AAV Gene Therapy Ameliorates Leigh-Like Cardiomyopathy from Cardiac COX15 Deletion

Mitochondrial disorders are a clinically and genetically heterogeneous set of diseases caused by mutations in mitochondrial or nuclear genes. Cardiomyopathy is a common and severe manifestation of these disorders, yet its pathogenesis remains poorly understood and therapeutic options are limited. In this thesis, we explored the effects of cardiomyocyte-specific ablation of COX15, a nuclear-encoded factor essential for heme A biosynthesis and cytochrome c oxidase assembly, by using a Cox15 f/f ::MerCreMer mouse model in which tamoxifen induces Cre recombinase expression in the heart. Targeted deletion of Cox15 caused a dilated cardiomyopathy with reduced ejection fraction, recapitulating the cardiac phenotype of Leigh syndrome patients. AAV-mediated delivery of a functional COX15 transgene partially restored complex IV activity and improved cardiac contractility. These findings highlight the indispensable role of COX15 in cardiac function and the therapeutic potential of gene replacement strategies for mitochondrial cardiomyopathies