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: Allison M Keeler, Thomas Conlon, Glenn Walter, Huadong Zeng, Scott A Shaffer, Fu Dungtao, Kirsten Erger, Travis Cossette, Qiushi Tang, Christian Mueller, Terence R Flotte
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 20 Issue 6 Pg. 1131-8 (Jun 2012) ISSN: 1525-0024 [Electronic] United States
• PMID: 22395529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• acylcarnitine
• Acyl-CoA Dehydrogenase, Long-Chain
• Carnitine

Topics

• Acyl-CoA Dehydrogenase, Long-Chain (deficiency, genetics)
• Animals
• Carnitine (analogs & derivatives, blood)
• Congenital Bone Marrow Failure Syndromes
• Dependovirus (genetics)
• Gene Expression
• Genetic Therapy
• Genetic Vectors (administration & dosage, pharmacokinetics)
• Lipid Metabolism
• Lipid Metabolism, Inborn Errors (genetics, therapy)
• Liver (metabolism)
• Mice
• Mice, Knockout
• Mitochondrial Diseases (genetics, therapy)
• Muscle, Skeletal (metabolism)
• Muscular Diseases (genetics, therapy)
• Phenotype
• Tissue Distribution
• Transduction, Genetic