422. Dominant-Negative Interference in the Pahenu2 Mouse Model of PKU: Effectiveness of Vectors Expressing Either Modified Forms of Phenylalanine Hydroxylase (PAH) or Ribozymes Plus a Hardened PAH mRNA

Abstract

The common human genetic disorder Phenylketonuria (PKU) is primarily caused by defects in the enzyme phenylalanine hydroxylase (PAH). An animal model for PKU, the BTBR Pahenu2 mouse, has a missense mutation (F263S) that inactivates PAH; the mouse exhibits classic PKU, with elevated blood Phe levels, cognitive deficiencies, and maternal PKU syndrome. Like the Pahenu2 mouse, a majority of human PKU patients also have missense mutations. We have corrected both the serum Phe levels and maternal PKU in Pahenu2 mice using recombinant AAV vectors containing the mouse PAH gene. Although successful, unusually high vector doses were needed to normalize serum Phe levels. More critically, there was a gradual loss of therapeutic effect 20|[ndash]|24 weeks after vector delivery in many animals, particularly females.