187. AAV Delivery of Tafazzin for the Correction of Mitochondrial Dysfunction in Barth Syndrome Using IPS Differentiated Cardiomyocytes

Barth Syndrome (BTHS) is caused by a single gene mutation affecting mitochondria and resulting in dilated cardiomyopathy, growth delay, neutropenia and severe exercise intolerance. This gene, Tafazzin (TAZ) located at Xq28, is responsible for cardiolipin (CL) remodeling in the inner mitochondrial membrane. Mutation/s in TAZ result in altered remodeling of CL and increasing Monolysocardiolpin (MLCL): CL ratios. This imbalance leads to abnormal mitochondrial cristae formation and decreased oxidative phosphorylation resulting in decreased ATP production and energy metabolism. Since BTHS is the result of a single gene defect, it is an ideal candidate for treatment by gene therapy. Therefore, we hypothesized that delivery of TAZ by adeno-associated virus (AAV) should increase TAZ gene expression and function, correcting the CL remodeling. Preliminary data, using fibroblasts directly differentiated to muscle resulted in increased gene expression of TAZ and a return to normal levels of CL. To further evaluate this gene therapy for effectiveness in the heart, we utilized patient derived induced pluripotent stem cells (IPSC) which were differentiated to cardiomyocytes. Upon confirmation of differentiation, control and diseased cells were treated with either AAV-TAZ or sham. TAZ gene and protein expression were measured as well as TAZ function through CL analysis. Muscle weakness and exercise intolerance have been described by patients, therefore to further stress the cardiomyocytes, cells were placed in hypoxia under nutrient limiting conditions and ATP production measured after 24 hours. Additional studies are being performed to evaluate mitochondrial activity as well as preclinical in vivo analysis.