JP2014511690A - 肝再生および肝不全の治療のための薬剤 - Google Patents
肝再生および肝不全の治療のための薬剤 Download PDFInfo
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- JP2014511690A JP2014511690A JP2014503179A JP2014503179A JP2014511690A JP 2014511690 A JP2014511690 A JP 2014511690A JP 2014503179 A JP2014503179 A JP 2014503179A JP 2014503179 A JP2014503179 A JP 2014503179A JP 2014511690 A JP2014511690 A JP 2014511690A
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Abstract
Description
発現カセットにおける阻害性RNAをコードする核酸構築物からの阻害性RNAの発現によりインビボでMKK4を不活性化するための、阻害性RNAの肝細胞への、すなわち、患者の肝臓への導入は、MKK4をコードするmRNAにハイブリダイズするshRNAの生成のための阻害性RNAをコードする発現カセットを用いるマウス(C57BL/6)の例において示されている。阻害性RNAの転写を制御するプロモーターは構成的であった。
肝細胞の一過性トランスフェクションについて、MKK4をコードするmRNAに特異的にハイブリダイズする阻害性RNAをコードする、例えば、配列番号1または配列番号2(どちらも、ヒトおよびマウスのMKK4のmRNAに特異的である)を含有する発現カセットを含有し、またはそれからなる核酸構築物を、肝細胞へ一過性に導入した。インビボでの一過性トランスフェクションについて、核酸構築物を、リポソーム内に製剤化し、実験動物に投与した。リポソーム製剤は、脂質の3-N-[(メトキシポリ(エチレングリコール)2000)カルバモイル]-1,2-ジミリスチルオキシ-プロピルアミン(PEG-C-DMA)、1,2-ジリノレイルオキシ-N,N-ジメチル-3-アミノプロパン(DLinDMA)、1,2-ジステアロイル-sn-グリセロ-3-ホスホコリン(DSPC)、およびコレステロールを、2:40:10:48のモルパーセント比で含有した。
MKK4のmRNAに特異的にハイブリダイズする阻害性RNAをインビボで肝組織へトランスフェクションすることによって、薬剤として用いられる阻害性RNAの適合性を示すことができた。阻害性RNAは、好ましくはリポソームまたは脂質ナノ粒子として製剤化された、shRNAまたはミクロRNAであり得た。一般的に、MKK4の低下または除去は、実施例1に記載されているような分析方法を用いて、阻害性RNAの製剤に接触した肝組織の少なくとも一部分において得ることができた。これは、MKK4のmRNAに特異的な阻害性RNAが、薬剤として、特に肝機能障害の治療のために、用いられ得ることを示している。
阻害性RNAによる肝組織におけるMKK4活性の阻害に代わるものとして、SP600125、ミリシチン、ゲニステイン、またはPD98059を、肝臓においてMKK4を不活性化するために用いた。一般的に、SP600125、ミリシチン、ゲニステイン、またはPD98059を、MKK4のインビボでの不活性化に効率的な用量でマウスに投与した。好ましくは、用量は、平均インビボMKK4活性の少なくとも80%、より好ましくは少なくとも90%または95%を不活性化するのに効率的であった。
インビトロトランスフェクションについて、実施例1または実施例2に記載されているように、実験動物から得られた培養初代肝細胞を、核酸構築物に接触させた。一般的に、核酸構築物は、実施例2によりリポソームとして製剤化することができた。一般的に、阻害性RNAの安定的または一過性発現は、培養肝細胞において得ることができ、MKK4の低下または除去は、実施例1に記載されているような分析方法を用いて検出することができた。
適合性または同一の血液型をもつ患者を表すマウス由来の肝細胞、好ましくは、後でのレシピエント(例えば、患者)と免疫学的に適合性である肝細胞、好ましくは、自己肝細胞を培養した。MKK4活性を、上記実施例に記載されているように、好ましくは、MKK4をコードするmRNAにハイブリダイズする阻害性RNAについての発現カセットを含有する核酸構築物での培養肝細胞のトランスフェクションにより、阻害性RNAでの、好ましくは繰り返しの、トランスフェクションにより、またはSP600125、ミリシチン、ゲニステイン、もしくはPD98059と接触させることにより、阻害した。
上記のように、好ましくは、MKK4をコードするmRNAに特異的なshRNAを発現する核酸構築物を安定的にトランスフェクションされた初代肝細胞を培養することにより、得られた培養肝細胞を、担体基質、例えば、ポリマー担体上で成長させた。担体基質に付着した培養肝細胞を容器内に配置し、その容器を、マウスまたはラットによって例示される、患者から引き出された血液で灌流した。容器を出た血液を、すぐに患者へ戻すことができた。最初の実験において、MKK4をコードするmRNAを不活性化するshRNAを安定的に発現するように遺伝子操作されている肝細胞が、担体基質上で成長した場合、安定していること、およびこれらの培養肝細胞が血液精製装置として用い得ることを示すことができた。
MKK4に対する化合物の阻害効果を、例えば、コード配列としてヌクレオチド配列、配列番号1204を含有する発現カセットからMKK4を過剰発現するように遺伝子操作された細胞系、および、例えば、MKK4タンパク質に対して方向づけられた抗体を用いる、親和性精製から得られた、精製MKK4タンパク質を用いるインビトロアッセイにおいて分析した。
Claims (17)
- 肝不全の治療におけるおよび/またはアポトーシスに対する肝細胞の保護のためのおよび/または肝細胞の再生のための薬剤として用いるための、配列番号1204のmRNAによってコードされるMKK4の活性の阻害剤である化合物。
- 生理的条件下で配列番号1204のmRNAにハイブリダイズするヌクレオチド配列を有するオリゴヌクレオチドを含有するsiRNAであることを特徴とする、請求項1に記載の化合物。
