Intracerebroventricular Iduronidase Delivery to the Brain

PROJECT SUMMARY MPS IHurler Syndromeis a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycanin various tissuesA primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulationEnzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the central nervous systemThis proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS Ia disease with good systemic effectsbut no effect on the neurodegenerative process symptoms due to poor transport across the blood brain barrierUsing iduronidaseIDUAconjugated to guanidinoneomycinGNeoa molecular transporterwe showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS IIDUAFurthermoreintranasal administration of GNeo IDUA demonstrated that small amounts of enzyme were delivered to the brain and were able to reduce pathological glycosaminoglycansThe purpose of this grant is to assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS I mouse model using intracerebroventricular administrationDose dependent biodistribution of GNeo IDUA and the effect on biochemical and histological pathology and behavior will be evaluatedEfficacy and safety will be assessed in single dose andweek dosing studiesThe results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans PROJECT NARRATIVE The goal of this proposal is to test a novel method of enzyme delivery to the brainIntravenous enzyme replacement therapy has proven successful for treating the somatic symptoms of lysosomal storage disordersbut delivery to the CNS is problematic because intravenously injected enzymes do not penetrate the blood brain barrierThis proposal describes a carrier system to ferry enzyme into the brainThe model under study is the mouse equivalent of MPS Ia lysosomal storage disorder for which there is currently no available treatment for treating the neurological symptoms caused by the disease