title: Reversal of metabolic and neurological symptoms of phenylketonuric mice treated with a PAH containing helper-dependent adenoviral vector.
abstract: Phenylketonuria (PKU) is one of the most common inborn errors of metabolism and is due to a deficit of phenylalanine hydroxylase, the enzyme that converts phenylalanine (Phe) into tyrosine (Tyr). The resultant hyperphenylalaninemia (HPA) leads to severe neurological impairment, whose pathogenesis has not been entirely elucidated. Treatment of PKU consists essentially in lifelong protein restriction and, in mild cases, in tetrahydrobiopterin supplementation. However, compliance to both strategies, particularly to the long-term diet, is low and therefore other therapies are desirable. We explored a gene therapy approach aimed at long-term correction of the pathologic phenotype of BTBR-PahEnu2 mice, a mouse model of PKU. To this aim, we developed a helper-dependent adenoviral (HD-Ad) vector expressing phenylalanine hydroxylase and administered it to 3-week-old PKU mice. This resulted in complete normalization of Phe and Tyr levels and reversal of coat hypopigmentation that lasted throughout the observation period of six months. The spatial learning deficits observed in PKU mice were also reversed and hippocampus levels of the N-methyl-D-Aspartate and 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid receptor subunits returned to normal. Long-term potentiation, which is impaired in PKU mice, was also restored by treatment. Therefore, HD-Ad vector-mediated gene therapy is a promising approach to PKU treatment.
authors.affiliation: CEINGE-Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cerreto
authors.forename: Bisan
authors.initials: B
authors.lastname: Mehdawy
authors.forename: Daniela
authors.initials: D
authors.lastname: Ombrone
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruoppolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Aurora
authors.initials: A
authors.lastname: Daniele
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology / Q000379:methods; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics / Q000628:therapy; D051379:Mice; D016202:N-Methylaspartate / Q000235:genetics / Q000378:metabolism; D010649:Phenylalanine / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D010661:Phenylketonurias / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy*; D010858:Pigmentation / Q000235:genetics; D014443:Tyrosine / Q000097:blood
chemical_list: D014443:Tyrosine; D010649:Phenylalanine; D016202:N-Methylaspartate; D010651:Phenylalanine Hydroxylase