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

Cary Harding, Melanie Gillingham, Kelly Hamman, H. Clark, E. Goebel-Daghighi, A. Bird, D. D. Koeberl

Research output: Contribution to journalArticle

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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 2006

Fingerprint

Phenylketonurias
Genetic Therapy
Phenylalanine
Liver
Phenylalanine Hydroxylase
Inborn Errors Metabolism
Dependovirus
Capsid
Portal Vein
Hepatocytes
Complementary DNA
Safety
Injections
Serum
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics

Cite this

Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. / Harding, Cary; Gillingham, Melanie; Hamman, Kelly; Clark, H.; Goebel-Daghighi, E.; Bird, A.; Koeberl, D. D.

In: Gene Therapy, Vol. 13, No. 5, 03.2006, p. 457-462.

Research output: Contribution to journalArticle

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