Project: Research project

Project Details


Gene therapy is a promising treatment modality for inborn errors of metabolism (IEMs). Many IEMs arc caused by inherited deficiency of liver-specific enzymes, so targeting of gene transfer to the liver is a natural choice for gene therapy of IEMs. Most contemporary liver-directed gene transfer methods have been limited by either temporary or insufficient therapeutic gene expression. The pathology associated with IEMs is often caused by a circulating toxic metabolite and not by local effects of the enzyme deficiency in the liver, so removal of circulating toxins by enzyme expressed ectopically in a heterologous tissue may be a viable treatment option for select IEMs. We have demonstrated that expression of phenylalanine hydroxylase (PAH) in skeletal muscle can reduce hyperphenylalaninemia in Pah(enu2) mice, a model of human phenylketonuria (PKU), if sufficient tetrahydrobiopterin (BH4) cofactor is provided exogenously. Several investigators have recently reported stable, physiologically-significant reporter or therapeutic gene expression in either liver or skeletal muscle following administration of gene transfer vectors based upon recombinant adeno-associated virus (rAAV), a non-pathogenic parvovirus. We have designed and are constructing rAAV containing the mouse PAH cDNA under the transcriptional control of promoters that are active either in liver or muscle. Our hypothesis is that rAAV-mediated PAH expression in either liver or muscle (with administration of BH4 in muscle-treated mice) will significantly lower serum phenylalanine levels in Pah(enu2) mice. In the proposed experiments, a single gene transfer technology (rAAV) will be applied to two different tissues (liver or muscle) in a single mouse model. This proposal will directly compare the effectiveness of liver-directed versus muscle-directed gene therapy for IEMs.
Effective start/end date9/15/997/31/01


  • National Institutes of Health


  • Medicine(all)


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