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

Rationale: Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (). 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 knockout mice (TAZ-KO) and cardiomyocyte-specific knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with human (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 in cardiomyocytes using caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of replacement by 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 knockout mice models. However, both neonatal and adult therapies required high cardiomyocyte transduction (≈70%) for durable efficacy.

Conclusions: TAZ-KO and cardiomyocyte-specific 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.