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 a short-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD-deficient mouse model. Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background. In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values. All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background. These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial enzyme deficiencies, as well as insights into the mechanisms of the disease.