Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1R671C/- mice

Hepatoencephalopathy due to mutations in the nuclear gene GFM1, known as combined oxidative phosphorylation (OXPHOS) deficiency type I (COXPD1), is an autosomal recessive mitochondrial disease caused by defects or deficiency of the mitochondrial translation elongation factor G1 (EFG1), with no currently available cure. Patients with COXPD1 develop a severe encephalopathy, sometimes combined with liver failure, with neonatal onset and rapid progression that normally causes premature death. The Gfm1R671C/- mouse recapitulates the COXPD1 molecular phenotype in liver and brain, with drastic reduction of EFG1 levels, impaired mitochondrial translation, and OXPHOS deficiency. We conducted a gene therapy study using two different recombinant adeno-associated virus (rAAV) vectors targeting the liver or the brain to introduce the human GFM1 gene into 6-week-old Gfm1R671C/- mice. Successful transduction of the liver and the brain was observed after four weeks, entailing substantial recovery from mitochondrial EFG1 depletion and OXPHOS correction in both tissues, which demonstrates that transgenic human EFG1 is functional in mouse mitochondrial translation. Our study constitutes the first evidence supporting AAV-mediated gene therapy as a potential treatment for COXPD1.