Systemic correction of a fatty acid oxidation defect by intramuscular injection of a recombinant adeno-associated virus vector

Thomas J. Conlon, Glenn Walter, Renius Owen, Travis Cossette, Kirsten Erger, Greg Gutierrez, Eric Goetzman, Dietrich Matern, Jerry Vockley, Terence R. Flotte

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Mitochondrial β-oxidation of fatty acids is required to meet physiologic energy requirements during illness and periods of fasting or physiologic stress, and is most active in liver and striated muscle. Acyl-CoA dehydrogenases of varying chain-length specificities represent the first step in the mitochondria for each round of β-oxidation, each of which removes two-carbon units as acetyl-CoA for entry into the tricarboxylic acid cycle. We have used recombinant adeno-associated virus (rAAV) vectors expressing short-chain acyl-CoA dehydrogenase (SCAD) to correct the accumulation of fatty acyl-CoA intermediates in deficient cell lines. The rAAV-SCAD vector was then packaged into either rAAV serotype 1 or 2 capsids and injected intramuscularly into SCAD-deficient mice. A systemic effect was observed as judged by restoration of circulating butyryl-carnitine levels to normal. Total lipid content at the injection site was also decreased as demonstrated by noninvasive magnetic resonance spectroscopy (MRS). SCAD enzyme activity in the injected muscle was found at necropsy to be above the normal control mouse level. This study is the first to demonstrate the systemic correction of a fatty acid oxidation disorder with rAAV and the utility of MRS as a noninvasive method to monitor SCAD correction after in vivo gene therapy.

Original languageEnglish (US)
Pages (from-to)71-80
Number of pages10
JournalHuman gene therapy
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Conlon, T. J., Walter, G., Owen, R., Cossette, T., Erger, K., Gutierrez, G., Goetzman, E., Matern, D., Vockley, J., & Flotte, T. R. (2006). Systemic correction of a fatty acid oxidation defect by intramuscular injection of a recombinant adeno-associated virus vector. Human gene therapy, 17(1), 71-80. https://doi.org/10.1089/hum.2006.17.71