Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy
Authors
Keeler, Allison M.Conlon, Thomas J.
Walter, Glenn
Zeng, Huadong
Shaffer, Scott A.
Dungtao, Fu
Erger, Kirsten E.
Cossette, Travis L.
Tang, Qiushi
Mueller, Christian
Flotte, Terence R.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDepartment of Pediatrics
Gene Therapy Center
Document Type
Journal ArticlePublication Date
2012-06-01Keywords
Acyl-CoA Dehydrogenase, Long-ChainDependovirus
Gene Therapy
Genetic Vectors
Allergy and Immunology
Genetics and Genomics
Pediatrics
Metadata
Show full item recordAbstract
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.Source
Mol Ther. 2012 Jun;20(6):1131-8. doi: 10.1038/mt.2012.39. Epub 2012 Mar 6. Link to article on publisher's siteDOI
10.1038/mt.2012.39Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43542PubMed ID
22395529Related Resources
Link to Article in PubMedRights
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.ae974a485f413a2113503eed53cd6c53
10.1038/mt.2012.39