Muscle-directed gene therapy for Duchenne muscular dystrophy and phenylketonuria

Muscle directed gene therapy is a promising approach to the treatment of primary muscle disorders such as Duchenne muscular dystrophy (DMD), but the stability of gene expression, accessibility of skeletal muscle, and the ease of the DNA transfer techniques involved make muscle-directed gene therapy an attractive therapeutic modality for a variety of inherited and acquired diseases which do not primarily involve muscle. Examples include production and secretion of therapeutic gene products, immunization against pathogenic viruses or bacteria, and the clearance of circulating toxic metabolites produced in inborn errors of metabolism. In this report we review the current status of direct muscle gene therapy as a treatment for primary muscle disease illustrated by experiments with dystrophin deficient mdx mice, a model of human DMD. Heterologous gene therapy for inborn errors of metabolism using phenylketonuria (PKU) as an example is discussed, and we describe a preliminary experiment that examines the effect of heterologous phenylalanine hydroxylase (PAH) expression in muscle upon the phenotype of hyperphenylalaninemic Pah(enu2) mice.