title: Biochemical correction of very long-chain acyl-CoA dehydrogenase deficiency following adeno-associated virus gene therapy.
abstract: We report the development of a gene replacement strategy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. VLCAD is a mitochondrial enzyme involved in fatty acid beta-oxidation, a key step in energy production during times of fasting or stress. Deficiency of VLCAD classically presents as hepatic dysfunction, hypoglycemia, cardiomyopathy, rhabdomyolysis, and/or sudden death. While dietary therapy for VLCAD deficiency has proven beneficial in preventing some symptoms, a risk of metabolic catastrophic decompensation remains throughout life during times of increased energy demand. We designed a recombinant adeno-associated virus (AAV) expressing the human VLCAD gene (AAV8-hVLCAD). To demonstrate its in vivo activity, AAV8-hVLCAD was administered via the tail vein to VLCAD-knockout mice. A reduction in accumulated serum long-chain acylcarnitines and increased fasting tolerance judged on blood glucose concentrations were observed as of 11 days postinjections through >100 days. Western analysis of liver, skeletal muscle, and heart extracts using PEP1 anti-hVLCAD antibody revealed short-term hVLCAD expression in the liver and muscle and longer-term expression in heart. This demonstrates the ability of human VLCAD to correct the biochemical phenotype of VLCAD-deficient mice.
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington 98105, USA. lawrence.merritt@seattlechildrens.org
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Merritt
authors.forename: Tien
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jan
authors.initials: J
authors.lastname: Daniels
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: David B
authors.initials: DB
authors.lastname: Schowalter
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005215:Fasting; D015316:Genetic Therapy; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000201:enzymology / Q000235:genetics; D051379:Mice; D009928:Organ Specificity
chemical_list: D044942:Acyl-CoA Dehydrogenase, Long-Chain