Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice.

[classical phenylketonuria]

Classical phenylketonuria (PKU ) is a metabolic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH ). If untreated , accumulation of phenylalanine will damage the developing brain of affected individuals , leading to severe mental retardation . Here , we show that a liver -directed PAH gene transfer brought about long -term correction of hyperphenylalaninemia and behavioral improvement in a mouse model of PKU . A recombinant adeno-associated virus (AAV ) vector carrying the murine PAH cDNA was constructed and administered to PAH -deficient mice (strain PAH (enu 2 )) via the portal vein . Within 2 weeks of treatment , the hyperphenylalaninemic phenotype improved and completely normalized in the animals treated with higher vector doses . The therapeutic effect persisted for 40 weeks in male mice , while serum phenylalanine concentrations in female animals gradually returned to pretreatment levels . Notably , this long -term correction of hyperphenylalaninemia was associated with a reversal of hypoactivity observed in PAH (enu 2 ) mice . While locomotory activity over 24 h and exploratory behavior were significantly decreased in untreated PAH (enu 2 ) mice compared with the age-matched controls , these indices were completely normalized in 12 -month -old male PKU mice with lowered serum phenylalanine . These results demonstrate that AAV-mediated liver transduction ameliorated the PKU phenotype , including central nervous system dysfunctions .

Diseases
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Diseases presenting "female animals" symptom

classical phenylketonuria

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