A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase

Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an i dentified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effecti ve treatments of a genetic disease. However, compliance with dietary treatm ent is dif ficult and when it is for life, as now recommended by an interna tionally used set of guidelines, is probably unrealistic. Herein we describ e experiments on a mouse model using another modality for treatment of PW c ompatible with better compliance using ancillary phenylalanine ammonia lyas e (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine mo nooxygenase (EC 1.14.16.1), which is deficient in PKU, PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid , a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N'-nitros ourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (P AL reduces HPA)-both pharmacologic (with a clear dose-response effect vs. H PA after PAL injection) and physiologic (protected enteral PAL is significa ntly effective vs. HPA). These findings open another way to facilitate trea tment of this classic genetic disease.