JP2013532141A - miR−378による代謝調節 - Google Patents
miR−378による代謝調節 Download PDFInfo
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- JP2013532141A JP2013532141A JP2013513412A JP2013513412A JP2013532141A JP 2013532141 A JP2013532141 A JP 2013532141A JP 2013513412 A JP2013513412 A JP 2013513412A JP 2013513412 A JP2013513412 A JP 2013513412A JP 2013532141 A JP2013532141 A JP 2013532141A
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Abstract
【選択図】 図13A−B
Description
本出願は、2010年6月4日出願の米国仮出願第61/351,683号(その全体が参照により本明細書に組み入れられるものとする)に基づく優先権を主張する。
添付の電子申請テキストファイル、すなわち、配列リストのコンピューター可読形式コピー(ファイル名:MIRG_022_01WO_SeqList_ST25.txt、記録日:2011年6月6日、ファイルサイズ5キロバイト)の内容は、その全体が参照により本明細書に組み入れられるものとする。
本発明は、マイクロRNA(miRNA)の活性または発現を変調する作用剤を投与することによる心臓障害および代謝障害の治療および予防に関する。特定的には、本発明は、被験体の細胞内でmiR−378/miR−378*の発現または活性を阻害することにより心臓障害および代謝障害を治療または予防する方法を提供する。それに加えて、本発明は、細胞をmiR−378/miR−378*の発現または活性のモジュレーターに接触させることにより細胞内で脂肪酸代謝を調節する方法を提供する。
現在の米国では、冠動脈疾患、心筋梗塞、鬱血性心不全、および心肥大を含めて、心疾患およびその症状は、明らかに主要な健康リスクを呈する。これらの疾患に罹患している患者の診断、治療、および支援にかかるコストは、何十億ドルにも及ぶ。心疾患の2つのとくに重篤な症状は、心筋梗塞および心肥大である。
本発明は、部分的には、miR−378の発現が、圧負荷後、心臓組織でダウンレギュレートされ、かつ心臓特異的なmiR−378の過剰発現が、ストレスにより誘導される心肥大応答を悪化させるという発見に基づく。骨格筋中でのmiR−378/miR−378*の過剰発現は、脂肪細胞肥大およびおそらく脂肪細胞過形成に基づいて精巣上体脂肪パッドの質量増加から生じる体重増加を生じる。かくして、本発明者らは、驚くべきことに、iR−378/miR−378*が、心臓組織および脂肪組織を含めて、さまざまな組織で代謝過程を調節することを見いだした。したがって、本発明は、処置の必要な被験体の細胞内でmiR−378および/またはmiR−378*の発現または活性を変調することにより、肥満症や糖尿病などの心血管疾患および他の代謝障害を治療または予防する方法を提供する。
心臓への慢性および急性のストレスの結果として、肥大、繊維化、筋細胞アポトーシスを伴った病理学的リモデリング応答を生じ、そして心力不全および不整脈による最終的な死に至る。古典的な薬理学的治療戦略(たとえば、β−ブロッカーおよびACE阻害剤)は心不全患者の生存を延長し得るが、これらの療法は、最終的には、疾患の進行の予防に効果的でないので、新しい機序的洞察および治療手段の必要性が高い。
ヒト成熟miR−378(配列番号1)
5’−ACUGGACUUGGAGUCAGAAGG−3’
ヒトmiR−378*(配列番号2)
5’−CUCCUGACUCCAGGUCCUGUGU−3’
ヒトpre−miR−378(配列番号3)
5’−AGGGCUCCUGACUCCAGGUCCUGUGUGUUACCUAGAAAUAGCACUGGACUUGGAGUCAGAAGGCCU−3’
マウス成熟miR−378(配列番号4)
5’−ACUGGACUUGGAGUCAGAAGG−3’
マウスmiR−378*(配列番号5)
5’−CUCCUGACUCCAGGUCCUGUGU−3’
マウスpre−miR−378(配列番号6)
5’−AGGGCUCCUGACUCCAGGUCCUGUGUGUUACCUCGAAAUAGCACUGGACUUGGAGUCAGAAGGCCU−3’
