Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer.

[classical phenylketonuria]

Classical phenylketonuria (PKU ), which predisposes affected individuals to severe mental retardation , is caused by a deficiency of hepatic phenylalanine hydroxylase (PAH ). A recombinant adenoviral vector containing the human PAH cDNA was constructed and administered to PAH -deficient mice (strain PAHenu 2 ). The hyperphenylalaninemic phenotype of these animals was completely normalized within 1 week of treatment . Although this therapeutic effect did not persist , analysis of the relationship between hepatic PAH activity and serum phenylalanine levels indicated that only 10 -20 % of normal enzymatic activity in the mouse liver is sufficient to restore normal serum phenylalanine levels . These results demonstrate that PKU and other metabolic disorders secondary to hepatic deficiencies can be completely corrected by gene therapy when more persistent vector systems are developed .