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.

Cerreto, M., Mehdawy, B., Ombrone, D., Nistico', R.g., Ruoppolo, M., Usiello, A., et al. (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.

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

NISTICO', ROBERT GIOVANNI;
2012-02-01

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.
1-feb-2012
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Adenoviridae; Animals; Disease Models, Animal; Electrophysiology; Genetic Vectors; Humans; Learning Disorders; Mice; N-Methylaspartate; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Pigmentation; Tyrosine; Genetic Therapy
Cerreto, M., Mehdawy, B., Ombrone, D., Nistico', R.g., Ruoppolo, M., Usiello, A., et al. (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.
Cerreto, M; Mehdawy, B; Ombrone, D; Nistico', Rg; Ruoppolo, M; Usiello, A; Daniele, A; Pastore, L; Salvatore, F
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
CurrGenTp'12PKU.pdf

solo utenti autorizzati

Descrizione: Reversal of metabolic and neurological symptoms of phenylketonuric mice treated with a PAH containing helper-dependent adenoviral vector
Licenza: Copyright dell'editore
Dimensione 1.54 MB
Formato Adobe PDF
1.54 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/133170
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 12
social impact