Functional correction of short-chain acyl-CoA dehydrogenase deficiency in transgenic mice: implications for gene therapy of human mitochondrial enzyme deficiencies

We report the therapeutic effects of liver-specific expression of ashort-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD- deficientmouse model. Transgenic mice were produced with a rat albuminpromoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCADnormal genetic background and a SCAD-deficient background. In threetransgenic lines produced on the SCAD-deficient background, recombinantSCAD activity and antigen in liver mitochondria were found up to 7-fold ofnormal control values. All three lines showed a markedly reduced organicaciduria and fatty liver, which are sensitive indicators of the metabolicabnormality seen in this disease found in children. We found no detrimentaleffects of high liver SCAD expression in transgenic mice on eitherbackground. These studies provide important basic and practical therapeuticinformation for the potential gene therapy of nuclear-encoded mitochondrialenzyme deficiencies, as well as insights into the mechanisms of thedisease.