αミオシン重鎖プロモーター(Yamauchi-Takihara et al. (1989) Proc. Nail. Acad. Sci. USA, Vol. 86(10):3504-3508)、ならびにANFプロモーター(LaPointe el al. (1988) J. Biol. Chem. , Vol. 263(19):9075-9078)が含まれる。一実施形態では、組織特異的プロモーターは、脂肪細胞タンパク質2(ap2)/脂肪酸結合性タンパク質4(FABP4)プロモーターまたはPPARyプロモーターなどの脂肪細胞特異的プロモーターである。
実施例1.miR−378/miR−378*は高ミトコンドリア組織中で高度に発現される
心不全でのmiRNAの発現プロファイリングは、以前に心疾患のマウスモデルを用いて報告されている。(van Rooij et al. (2006) Proc. Natl. Acad. Sci. USA, Vol. 103 : 18255-18260)圧負荷により誘導された肥大心臓から得られた組織で行われたマイクロRNAマイクロアレイ解析では、カルシニューリン過剰発現またはイソプロテレノール投与により、miR−378(GeneID:723889)が、これらの条件下で最もロバストに調節されたmiRNAの1つであることが明らかにされた。miR−378はまた、心筋梗塞でダウンレギュレートされることから、miR−378が心臓ストレス応答プログラムの重要な決定要因であるというさらなる証拠が提供される(van Rooij et al. (2008) Proc. Natl. Acad. Sci. USA, Vol. 105: 13027-13032)。miR−378は、ネズミ18番染色体上のペルオキシソーム増殖因子活性化受容体γコアクチベーター1−β(PPARGC1β、GeneID:170826)遺伝子の最初のイントロン内に位置する(図1A)。
心疾患におけるmiR−378の役割をさらに解明するために、野生型マウスで胸部大動脈絞扼(TAB)による心肥大の誘導の後、心臓組織でmiR−378発現を評価した。特定的には、大動脈を27ゲージ針の直径に縫合して、心臓に圧負荷を誘導し、高血圧を模倣した。対照動物は、大動脈を変化させない偽手術に付した。TAB手順の21日後に単離された心臓組織のマイクロRNAマイクロアレイ解析およびリアルタイムPCRから、miR−378が圧負荷に応答してダウンレギュレートされることが判明した(図2A)。
骨格筋でmiR−378の過剰発現の効果を調べるために、筋クレアチンキナーゼ(MCK)プロモーターの制御下でmiR−378/miR−378*を過剰発現するトランスジェニックマウスを作製した。CKmiR−378トランスジェニック動物の予備調査では、miR−378は、グルコースおよび脂肪酸利用を変調することが判明した。特定的には、より高年齢(10ヶ月齢)のトランスジェニック動物は、野生型同腹仔よりも有意に体重増加した(図3)。野生型動物と比較して、体重の差は、突然変異型動物の精巣上体白色脂肪パッドの増大された重量に起因した(図3)。白色脂肪組織の組織学的解析は、miR−378−過剰発現するマウス(図3)の脂肪細胞肥大を示した。MCKmiR−378トランスジェニック動物の脂肪細胞中のトリグリセリドの増大された蓄積は、おそらく増大されたインスリン抵抗性およびグルコース利用の全体的な欠損の結果である。
グルコース利用の調節におけるmiR−378の役割をさらに調べるために、骨格筋(MCK−miR−378 Tg; 実施例3参照)でmiR−378を過剰発現するトランスジェニックマウスを耐グルコース能試験(GTT)に付して、血液からのグルコースのクリアランスの欠損の可能性を検出する。マウスを16時間絶食させ、続いて、1.5g/kgのグルコースを腹腔内(i.p.)に注射した。グルコース注射前ならびにグルコース注射の15、30、60、および120分間後に血液サンプルを取得した。図5に示されるように、血糖値は、野生型マウスと比較して、miR−378トランスジェニックマウスで高く、血液からグルコースのクリアランスは遅れた。これらの結果から、骨格筋でmiR−378を過剰発現させると、おそらく、これらの動物インスリン抵抗性の増大するため、耐グルコース能が低下する。
miR−378/miR−378*の機能をin vivoで調べるために、miR−378/miR−378*の遺伝子欠失を有するマウス系列を作製した。ターゲッティングベクターおよび相同的組換え(図8A)を用いて、miR−378/miR−378*を標的とし、遺伝子欠失の生殖系列伝播をサザンブロット分析を用いて確認した(図8B)。ノーザンブロット解析では、miR−378グローバル突然変異体で調べられたすべての組織でmiR−378/miR−378*発現の損害を確認した、(図8C)。PPARGC1βに対してTaqmanプローブを用いたリアルタイムPGR解析およびPPARGC1β(PGC−1β)に対するウェスタンブロット解析により、PPARGC1β(PGC−1β)発現がmiR−378ノックアウト動物で変化しないことが示された(図8D)。
