JP2022065020A - P450オキシドレダクターゼ欠損を有するヒト肝臓キメラ非ヒト動物およびそれを使用する方法 - Google Patents
P450オキシドレダクターゼ欠損を有するヒト肝臓キメラ非ヒト動物およびそれを使用する方法 Download PDFInfo
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Abstract
Description
本出願は、2016年6月27日に出願された米国仮特許出願第62/355,102号および2017年5月23日に出願された米国仮特許出願第62/509,942号についての優先権と利益を主張する。これらの出願のそれぞれの全内容は、その全体が参照により本明細書中に援用される。
2017年6月20日に作成され、67KBのサイズがある、テキストファイル名「KARL-001-WO_ST25」の内容は、その全体が参照によって本明細書に援用される。
開発中の10種類の薬物のうちのたった1種類しか臨床用途のために承認されない。その大部分が、ヒトにおける無効力または毒性のため臨床試験中に脱落する。ヒト異物代謝を正確に予測する実験的動物モデルの不足が顕著な制限となり、そしてそれがヒトの寿命を危険にさらし、かつ、薬物開発コストを酷使している。したがって、もっと優れた前臨床ツールを開発する切迫したニーズが存在する。本開示は、ヒト肝臓キメラ非ヒト動物モデル、およびヒトに特有の薬物代謝を予測するための、ヒト肝臓キメラ非ヒト動物モデルを使用する方法を提供することにより、当該技術分野におけるこれらのニーズを解決する。
本開示は、ヒト肝細胞を含むキメラ非ヒト動物を調製する方法であって、以下の:(a)Porタンパク質の発現の低減または不存在をもたらす、NADPH-P450オキシドレダクターゼ(Por)遺伝子の削減または欠失を含む非ヒト動物を提供し、そして(b)ヒト肝細胞をその非ヒト動物に移殖すること、を含む方法を提供する。
ヒト肝臓キメラマウスは、ヒト生体異物代謝および毒性を予測するために最近導入された。それらの可能性にもかかわらず、P450シトクロムの拡張セットを含むマウス肝臓が残留していることは、ヒト薬物代謝を正確に予測することを難しくする。そのため、本開示は、NADPH-P450オキシドレダクターゼ(Por)遺伝子の条件付きノックアウトマウスを提供し、そしてそれが、すべてのマウスシトクロムの唯一の電子供与体であり、そして、欠失された場合、胎生致死であり1、それによって、すべてのマウスシトクロムの機能的不活性化を可能にする。
Porノックアウト第一ターゲッティングベクターを、国立衛生研究所(NIH)ノックアウトマウスプログラム(KOMP)から購入した(図4A)。そのベクターを、AsisI制限酵素を用いて線形化し、そして、DNAを、ベイラー医科大学のマウス胚性幹細胞コアによるJm8A3マウス胚性幹細胞(ESC)(Pettitt, S.J. et al. “Agouti C57BL/6N embryonic stem cells for mouse genetic resources.” Nat Methods 6, 493-495 (2009))内にエレクトポレーション処理した。統合クローンを、ネオマイシン耐性を使用して選択した。ESCクローンのDNAを、NSiI制限酵素によって消化し、そして、製造業者の取扱説明書に従ってDIG非同位体検出システム(Roche Applied Biosciences)を使用したサザンブロッティングによって部位特異的組込みについてスクリーニングした(図17の全ブロット)。ベクターの相同性アームの外側に結合する、500bpサイズの5’および3’プローブを、以下のプライマセットを使用して合成した。
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Claims (32)
- ヒト肝細胞を含むキメラ非ヒト動物を調製する方法であって、以下の:
(a)Porタンパク質の発現の低減または不存在をもたらす、NADPH-P450オキシドレダクターゼ(Por)遺伝子の削減または欠失を含む非ヒト動物を提供し、そして
(b)ヒト肝細胞をその非ヒト動物に移殖すること、
を含む方法。 - 前記非ヒト動物を提供することが、Porタンパク質の発現の低減または不存在をもたらす、Por遺伝子の削減または欠失を含む、請求項1に記載の方法。
- 前記削減または欠失されたPor遺伝子が、Por遺伝子の条件付きノックダウンまたはノックアウトである、請求項1に記載の方法。
- 前記削減または欠失されたPor遺伝子が、突然変異、導入遺伝子、外因性物質または体細胞ゲノム工学を用いた処理の結果である、請求項1に記載の方法。
- 前記体細胞ゲノム工学が、Guide RNA(gRNA)およびカスパーゼ9(Cas9)を含む、請求項4に記載の方法。
- 前記非ヒト動物が、Por遺伝子のfloxed対立遺伝子を含み、かつ、該非ヒト動物が、Por遺伝子の条件付きノックアウトを生じさせるのに十分なCreリコンビナーゼと共に提供される、請求項1に記載の方法。
- 前記Por遺伝子のfloxed対立遺伝子を含む非ヒト動物には、Creリコンビナーゼをコードするウイルスの初回投与と共に少なくとも提供される、請求項6に記載の方法。
- 前記非ヒト動物には、Creリコンビナーゼをコードするウイルスの二回目の投与が少なくとも提供される、請求項7に記載の方法。
- 以下の:
(a)Por遺伝子のfloxed対立遺伝子を含む非ヒト動物を、Creリコンビナーゼをコードするウイルスの最初の投与と共に提供し;
