162. Functional Correction of Mucopolysaccharidosis I in Adult Mice by a Systemic rAAV9-IDUA Gene Delivery

Abstract

Mucopolysaccharidosis (MPS) I is a lysosomal storage disease caused by autosomal recessive defect in iduronidase (IDUA). The lack of IDUA activity results in the accumulation of GAGs in cells in virtually all organs, leading to profound somatic and neurological disorders. No treatment is currently available for the neurological disorders of MPS I. In this study, we have developed a self-complementary (sc) AAV9 vector expressing human IDUA, targeting the root cause. A single intravenous injection of scAAV9-hIDUA vector at 5×1012vg/kg led to the rapid and persistent restoration of IDUA activity and the clearance of lysosomal storage pathology throughout the CNS, peripheral nervous system (PNS) and broad peripheral tissues, as well as the correction of astrocytosis in the CNS and PNS. Furthermore, we demonstrate that a single systemic scAAV9-IDUA gene delivery provides long-term neurological benefits in MPS I mice, resulting in significant improvement in cognitive and motor function, and extension of survival (ongoing). More importantly, functional benefits were also achieved in MPS I mice that were treated at advanced disease stages. These data demonstrate the promising clinical potential of systemic scAAV9-hIDUA gene delivery for treating MPS I and other neurogenetic diseases.