アンチセンスオリゴヌクレオチドを用いたmiR−378の阻害は、2型糖尿病のモデルである肥満(ob/ob)マウスでグルコース利用の改善をもたらした(実施例4参照)。代謝の調節におけるmiR−378/miR−378*の役割をさらに探究するために、miR−378ノックアウトマウス(実施例5参照)を肥満マウスと交配し、グルコース利用を評価した。マウスを16時間絶食させ、1.5g/kgグルコースを腹腔内に注射した。血糖値を評価するために、注射後種々の時間間隔で血液サンプルを取得した。図12に示されるように、肥満(ob/ob)動物と比較して、miR−378ノックアウトおよびob/ob交配(ob/ob KO)の子孫は、改善された耐グルコース能を呈す。
Claims (48)
- 治療または予防の必要な被験体において、病的心肥大、心臓リモデリング、心筋梗塞、または心不全を治療または予防する方法であって、前記被験体にmiR−378および/またはmiR−378*の阻害剤を投与することを含む、方法。
- 前記阻害剤の投与後、前記被験体の心臓細胞でmiR−378および/またはmiR−378*の発現または活性が低減される、請求項1に記載の方法。
- miR−378および/またはmiR−378*の前記阻害剤がアンチセンスオリゴヌクレオチドである、請求項1に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、miR−378および/またはmiR−378*の成熟配列に少なくとも部分的には相補的な配列を含む、請求項3に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、配列番号1または配列番号2に少なくとも部分的に相補的な配列を含む、請求項4に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが少なくとも1つの糖修飾および/または骨格修飾を含む、請求項4に記載の方法。
- 前記糖修飾がロックド核酸である、請求項6に記載の方法。
- 前記骨格修飾がホスホロチオエート結合である、請求項6に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが約7〜約18ヌクレオチド長である、請求項4に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、および配列番号22からなる群から選択される配列を有する、請求項4に記載の方法。
- 前記被験体がヒトである、請求項1に記載の方法。
- 前記阻害剤が、皮内、皮下、筋肉内、腹腔内、もしくは静脈内投与経路により、または心臓組織中への直接注射により、前記被験体に投与される、請求項1に記載の方法。
- 治療または予防の必要な被験体の代謝障害を治療または予防する方法であって、miR−378および/またはmiR−378*の阻害剤を前記被験体に投与することを含み、投与後、前記被験体の細胞でmiR−378および/またはmiR−378*の発現または活性が低減される、方法。
- 前記代謝障害が、メタボリック症候群、肥満症、糖尿病、糖尿病性腎症、インスリン抵抗性、アテローム硬化症、脂質蓄積障害、糖原病、中鎖アシル−補酵素Aデヒドロゲナーゼ欠損、または異常なグルコース取込みおよび/もしくは利用である、請求項13に記載の方法。
- 前記脂質蓄積障害が、ニーマン・ピック病、ゴーシェ病、ファーバー病、ファブリ病、ウォルマン病、およびコレステリルエステル蓄積症からなる群から選択される、請求項14に記載の方法。
- 前記miR−378および/またはmiR−378*の阻害剤がアンチセンスオリゴヌクレオチドである、請求項13に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、miR−378および/またはmiR−378*の成熟配列に少なくとも部分的に相補的な配列を含む、請求項16に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、配列番号1または配列番号2に少なくとも部分的に相補的な配列を含む、請求項17に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが少なくとも1つの糖修飾および/または骨格修飾を含む、請求項17に記載の方法。
- 前記糖修飾がロックド核酸である、請求項19に記載の方法。
- 前記骨格修飾がホスホロチオエート結合である、請求項19に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが約7〜約18ヌクレオチド長である、請求項17に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、および配列番号22からなる群から選択される配列を有する、請求項17に記載の方法。
- 前記被験体がヒトである、請求項13に記載の方法。
