりも多くを含む、請求項1から4のいずれか一項に記載の組成物。
- 前記少なくとも1つの特殊化細胞種誘導剤が、表1に列挙する剤またはそれらの機能ドメインを含む、請求項1から4のいずれか一項に記載の組成物。
- 前記少なくとも1つの特殊化細胞種誘導剤が、表1に列挙する1つもしくは複数のタンパク質もしくはRNA分子またはそれらの機能ドメインを含む、請求項1から4のいずれか一項に記載の組成物。
- 前記特殊化細胞種が、心筋細胞様細胞(iCM)であり、1つまたは複数の特殊化細胞種誘導剤が、Gata4、MEF2C、TBX5、MESP1、Hand2、MYOCD、miR−1およびmiR−133から選択される、請求項4から7のいずれか一項に記載の組成物。
- 前記ナノ粒子上の第2の機能化基を介して前記ナノ粒子にコンジュゲートした貫通ペプチド(CPP)をさらに含む、請求項1から8のいずれか一項に記載の組成物。
- 前記ナノ粒子が、直径約100nm未満の大きさを有する、請求項1から9のいずれか一項に記載の組成物。
- 前記ナノ粒子が、直径約75、50、40または30nm未満の大きさを有する、請求項10に記載の組成物。
- 前記中心ナノ粒子が、鉄または金分子を含む、請求項1から11のいずれか一項に記載の組成物。
- 前記中心ナノ粒子が、ポリマー分子を含む、請求項1から12のいずれか一項に記載の組成物。
- 前記ナノ粒子が、ポリマーコーティングを含む、請求項1から13のいずれか一項に記載の組成物。
- 前記ナノ粒子が、ポリマーコーティングを含み、第1および/または第2の官能基が、前記ポリマーコーティングに結合している、請求項9から14のいずれか一項に記載の組成物。
- 前記第1の官能基と表1に列挙する前記少なくとも1つの特殊化細胞種誘導剤とを連結する第1のリンカー分子をさらに含む、請求項2から15のいずれか一項に記載の組成物。
- 前記第2の官能基と前記CPPとを連結する第2のリンカー分子をさらに含む、請求項9から16のいずれか一項に記載の組成物。
- 前記第1のリンカー分子が、第1の長さを有し、前記第2のリンカー分子が、第2の長さを有し、前記第2の長さが、前記第1の長さより長い、請求項17に記載の組成物。
- 前記CPPが、少なくとも5個の塩基性アミノ酸を含む、請求項9から18のいずれか一項に記載の組成物。
- 前記CPPが、約5、6、7、8、9、10、11、12、13、14、15個またはそれよりも多い塩基性アミノ酸を含む、請求項19に記載の組成物。
- 前記CPPが、5、6、7、8、9、10、11、12、13、14、15個またはそれよりも多い連続する塩基性アミノ酸を含む、請求項19および20のいずれか一項に記載の組成物。
- 請求項1から21のいずれか一項に記載の組成物を含む細胞。
- 体細胞に由来する、請求項22に記載の細胞。
- 線維芽細胞に由来する、請求項23に記載の細胞。
- 目的の誘導特殊化細胞種である、請求項22に記載の細胞。
- 前記目的の誘導特殊化細胞種が、心筋細胞様細胞(iCM)、肝細胞、神経、ベータ細胞、血液前駆細胞、筋細胞、骨芽細胞または他の細胞種である、請求項25に記載の細胞。
- ヒト細胞である、請求項22から26のいずれか一項に記載の細胞。
- 体細胞の、表1に列挙する目的の特殊化細胞種への分化を誘導する方法であって、前記体細胞を請求項1から21のいずれか一項に記載の組成物と接触させることを含む方法。
- 前記目的の誘導特殊化細胞種が、心筋細胞様細胞(iCM)、肝細胞、神経、ベータ細胞、血液前駆細胞、筋細胞、骨芽細胞または他の細胞種である、請求項28に記載の方法。
- 前記体細胞が、線維芽細胞である、請求項28および29のいずれか一項に記載の方法。
- 前記体細胞を、前記体細胞の分化を可能にするのに十分な培養条件下でin vitroで接触させる、請求項28から30のいずれか一項に記載の方法。
- 前記体細胞が、ヒト細胞である、請求項28から31のいずれか一項に記載の方法。
- 目的の誘導特殊化細胞種における活性についてin vitroで候補医薬組成物をスクリーニングする方法であって、
前記誘導特殊化細胞を前記候補医薬組成物と接触させることと、
前記誘導特殊化細胞を活性の徴候について観察することと
を含む方法。 - 前記誘導特殊化細胞が、表1に列挙する細胞種のうちの1つから選択される、請求項33に記載の方法。
- 前記誘導特殊化細胞が、心筋細胞様細胞(iCM)、肝細胞、神経、ベータ細胞、血液前駆細胞、筋細胞、骨芽細胞または他の細胞種である、請求項33および34のいずれか一項に記載の方法。
- 体細胞から前記特殊化細胞の発生を誘導することをさらに含む、請求項33から35のいずれか一項に記載の方法。
- 前記特殊化細胞が、請求項28から32のいずれか一項に記載の方法に従って誘導される、請求項33から36のいずれか一項に記載の方法。
- 前記体細胞が、正常な対象または特定の病理状態を有する対象から得られ、活性の前記徴候が、前記対象における前記病理状態の処置のための前記医薬組成物の活性の徴候である、請求項36および37のいずれか一項に記載の方法。
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KR20190028665A (ko) | 2019-03-19 |
IL263410A (en) | 2018-12-31 |
AU2023202459A1 (en) | 2023-05-11 |
RU2018146815A (ru) | 2020-07-10 |
JP7441543B2 (ja) | 2024-03-01 |
EP3463383A1 (en) | 2019-04-10 |
CA3026365A1 (en) | 2017-12-07 |
SG11201810827VA (en) | 2018-12-28 |
AU2017274665A1 (en) | 2018-12-20 |
EP3463383A4 (en) | 2020-02-12 |
CN109641007A (zh) | 2019-04-16 |
CN114634908A (zh) | 2022-06-17 |
US20190224335A1 (en) | 2019-07-25 |
MX2018014967A (es) | 2019-08-12 |
BR112018075051A2 (pt) | 2019-03-06 |
WO2017210638A1 (en) | 2017-12-07 |
RU2018146815A3 (ja) | 2020-10-15 |
JP2022103281A (ja) | 2022-07-07 |
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