RATIONALE Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper genetic animal model that recapitulates the features of Barth syndrome has hindered understanding of disease pathogenesis and therapeutic development. OBJECTIVE We characterized murine germline TAZ knockout mice (TAZ-KO) and cardiomyocyte-specific TAZ knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with human TAZ (hTAZ). METHODS AND RESULTS TAZ-KO caused embryonic and neonatal lethality, impaired growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac dysfunction, and fibrosis. Cardiomyocyte-specific inactivation of floxed Taz in cardiomyocytes using Myh6-Cre caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of Taz replacement by AAV gene therapy. Neonatal AAV-hTAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and cardiomyocyte-specific TAZ knockout mice models. However, both neonatal and adult therapies required high cardiomyocyte transduction (≈70%) for durable efficacy. CONCLUSIONS TAZ-KO and cardiomyocyte-specific TAZ knockout mice recapitulate many of the key clinical features of Barth syndrome. AAV-mediated gene replacement is efficacious when a sufficient fraction of cardiomyocytes are transduced.

中文翻译：

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AAV 基因疗法可预防和逆转巴斯综合征小鼠敲除模型中的心力衰竭。

基本原理 Barth 综合征是一种由 Tafazzin (TAZ) 基因突变引起的 X 连锁心脏和骨骼肌病。目前，巴特综合征尚无针对性治疗方法。缺乏概括巴特综合征特征的适当遗传动物模型阻碍了对疾病发病机制和治疗方法的了解。目的 我们对鼠种系 TAZ 敲除小鼠 (TAZ-KO) 和心肌细胞特异性 TAZ 敲除小鼠模型进行了表征，并测试了腺相关病毒 (AAV) 介导的人 TAZ (hTAZ) 基因替代疗法的功效。方法和结果 TAZ-KO 导致胚胎和新生儿死亡、生长受损、扩张型心肌病和骨骼肌病。新生儿期幸存的 TAZ-KO 小鼠出现进行性、严重的心脏功能障碍和纤维化。使用 Myh6-Cre 对心肌细胞中 floxed Taz 进行心肌细胞特异性灭活，导致进行性扩张型心肌病，但没有胎儿或围产期损失。使用组成型和条件性敲除模型，我们测试了 AAV 基因疗法替代 Taz 的功效和持久性。新生儿 AAV-hTAZ 可挽救 TAZ-KO 小鼠的新生儿死亡、心脏功能障碍和纤维化，并预防和逆转 TAZ-KO 和心肌细胞特异性 TAZ 敲除小鼠模型中已建立的心脏功能障碍。然而，新生儿和成人治疗都需要高心肌细胞转导（约 70%）才能获得持久疗效。结论 TAZ-KO 和心肌细胞特异性 TAZ 敲除小鼠概括了 Barth 综合征的许多关键临床特征。当足够比例的心肌细胞被转导时，AAV 介导的基因替换是有效的。