369. Therapeutic Effectiveness of AAV-Mediated Iduronidase Delivery to the CNS Following Intravenous Administration in a Murine Model of Mucopolysaccharidosis Type I

Abstract

Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disease caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparin and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodegeneration, mental retardation, and death by age 10. Current treatments for this disease include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, these treatments are insufficiently effective in addressing CNS manifestations of the disease. Our goal is to improve therapy for severe MPS I by supplementing current ERT and HSCT with IDUA gene transfer to the CNS, thereby preventing neurological manifestations of the disease. In this study we tested the ability of intravenously administered AAV serotypes 9 and rh10 (AAV9 and AAVrh10) to cross the blood brain barrier for delivery and expression of the IDUA gene in the CNS. 4-5 month old adult MPS I animals were infused intravenously via the tail vein with either an AAV9 or AAVrh10 vector encoding the human IDUA gene. Blood and urine samples were collected on a weekly basis until the animals were sacrificed at 10 weeks post-injection. Plasma IDUA activities in treated animals were close to 1000-fold higher than that of heterozygote controls at 3 weeks post-injection. Brains, spinal cords, and peripheral organs were analyzed for IDUA activity, clearance of GAG accumulation, and IDUA immunofluorescence of tissue sections. Treated animals demonstrated widespread restoration of IDUA enzyme activity in all organs including the CNS. High levels of IDUA enzyme activity were observed in the brain and spinal cord, which ranged from 40 to 300-fold higher than heterozygote controls, while levels in peripheral organs were also high, ranging from 100 to 1000-fold higher than control animals. Levels of urinary and tissue GAGs were significantly reduced starting at 3 weeks after vector infusion, with restoration of normal GAG levels by the end of the study. These data demonstrate the non-invasive effectiveness of systemic intravenous AAV9 and AAVrh10 vector infusion in counteracting CNS manifestations of MPS I.