JP6420865B2 - 心臓筋細胞増殖の誘導による心臓再生のためのマイクロrna - Google Patents
心臓筋細胞増殖の誘導による心臓再生のためのマイクロrna Download PDFInfo
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Description
WO2011133288;WO2012160551;US20120295963;WO2012149557;US20120270826;WO2012122447;EP2496711;WO2012119051;WO2012115885;US20120207744;EP2288703;EP2475372;WO2012094366;EP2474616;US20120165392;WO2012083004;EP2462228;WO2012072685;US20120137379;US20120128761;WO2012061810;WO2012052953;US20120093885;US20120088687;EP2425016;US20120053227;US20120053333;WO2012020308;WO2012020307;WO2012012870;WO2012010905;EP2401365;WO2011157294;US20110262928;WO2011133036;EP2377559;CA2795776;WO2011112732;US20110160290;US20110160285;US20110152352;US20110144914;EP2322616;US20110086353;US20110086348;EP2305810;US20110003704;EP2257625;EP2254586;US20100267804;EP2234483;EP2228444;US20100227325;EP2202309;US7709616;EP2179060;WO2010033871;US20100029003;US20090306181;US20090298910;US20090291131;US20090081640;US20080261908;US20080256072;US20050256072である。
i)心臓筋細胞の増殖を刺激する活性を備え、したがって、心筋細胞増殖を刺激することによってインビボにおいて心臓の再生を刺激するための方法および医薬を利用可能にするマイクロRNA、好ましくはヒト由来で、特に36種の選択されたマイクロRNA群、ならびにこれをもとにして、心臓筋細胞の喪失(特に、心筋梗塞、虚血または非虚血が原因の心筋症、心筋炎および心不全の結果)に関連した心臓病変の治療のために投与するための方法、医薬および組成物、ベクターならびに製剤。
本発明は、インビトロおよびインビボにおいて心筋細胞の増殖を誘導する特性を有し、特にハイコンテンツな画像解析をベースにしたハイスループットスクリーニング法によってライブラリーから選択される、好ましくはヒト由来のマイクロRNAを提供する。好ましい方法は、注釈を付けたヒトマイクロRNA(2009年公開のmiRBase 13.0)全てに対応する合成マイクロRNA成熟配列を使用した、ラット新生仔心筋細胞における蛍光顕微鏡をベースにしたハイスループットスクリーニングである。
a.マイクロRNAのライブラリーを得ること、
b.第1の動物対象から単離された第1の心筋細胞内に各マイクロRNAを遺伝子導入すること、
c.前記第1の遺伝子導入した心筋細胞を培養すること、
d.前記第1の遺伝子導入した心筋細胞の増殖能力を試験すること、
e.前記第1の遺伝子導入した心筋細胞において増殖を誘導することができるマイクロRNAを選択すること、
f.前記第1の動物とは異なる種の第2の動物対象から単離された第2の心筋細胞内に工程e)の選択された各マイクロRNAを遺伝子導入すること、
g.前記第2の遺伝子導入した心筋細胞を培養すること、
h.前記第2の遺伝子導入した心筋細胞の増殖能力を試験すること、
i.工程h)の前記第2の遺伝子導入した心筋細胞において増殖を誘導することができるマイクロRNAを選択すること
を含む。
工程i)の後、以下の、
j.工程i)の選択された各マイクロRNAをヒト対象から以前に単離された第3の心筋細胞に遺伝子導入する工程、
k.前記第3の遺伝子導入した心筋細胞を培養する工程、
l.前記第3の遺伝子導入した心筋細胞の増殖能力を試験する工程、
m.工程l)の前記第3の遺伝子導入した心筋細胞において増殖を誘導することができるマイクロRNAを選択する工程
がさらに行われる。
細胞増殖を含むいくつかの生物学的プロセスの調節においてマイクロRNAが関与することを考え、マイクロRNAがエキソビボにおいて初代心臓筋細胞の増殖を制御できるかどうかを調べ、これらの細胞の増殖能力を増加させるのに最も有効なマイクロRNAを同定することを所望した。
動物の飼育および世話は、国内外の法律および政策に従った機関ガイドラインに基づいて実施した(EEC Council Directive 86/609, OJL 358, December 12, 1987)。
