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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 germlineTAZ knockout mice (TAZ-KO) and cardiomyocyte-specificTAZ knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with humanTAZ (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 floxedTaz in cardiomyocytes usingMyh6-Cre caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability ofTaz replacement byAAV 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-specificTAZ knockout mice models. However, both neonatal and adult therapies required high cardiomyocyte transduction (≈70%) for durable efficacy.Conclusions: TAZ-KO and cardiomyocyte-specificTAZ 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.

AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome