Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD
Gene Therapy Center; Department of Pediatrics
Actins; Animals; Butyryl-CoA Dehydrogenase; Carnitine; Cytomegalovirus; *Dependovirus; *Gene Therapy; Genetic Vectors; Injections, Intravenous; *Liver; Metabolism, Inborn Errors; Mice; Mice, Mutant Strains; Portal Vein; Promoter Regions, Genetic; Transduction, Genetic
Allergy and Immunology | Genetics and Genomics | Pediatrics
Recombinant adeno-associated viral vectors pseudotyped with serotype 5 and 8 capsids (AAV5 and AAV8) have been shown to be efficient gene transfer reagents for the liver. We have produced AAV5 and AAV8 vectors that express mouse short-chain acyl-CoA dehydrogenase (mSCAD) cDNA under the transcriptional control of the cytomegalovirus-chicken beta-actin hybrid promoter. We hypothesized that these vectors would produce sufficient hepatocyte transduction (after administration via the portal vein) and thus sufficient SCAD enzyme to correct the phenotype observed in the SCAD-deficient (BALB/cByJ) mouse, which includes elevated blood butyrylcarnitine and hepatic steatosis. Ten weeks after portal vein injection into 8-week-old mice, AAV8-treated livers contained acyl-CoA dehydrogenase activity (14.3 mU/mg) toward butyryl-CoA, compared with 7.6 mU/mg in mice that received phosphate-buffered saline. Immunohistochemistry showed expression of mSCAD within rAAV8-mSCAD-transduced hepatocytes, as seen by light microscopy. A significant reduction of circulating butyrylcarnitine was seen in AAV5-mSCAD- and AAV8-mSCAD-injected mice. Magnetic resonance spectroscopy of fasted mice demonstrated a significant reduction in relative lipid content within the livers of AAV8-mSCAD-treated mice. These results demonstrate biochemical correction of SCAD deficiency after AAV8-mediated SCAD gene delivery.
DOI of Published Version
Hum Gene Ther. 2008 Jun;19(6):579-88. Link to article on publisher's site
Human gene therapy
Beattie, Stuart G.; Goetzman, Eric; Conlon, Thomas; Germain, Sean; Walter, Glenn; Campbell-Thompson, Martha; Matern, Dietrich; Vockley, Jerry; and Flotte, Terence R., "Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD" (2008). Pulmonary and Allergy. 24.