発生中、マウス心臓の心筋細胞はラット心臓の心筋細胞よりも早く分割を停止する(それぞれ、誕生直後および誕生の3から4日後)。この結果として、新生仔のマウスから単離された心筋細胞は、同齢のラットから単離された心筋細胞よりも増殖能力が著しく低く、新生仔ラット(出生後0日目)から単離された心筋細胞の増殖は約12.5%で、マウスの心筋細胞では約5%である。
CD1マウスは、Charles River Laboratories Italia Srl.から購入した。マウス心筋細胞は、ラット心筋細胞について実施例1で説明したように、新生仔マウス(出生後0日目)から単離した。
Ki−67増殖マーカーによる染色およびDNA合成中のEdU組み込みによって評価した心筋細胞増殖の増加が、心筋細胞の細胞分裂事象(細胞質分裂)の増加と相関することを示すために、心筋細胞を個々のマイクロRNAで処理し、他のマーカー、すなわち、i)G2後期/有糸分裂の細胞を検出する、セリン10(P−S10−H3)でリン酸化されたヒストンH3の染色、ii)分裂する細胞の完全な分離直前の細胞質分裂の最後近くに出現し、分離後短期間維持される一時的な構造である中心体の成分、AuroraBキナーゼの染色、およびiii)マイクロRNAを遺伝子導入して6日後の心筋細胞数を評価した。
選択された個々のマイクロRNAは、ロボットによってPrimaria 96ウェルプレート(BD Falcon)に移された。選択したマイクロRNAのラット新生仔心筋細胞への遺伝子導入および免疫蛍光法は、実施例1の方法で記載したように実施した。細胞は、以下の1次抗体、サルコメアアルファアクチニンに対するマウスモノクローナル抗体(Abcam)、セリン10でリン酸化されたヒストンH3に対するウサギ抗体(Millipore)およびAuroraBキナーゼに対するウサギ抗体(Sigma)で染色した。
新生仔動物から単離された心筋細胞の一部分はまだ細胞周期と連動しており、増殖することができ(種に応じて心筋細胞の約3〜15%)、したがって、マイクロRNAがこれらの細胞の増殖能力を高めると考えることができる。
心室の心筋細胞は、わずかな変更を加えて、以前記載されたように(Xiao et al. 2001)、雌成体ウィスターラット(2ヵ月齢)のランゲンドルフ灌流心臓から単離した。簡単に説明すると、心臓を取り出し、カルシウムを含まないクレブス−ヘンゼライト炭酸水素(KHB)緩衝液で逆方向に灌流した。次に、1mg/ml リベラーゼ(Roche)を含有するKHB緩衝液で心臓を10分間灌流した。心房および大血管を除去した後、心臓をKHB緩衝液中で細かく刻み、細胞混合物をセルストレーナー(100μm、BD Falcon)で濾過した。次に細胞を室温で530gで3分間遠心することによってペレットにした。細胞ペレットを、DMEM 1.0g/l グルコース(Life Technologies)および灌流緩衝液(1:1)の混合物中に再懸濁し、他の細胞種からの心筋細胞の分離は、6%ウシ血清アルブミン(BSA、Sigma)クッション上で15分間沈降させることによって実施した。心筋細胞ペレットを再懸濁し、2g/l BSA、2mM L−カルニチン(Sigma)、5mM クレアチニン(Sigma)、5mM タウリン(Sigma)、1mM 2,3−ブタンジオンモノオキシム(BDM;Sigma)を補給し、100U/mlのペニシリンおよび100μg/mlのストレプトマイシンを含むDMEM 1.0g/l グルコースにプレーティングした。ラミニン(Sigma)でコーティングした24ウェルプレートに細胞をプレーティングし、5%CO2および湿潤雰囲気中で37℃で維持した。培地は、24時間後に5% FBS、20μg/ml ビタミンB12を補給したDMEM 4.5g/l グルコースに交換し、以下に説明したように細胞を遺伝子導入した。
インビトロにおいて、選択したマイクロRNAで処理して心筋細胞増殖の増加が観察されたことを考え、これらのマイクロRNAがインビボにおいても増殖を増加させるかどうかを測定することを所望した。1例として、ここでは、選択したマイクロRNAの2つ、hsa−miR−199a−3pおよびhsa−miR−590−3p(それぞれインビトロにおいてマウスおよびラットの心筋細胞増殖の誘導を最も良く実施するマイクロRNA)の効果を示す。
新生仔ウィスターラット(出生後1日目)を氷床上で5分間冷却することによって麻酔した。皮膚切開後、肋間筋を切離することによって、第4肋間腔で側方開胸術を実施した。30ゲージ針を組み込んだインスリンシリンジ(Roche)を使用してマイクロRNA複合体を心臓内注射した後、新生仔を氷床から取り出し、胸壁および皮膚切開を縫合した。次に、新生仔を加熱ランプの下に置き、回復するまで数分間温めた。マイクロRNA複合体は、マイクロRNA(cel−miR−67、hsa−miR−590−3pまたはhsa−miR−199a−3pの約2.8μg、Dharmacon Thermo Scientific)をリポフェクタミンRNAimax遺伝子導入試薬(Invitrogen)と30分間室温で混合することによって調製した。ラット心臓毎に注射した混合物の全容量は、30μlであった。
インビトロおよびインビボにおいて選択したマイクロRNAで処理すると心筋細胞増殖の増加が観察されることを考慮して、マウスにおける心筋梗塞後の心臓機能に対するマイクロRNAの効果を評価した。
