AAV9-mediated gene therapy restores liver function in the MEGDHEL mouse model.

MEGDHEL syndrome is a severe mitochondrial disorder caused by mutations in the SERAC1 gene, characterized by sensorineural deafness, encephalopathy, hepatopathy, and Leigh-like syndrome. A hallmark feature is neonatal liver failure, often leading to high mortality. There is currently no effective treatment. In this study, we used AAV9-SERAC1 gene therapy to address liver dysfunction and mitochondrial impairments in the Serac1-/- mouse model. Treatment with 4 × 1011 viral genomes led to improvements in liver histology, including reduced fatty degeneration and cholesterol accumulation, as well as enhanced mitochondrial morphology and function. Transmission electron microscopy revealed restored mitochondrial cristae and an increased number of mitochondria in treated mice. Respiratory complex showed activity recovery and mitochondrial DNA content was increased. Behavioral assessments also demonstrated significant improvements in motor coordination, with treated mice showing enhanced grasping strength and balance compared to controls. These findings suggest that AAV9-SERAC1 gene therapy can improve liver function and locomotor abilities in Serac1-/- mice, offering a promising therapeutic strategy for MEGDHEL syndrome.