title: Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy.
abstract: Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 10(12) vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD(-/-) mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD(-/-) mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD(-/-) mice maintained euglycemia, whereas untreated VLCAD(-/-) mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.
authors.affiliation: Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Keeler
authors.forename: Thomas
authors.initials: T
authors.lastname: Conlon
authors.forename: Glenn
authors.initials: G
authors.lastname: Walter
authors.forename: Huadong
authors.initials: H
authors.lastname: Zeng
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.forename: Fu
authors.initials: F
authors.lastname: Dungtao
authors.forename: Kirsten
authors.initials: K
authors.lastname: Erger
authors.forename: Travis
authors.initials: T
authors.lastname: Cossette
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Tang
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D000080984:Congenital Bone Marrow Failure Syndromes; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D050356:Lipid Metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics / Q000628:therapy*; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics / Q000628:therapy*; D010641:Phenotype; D014018:Tissue Distribution; D014161:Transduction, Genetic
chemical_list: C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine