Reversal of metabolic and neurological symptoms of phenylketonuric mice treated with a pah containing helper-dependent adenoviral vector

Monica Cerreto, Bisan Mehdawy, Daniela Ombrone, Robert Nisticò, Margherita Ruoppolo, Alessandro Usiello, Aurora Daniele, Lucio Pastore, Francesco Salvatore

Research output: Contribution to journalArticle

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 hyperphenyla-laninemia (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.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalCurrent Gene Therapy
Volume12
Issue number1
Publication statusPublished - Feb 2012

Keywords

  • Behavioral tasks in PKU
  • HD-Ad PAH-containing vector
  • Long-term potentiation in PKU
  • Pku

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)
  • Drug Discovery

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  • Cite this

    Cerreto, M., Mehdawy, B., Ombrone, D., Nisticò, R., Ruoppolo, M., Usiello, A., Daniele, A., Pastore, L., & Salvatore, F. (2012). Reversal of metabolic and neurological symptoms of phenylketonuric mice treated with a pah containing helper-dependent adenoviral vector. Current Gene Therapy, 12(1), 48-56.