Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria

C. O. Harding, M. B. Gillingham, K. Hamman, H. Clark, E. Goebel-Daghighi, A. Bird, D. D. Koeberl

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pahenu2 mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pahenu2 mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5±2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism.

Original languageEnglish (US)
Pages (from-to)457-462
Number of pages6
JournalGene therapy
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2006

Keywords

  • Adeno-associated virus
  • Liver gene therapy
  • Mouse model
  • Phenylalanine
  • Phenylalanine hydroxylase
  • Phenylketonuria

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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