- 前記オリゴヌクレオチドが、miR-15b、miR-24、miR-25、miR-141、および配列番号1〜配列番号1203を含む群から選択されることを特徴とする、請求項2に記載の化合物。
- 前記オリゴヌクレオチドが、第1セクションに逆相補的である第2セクションを含有する核酸構築物において第1セクションとして含まれることを特徴とする、請求項2または3に記載の化合物。
- 前記オリゴヌクレオチドが、発現カセットにおいてプロモーターの制御下に配置されることを特徴とする、請求項2から4のいずれか一項に記載の化合物。
- 前記オリゴヌクレオチドが、リポソーム製剤内、および/またはウイルス粒子もしくはウイルス様粒子内にパッケージングされるウイルスベクター内に含有されることを特徴とする、請求項2から5のいずれか一項に記載の化合物。
- SP600125、ミリシチン、ゲニステイン、PD98059、およびTable 1(表1)の化合物からなる群から選択されることを特徴とする、請求項1に記載の化合物。
- リポソームまたは脂質ナノ粒子として製剤化されることを特徴とする、請求項1から7のいずれか一項に記載の化合物。
- 肝不全の治療においてまたは血液精製のために用いるための培養肝細胞であって、配列番号1204によってコードされるMKK4の活性の阻害剤である化合物を含有することを特徴とする、培養肝細胞。
- 肝不全の治療のためまたは肝再生のための薬剤として用いられることを特徴とする、請求項9に記載の培養肝細胞。
- 患者の血液の流入のための入口、および血液を患者へ再循環させるための出口を有する容器内に配置されることを特徴とする、請求項9または10に記載の培養肝細胞。
- オリゴヌクレオチドmiR-15b、miR-24、miR-25、miR-141、および配列番号1〜配列番号1203、SP600125、ミリシチン、ゲニステイン、PD98059、およびTable 1(表1)の化合物を含む群から選択されることを特徴とする、請求項9から11のいずれか一項に記載の培養肝細胞。
- 肝不全の治療のための、アポトーシスに対する肝細胞の保護のための、ならびにインビボおよびインビトロでの肝細胞の再生のための薬剤の生成に用いるための、配列番号1204のmRNAによってコードされるMKK4の活性の阻害剤である化合物の使用。
- 培養中、肝細胞が、配列番号1204のmRNAによってコードされるMKK4の活性の阻害剤である化合物に接触することを特徴とする、細胞培養培地における培養による肝細胞の生成のための方法。
- 前記化合物が、配列番号1204のmRNAに生理的条件下でハイブリダイズするヌクレオチド配列を有するオリゴヌクレオチドを含有するsiRNAであることを特徴とする、請求項13に記載の方法。
- 前記オリゴヌクレオチドが、miR-15b、miR-24、miR-25、miR-141、および配列番号1〜配列番号1203のそれぞれを含む群から選択されることを特徴とする、請求項14に記載の方法。
- 前記化合物が、SP600125、ミリシチン、ゲニステイン、PD98059、およびTable 1(表1)の化合物からなる群から選択されることを特徴とする、請求項13に記載の方法。
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EP2295072A1 (en) * | 2009-09-15 | 2011-03-16 | Max-Delbrück-Centrum für Molekulare Medizin (MDC) | Use of ARC for inhibiting cell death during liver failure |
EP2508607A1 (en) * | 2011-04-07 | 2012-10-10 | Helmholtz-Zentrum für Infektionsforschung GmbH | Medicament for liver regeneration and for treatment of liver failure |
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JP2019516688A (ja) * | 2016-05-04 | 2019-06-20 | ベ.セ.イ. ファルマ | プロテインキナーゼ阻害剤としてのアデニン誘導体 |
JP2020505452A (ja) * | 2017-01-17 | 2020-02-20 | ヘパリジェニックス ゲーエムベーハー | 肝再生の促進又は肝細胞死の低減もしくは予防のためのプロテインキナーゼ阻害 |
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WO2012136859A1 (en) | 2012-10-11 |
ES2621944T3 (es) | 2017-07-05 |
JP6482582B2 (ja) | 2019-03-13 |
AU2012238525B2 (en) | 2017-02-23 |
JP6138110B2 (ja) | 2017-05-31 |
AU2012238525A1 (en) | 2013-10-03 |
US20190099453A1 (en) | 2019-04-04 |
EP2694652A1 (en) | 2014-02-12 |
CA2831342C (en) | 2020-07-21 |
DK3192870T3 (en) | 2019-01-14 |
JP2017086086A (ja) | 2017-05-25 |
EP2508607A1 (en) | 2012-10-10 |
EP3192870A1 (en) | 2017-07-19 |
US20140141510A1 (en) | 2014-05-22 |
US10188682B2 (en) | 2019-01-29 |
US20160022742A1 (en) | 2016-01-28 |
US20190091265A1 (en) | 2019-03-28 |
EP3192870B1 (en) | 2018-10-17 |
US9186381B2 (en) | 2015-11-17 |
EP2694652B1 (en) | 2017-02-01 |
DK2694652T3 (en) | 2017-03-20 |
CA2831342A1 (en) | 2012-10-11 |
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