Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease

For many inborn errors of metabolism, early treatment is critical to preven t long-term developmental sequelae, Ne have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type V II (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 x 10(6) infectious units of recombinant adeno-associated virus enc oding the human P-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB exp ression were achieved by 1 week of age in liver, heart, lung, spleen, kidne y, brain, and retina, GUSB expression persisted in most organs for the 16-w eek duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microgli a, and meninges of the central nervous system were virtually cleared of dis ease. In addition, neonatal treatment of MPS VII mice provided access to th e central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adenoassociated virus can achieve therapeutically relevant levels of enzym e very early in life and that the rapid growth and differentiation of tissu es does not limit long-term expression.