心筋梗塞は、雌CD1マウス(8〜12週齢)で、持続的な左冠動脈前下行枝(LAD)結紮によって作製した。簡単に説明すると、マウスにケタミンおよびキシラジンを腹腔内注射して麻酔し、気管内挿管し、げっ歯類人工呼吸器を装着した。体温は加熱パッドで37℃に維持した。左開胸術によって拍動する心臓に接近した。心膜除去後、LAD冠動脈の下行枝を、実体顕微鏡(Leica)で目視し、ナイロン製縫合糸で閉塞した。結紮は結紮直後に左心室領域が白くなることによって確認した。実施例5で説明したように作製した組換えAAVベクターを動物1匹当たり1×1011vgの用量で、LAD結紮直後に、梗塞領域辺縁の心筋に、30ゲージ針を組み込んだインスリンシリンジ(Roche)を使用して注射した(単回注射)。AAV−LacZ、AAV−hsa−miR−199aまたはAAV−hsa−miR−590を投与された動物3群(n=12/群)について研究した。胸部を閉じ、動物は自発呼吸が出現するまで腹臥位をとらせた。
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Claims (12)
- 心臓筋細胞増殖によって心臓の再生を刺激するための医薬として使用するための、ベクターを含む医薬組成物であって、
前記ベクターが、
ACUGCCCUAAGUGCUCCUUCUGG (配列番号1)、
CAGUGCCUCGGCAGUGCAGCCC (配列番号10)、
ACCUUCUUGUAUAAGCACUGUGCUAAA (配列番号33)、および
UCCAGUGCCCUCCUCUCC (配列番号35)
からなる群から選択される、少なくとも1種のマイクロRNA、もしくはかかるマイクロRNAの1次転写物、もしくはかかるマイクロRNAの前駆体、もしくはかかるマイクロRNAの模倣体、もしくはそれらの組み合わせ、および/または少なくとも前記マイクロRNAをコードするDNAおよび/または少なくとも前記マイクロRNAの1次転写物もしくは前駆体をコードするDNAまたはそれらの組み合わせを含む、
医薬組成物。 - 前記ベクターが、天然または人工のいずれかの、任意のキャプシド血清型のアデノ随伴ベクター(AAV)である、請求項1に記載の医薬組成物。
- 心臓筋細胞増殖を誘導することによって心臓の再生を刺激するための医薬として使用するための、
ACUGCCCUAAGUGCUCCUUCUGG (配列番号1)、
CAGUGCCUCGGCAGUGCAGCCC (配列番号10)、
ACCUUCUUGUAUAAGCACUGUGCUAAA (配列番号33)、および
UCCAGUGCCCUCCUCUCC (配列番号35)
からなる群から選択される、少なくとも1種のマイクロRNA、および/または前記マイクロRNAの1次転写物、および/または前記マイクロRNAの前駆体、および/または少なくとも前記マイクロRNA、1次転写物もしくは前駆体をコードするDNA、および/または少なくとも前記マイクロRNAの模倣体、またはそれらの組み合わせ、ならびに少なくとも1種の薬学的に許容される媒体または賦形剤を含む、
医薬組成物。 - 心臓筋細胞の喪失に関連した心臓病変の治療のための医薬として使用するための請求項3に記載の医薬組成物。
- 前記病変が、心筋梗塞、虚血性および非虚血性心筋症、心筋炎ならびに心不全の結果からなる群から選択される、請求項3または4に記載の医薬組成物。
- 投与が非経口静脈内、冠動脈内および心臓内からなる群から選択される、請求項3から5のいずれか一項に記載の医薬組成物。
- 脂質分子、ペプチド、ポリマーおよび他の担体分子をさらに含む、請求項3から6のいずれか一項に記載の医薬組成物。
- 脂質分子が陽イオン性脂質である、請求項7に記載の医薬組成物。
- 遺伝子療法において使用するための請求項3から8のいずれか一項に記載の医薬組成物。
- インビトロもしくはエキソビボにおける幹細胞由来の心筋細胞、または成体心筋細胞を拡大するための方法であって、前記細胞に請求項1に記載のマイクロRNAの少なくとも1種を添加することを含む、方法。
- 細胞培養において心筋細胞の増殖を刺激するための方法であって、前記細胞培養に請求項1に記載のマイクロRNAの少なくとも1種を添加することを含む、方法。
- 心臓筋細胞増殖によって心臓の再生を刺激するための医薬として使用するための、RNAストレッチを含む医薬組成物であって、
前記ストレッチが、
ACUGCCCUAAGUGCUCCUUCUGG (配列番号1)、
CAGUGCCUCGGCAGUGCAGCCC (配列番号10)、
ACCUUCUUGUAUAAGCACUGUGCUAAA (配列番号33)、および
UCCAGUGCCCUCCUCUCC (配列番号35)
からなる群から選択されるマイクロRNA、ならびに/または
それらの1次転写物、前駆体もしくは模倣体の少なくとも1種または組み合わせを含み、
前記RNAストレッチが、無細胞転写法によってインビトロで得られるか、合成によって生成されるか、関連するDNAコーディング配列の移入によって細胞中で発現されるか、またはプラスミド、ウイルスもしくは他の種類のベクターの投与によって細胞内に導入もしくは発現される、
医薬組成物。
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US20220228143A1 (en) | 2022-07-21 |
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