MPS IIIA is lysosomal storage disease; a disease in which a key enzyme, sulfamidase (SGSH) is missing in cells, resulting in the toxic accumulation of complex sugars called glycosaminoglycans, principally in the central nervous system (CNS). A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the CNS. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with severe neurodegenerative symptoms but with very limited current therapies due to poor transport across the blood-brain barrier. We have tested our approach on a similar disease, MPSI; which is missing a different key enzyme called iduronidase (IDUA). Using iduronidase (IDUA) conjugated to guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intranasal administration of small amounts of the conjugated enzyme were sufficient to reduce pathological glycosaminoglycans in the brain. The purpose of this grant is conjugate SGSH with GNeo (GNeo-SGSH) and assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS IIIA mouse model using intracerebroventricular administration. Dose-dependent biodistribution of GNeo-SGSH and effects on biochemical and histological pathology will be evaluated. Efficacy and safety will be assessed in single dose and 2-week dosing studies. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.
The goal of this proposal is to test a novel method of enzyme delivery to the brain. Intravenous enzyme replacement therapy has proven successful for treating the somatic symptoms of lysosomal storage disorders, but delivery to the CNS is problematic because intravenously injected enzymes do not penetrate the blood brain barrier. This proposal describes a carrier system to ferry enzyme into the brain. The model under study is the mouse equivalent of MPS IIIA, a lysosomal storage disorder with severe neurological symptoms for which available treatments are severely limited.
