Gene Therapy Center; Department of Pediatrics; Department of Biochemistry and Molecular Pharmacology
Acyl-CoA Dehydrogenase, Long-Chain; Dependovirus; Gene Therapy; Genetic Vectors
Allergy and Immunology | Genetics and Genomics | Pediatrics
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 x 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 degrees 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.
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DOI of Published Version
Mol Ther. 2012 Jun;20(6):1131-8. doi: 10.1038/mt.2012.39. Epub 2012 Mar 6. Link to article on publisher's site
Molecular therapy : the journal of the American Society of Gene Therapy
Keeler AM, Conlon TJ, Walter G, Zeng H, Shaffer SA, Dungtao F, Erger KE, Cossette TL, Tang Q, Mueller C, Flotte TR. (2012). Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy. Pediatric Publications. https://doi.org/10.1038/mt.2012.39. Retrieved from https://escholarship.umassmed.edu/peds_pp/11