GENE-THERAPY FOR PHENYLKETONURIA - PHENOTYPIC CORRECTION IN A GENETICALLY DEFICIENT MOUSE MODEL BY ADENOVIRUS-MEDIATED HEPATIC GENE-TRANSFER

Classical phenylketonuria (PKU), which predisposes affected individual s to severe mental retardation, is caused by a deficiency of hepatic p henylalanine hydroxylase (PAH). A recombinant adenoviral vector contai ning the human PAH cDNA was constructed and administered to PAH-defici ent mice (strain PAH(enu2)). The hyperphenylalaninemic phentoype of th ese animals was completely normalized within 1 week of treatment. Alth ough this therapeutic effect did not persist, analysis of the relation ship between hepatic PAH activity and serum phenylalanine levels indic ated that only 10-20% of normal enzymatic activity in the mouse liver is sufficient to restore normal serum phenylalanine levels. These resu lts demonstrate that PKU and other metabolic disorders secondary to he patic deficiencies can be completely corrected by gene therapy when mo re persistent vector systems are developed.