METABOLIC ENGINEERING AS THERAPY FOR INBORN-ERRORS OF METABOLISM - DEVELOPMENT OF MICE WITH PHENYLALANINE-HYDROXYLASE EXPRESSION IN MUSCLE

Treatment of many inherited liver enzyme deficiencies requires the rem oval of toxic intermediate metabolites from the blood of affected indi viduals. We propose thai circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was expressed in skeletal and cardiac muscle of mice which carried the PAH cDNA und er the transcriptional control of the mouse muscle creatine kinase pro moter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hy perphenylalaninemic mice to yield progeny that lack PAH activity in li ver but express PAH in muscle. These mice exhibited hyperphenylalanine mia at baseline, but serum phenylalanine levels decreased significantl y when the mice were supplemented with tetrahydrobiopterin (BH4), a re quired cofactor for PAH. This is the first demonstration that a liver- specific enzyme, when Expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, s uch as muscle, will be effective ill the treatment of selected inborn errors of metabolism.