Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged beta-glucuronidase expression in situ and correction ofliver pathology in mucopolysaccharidosis type VII mice

For many metabolic diseases, early correction of the inherited deficiency i s required to prevent long-term sequelae. We examined the ability of adeno- associated virus (AAV) to mediate efficient gene transfer during the neonat al period in mice with the lysosomal storage disease mucopolysaccharidosis type VII (MPS VII), Quadriceps of newborn MPS VII mice were injected with a n AAV vector containing human beta-glucuronidase (GUSB) cDNA. High-level in tramuscular GUSB expression was seen as early as 2 weeks of age, and persis ted for at least 16 weeks with no reduction in activity. In addition, GUSB activity was detected in both liver and spleen at later time points. The le vel of GUSB activity resulted in a significant reduction in lysosomal stora ge in the liver and a minimal reduction in the spleen at 16 weeks. However, the temporal and spatial pattern of hepatic GUSB activity, coupled with th e presence of GUSB cDNA in liver sections, suggests that hematogenous disse mination of virus at the time of injection led to gene transfer to hepatic cells. These results demonstrate that AAV vectors can successfully infect n eonatal muscle and persist through the rapid growth phase following birth. However, GUSB secretion from an intramuscular source is inefficient, limiti ng the therapeutic efficacy of this approach.