biostudies-literatureUnknown33(1)Keshavan NPrimary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-<i>hDGUOK</i> intravenously to newborn <i>Dguok</i> knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.Molecular therapy. Methods & clinical development101397https://www.ebi.ac.uk/biostudies/studies/S-EPMC11782815biostudies-literatureGene therapy prevents hepatic mitochondrial dysfunction in murine deoxyguanosine kinase deficiency.PMC11782815Sebire NKarda RRahman SPrunty HPrivolizzi RKeshavan NDiaz JAGreenwood MCounsell JWaddington SKarlsson AfalseGene therapy prevents hepatic mitochondrial dysfunction in murine deoxyguanosine kinase deficiency.Primary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-<i>hDGUOK</i> intravenously to newborn <i>Dguok</i> knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.2025-01-01T00:00:00Z2025 Mar2025-04-04T23:11:28.435Z2025-04-04T23:11:28.435ZS-EPMC117828153989764010.1016/j.omtm.2024.101397