- 前記阻害剤が、皮内、皮下、筋肉内、腹腔内、または静脈内投与経路により前記被験体に投与される、請求項13に記載の方法。
- 細胞の脂肪酸代謝を調節する方法であって、前記細胞をmiR−378および/またはmiR−378*の発現または活性のモジュレーターに接触させることを含む、方法。
- 前記モジュレーターがmiR−378および/またはmiR−378*の発現または活性の阻害剤である、請求項26に記載の方法。
- 脂肪酸代謝が、前記miR−378および/またはmiR−378*阻害剤との接触後の細胞において、前記阻害剤に暴露されなかった細胞と比較して、増大する、請求項27に記載の方法。
- 前記miR−378および/またはmiR−378*の阻害剤がアンチセンスオリゴヌクレオチドである、請求項27に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが、miR−378および/またはmiR−378*の成熟配列に少なくとも部分的に相補的な配列を含む、請求項29に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが少なくとも1つの糖修飾および/または骨格修飾を含む、請求項30に記載の方法。
- 前記糖修飾がロックド核酸である、請求項31に記載の方法。
- 前記骨格修飾がホスホロチオエート結合である、請求項31に記載の方法。
- 前記アンチセンスオリゴヌクレオチドが約7〜約18ヌクレオチド長である、請求項30に記載の方法。
- 前記モジュレーターがmiR−378および/またはmiR−378*の発現または活性のアゴニストである、請求項26に記載の方法。
- 脂肪酸代謝が、前記miR−378および/またはmiR−378*アゴニストとの接触後の細胞において、前記アゴニストに暴露されなかった細胞と比較して、増大する、請求項35に記載の方法。
- 前記アゴニストがmiR−378および/またはmiR−378*の成熟配列を含むポリヌクレオチドである、請求項35に記載の方法。
- 前記細胞が、心筋細胞、骨格筋細胞、前脂肪細胞、または脂肪細胞である、請求項26に記載の方法。
- 前記細胞がin vitroまたはin vivoである、請求項26に記載の方法。
- miR−378および/またはmiR−378*の阻害剤と薬学的に許容可能な担体とを含む医薬組成物。
- miR−378および/またはmiR−378*の前記阻害剤がアンチセンスオリゴヌクレオチドである、請求項40に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドが、miR−378および/またはmiR−378*の成熟配列に少なくとも部分的に相補的な配列を含む、請求項41に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドが、配列番号1または配列番号2に少なくとも部分的に相補的な配列を含む、請求項42に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドが少なくとも1つの糖修飾および/または骨格修飾を含む、請求項42に記載の組成物。
- 前記糖修飾がロックド核酸である、請求項44に記載の組成物。
- 前記骨格修飾がホスホロチオエート結合である、請求項44に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドは約7〜約18ヌクレオチド長である、請求項42に記載の組成物。
- 前記アンチセンスオリゴヌクレオチドが、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、および配列番号22からなる群から選択される配列を有する、請求項42に記載の組成物。
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CN103038349B (zh) | 2015-08-12 |
EP2576785A2 (en) | 2013-04-10 |
CA2801342A1 (en) | 2011-12-08 |
EP2576785A4 (en) | 2014-12-24 |
WO2011153542A3 (en) | 2012-02-23 |
RU2585491C2 (ru) | 2016-05-27 |
US8716258B2 (en) | 2014-05-06 |
AU2011261213B2 (en) | 2015-05-21 |
JP6109069B2 (ja) | 2017-04-05 |
CN103038349A (zh) | 2013-04-10 |
RU2013100002A (ru) | 2014-07-20 |
WO2011153542A2 (en) | 2011-12-08 |
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