(b)ヒト肝細胞を、その非ヒト動物に移殖し;そして
(c)Creリコンビナーゼをコードするウイルスの二回目の投与をその非ヒト動物に提供すること、
を含む、請求項1に記載の方法。 - 前記ステップ(a)と(b)が連続して起こる、請求項9に記載の方法。
- 前記ステップ(a)と(b)が同時に起こる、請求項9に記載の方法。
- 前記Por遺伝子のfloxed対立遺伝子を含む非ヒト動物を、Creリコンビナーゼを発現するトランスジェニック非ヒト動物株と交配させる、請求項7に記載の方法。
- 前記非ヒト動物が、薬物代謝に関与した酵素をコードする少なくとも1つの追加遺伝子の削減または欠失を更に含む、請求項1に記載の方法。
- 前記少なくとも1つの追加酵素が、第II相薬物酵素である、請求項13に記載の方法。
- 前記非ヒト動物が、UDP-グルコース6-デヒドロゲナーゼ(UGDH)遺伝子の削減または欠失を更に含む、請求項1に記載の方法。
- 前記非ヒト動物が、グルタチオンシンテターゼ(GSS)遺伝子の削減または欠失を更に含む、請求項1に記載の方法。
- 前記非ヒト動物が、霊長類、トリ、マウス、ラット、ニワトリ、イヌ、ネコ、ウシ、ウマ、ヤギ、ラクダ、ヒツジ、およびブタから成る群から選択される、請求項1に記載の方法。
- 前記非ヒト動物がマウスである、請求項1に記載の方法。
- 前記非ヒト動物が、(i)FRG(Fah-/-/Rag2-/-/Il2rg-/-)非ヒト動物、(ii)トランスジェニックウロキナーゼ型プラスミノーゲン活性化因子(uPA)非ヒト動物(誘導プロモータ、好ましくは肝臓に制限されたアルブミンプロモータ下でuPAを過剰発現するもの)、(iii)チミジンキナーゼ-NOD/Shi-scid/IL-2Rγnull(TK-NOG)非ヒト動物(肝臓に制限されたプロモータ制御下のチミジンキナーゼのトランスジェニック発現を有する免疫不全NOG非ヒト動物)、(iv)肝臓で誘導性カスパーゼ8を発現する非ヒト動物、および(v)肝臓で誘導性カスパーゼ9を発現する非ヒト動物、から成る群から選択される、請求項1に記載の方法。
- キメラ非ヒト動物、その子、またはその一部であって、ヒト肝細胞を含むキメラ肝臓を有する、請求項1~19のいずれか1項に記載の方法によって調製されたもの。
- 前記非ヒト動物が、霊長類、トリ、マウス、ラット、ニワトリ、イヌ、ネコ、ウシ、ウマ、ヤギ、ラクダ、ヒツジ、およびブタから成る群から選択される、請求項20に記載のキメラ非ヒト動物。
- 前記非ヒト動物がマウスである、請求項20に記載のキメラ非ヒト動物。
- 前記キメラ非ヒト動物が、実質的に自家肝細胞を欠いている、請求項20に記載のキメラ非ヒト動物。
- 前記ヒト肝細胞が、キメラ肝臓のすべての肝細胞のうちの少なくとも60%を占める、請求項20に記載のキメラ非ヒト動物。
- 前記ヒト肝細胞が、キメラ肝臓のすべての肝細胞のうちの少なくとも70%を占める、請求項20に記載のキメラ非ヒト動物。
- 前記ヒト肝細胞が、キメラ肝臓のすべての肝細胞のうちの少なくとも80%を占める、請求項20に記載のキメラ非ヒト動物。
- 前記ヒト肝細胞が、キメラ肝臓のすべての肝細胞のうちの少なくとも90%を占める、請求項20に記載のキメラ非ヒト動物。
- 前記キメラ非ヒト動物が免疫不全である、請求項20に記載のキメラ非ヒト動物。
- ヒト肝機能に作用する物質をスクリーニングする方法であって、以下の:
(a)請求項20に記載のキメラ非ヒト動物に試験物質を投与し;
(b)(a)において試験物質がそこに投与されたキメラ非ヒト動物において1若しくは複数の値を計測し;そして
(c)試験物質がそこに投与されていないキメラ非ヒト動物において計測される1若しくは複数の値と比較して、(b)において計測された1若しくは複数の値の増大または減少を引き起こす試験物質を選択すること、を含む方法。 - 前記1もしくは複数の値が、試験物質の代謝産物、ヒトアルブミン濃度、体重曲線、肝臓重量対体重比、総アルブミン値、総タンパク質レベル、アラニンアミノトランスフェラーゼ(ALT)レベル、アスパルタートアミノトランスフェラーゼ(AST)レベル、および総ビリルビンレベル、クレアチニン、血中尿素窒素(BUN)、トロポニン、血球数、TSH、ならびにヒトおよび非ヒト臓器の病理の組織学的評価から成る群から選択される、請求項29に記載の方法。
- 非ヒトキメラ動物においてヒト肝細胞およびその他の非ヒト臓器に対する試験物質の毒性を評価する方法であって、以下の:
(a)請求項20に記載のキメラ非ヒト動物に試験物質を投与し;
(b)(a)において試験物質がそこに投与されたキメラ非ヒト動物において1若しくは複数の指標を計測し;そして
(c)試験物質がそこに投与されていないキメラ非ヒト動物において計測される1若しくは複数の指標と比較して、(b)において計測された1若しくは複数の指標を使用して、ヒト肝細胞に対する試験物質の効果を評価すること、を含む方法。 - 前記1もしくは複数の指標が、任意の1若しくは複数の試験物質の代謝産物、ヒトアルブミン濃度、体重曲線、肝臓重量対体重比、総アルブミン値、総タンパク質レベル、ALTレベル、ASTレベル、および総ビリルビンレベルの増加または減少、クレアチニン、BUN、トロポニン、血球数およびTSH、ならびにこれだけに限定されるものではないが、ヒトおよび非ヒト臓器における壊死およびアポトーシスを含めた組織学的変化から成る群から選択される、請求項31に記載の方法。
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