Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia
Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia
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DOI：
10.1038/nm.3510
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发表时间：
2014-05-01
期刊：
影响因子：
82.9
通讯作者：
Puccio, Helene
中科院分区：
文献类型：
--
作者：
Perdomini, Morgane;Belbellaa, Brahim;Puccio, Helene
心脏衰竭是弗里德赖希共济失调 (FRDA) 死亡的最常见原因，FRDA 是一种以神经变性、肥厚性心肌病和糖尿病为特征的线粒体疾病(1-3)。 FRDA 是由 frataxin (FXN) 水平降低引起的，FXN 是参与铁硫 (Fe-S) 簇生物合成的重要线粒体蛋白 (4-8)。 FRDA(9-12) 患者的心肌会出现线粒体氧化磷酸化受损、生物能失衡、Fe-S 簇酶缺乏和线粒体铁超载的情况。 FRDA 心肌病尚无治疗方法(13,14)。心脏和骨骼肌中完全缺失 frataxin 的条件小鼠模型（Mck-Cre-Fxn(L3/L-) 小鼠）概括了 FRDA 心肌病的大多数特征，尽管病程更快、更严重 (15,16)。在这里，我们表明，向这些小鼠静脉注射表达人 FXN 的腺相关病毒 rh10 载体完全预防了心脏病的发作。此外，在心力衰竭发作后，随后给予表达frataxin的载体，能够在几天内在功能、细胞和分子水平上完全逆转这些小鼠的心肌病。我们的结果表明，基因治疗可以快速挽救和重塑严重能量衰竭和超微结构紊乱的心肌细胞，并为基因治疗治疗 FRDA 心肌病的潜力提供临床前概念证明。
Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes(1-3). FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters(4-8). Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA(9-12). No treatment exists as yet for FRDA cardiomyopathy(13,14). A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn(L3/L-) mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course(15,16). Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin-expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy.