Research Project
8979416
? DESCRIPTION (provided by applicant): MPS IIIA (Sanfilippo A) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan in various tissues. 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. Unfortunately, enzyme replacement does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with no current therapeutic options. We show that we can deliver the missing enzyme to cells derived from MPS IIIA patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS IIIA (Sgsh-/-). Furthermore, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological glycosaminoglycans. The purpose of this grant is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse model and then assess the efficacy and safety in a long-term (6-month) study. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.
