874. Hepatocellular Morphology in the Pahenu2 Mouse Model of PKU Is Altered Following Portal Vein Administration of rAAV-mPAH-WPRE Vectors

Abstract

Phenylketonuria (PKU) is among the most common human birth defects. The disease is caused by a defect in the enzyme phenylalanine hydroxylase (PAH) resulting in elevated serum phenylalanine (Phe) levels, leading to severe mental retardation. The current treatment for PKU is a restrictive diet. We developed a recombinant AAV vector carrying the mouse PAH gene (rAAV-mPAH) and delivered it through portal vein injection. Male Pahenu2 mice responded at vector doses of 6 × 1010 I.U. or above, lowering serum Phe to therapeutic levels. Female mice were unresponsive to similar doses. A dominant negative interaction between normal subunits of the PAH tetramer made from the vector delivered gene and endogenous PAH missense subunits is a possible explanation. To overcome a dominant negative effect, a Woodchuck Hepatitis Virus post-transcriptional regulatory element was added to the rAAV-mPAH vector (rAAV-mPAH-WPRE). Portal vein delivery to male Pahenu2 mice resulted in reduction of serum Phe levels at about 10% of previous doses.