Intracerebroventricular alpha-N-acetylglucosaminidase Delivery to the Brain

PROJECT SUMMARY MPS IIIB is lysosomal storage diseasea disease in which a key enzymealpha N acetylglucosaminidaseNAGLUis missing in cellsresulting in the toxic accumulation of complex sugars called glycosaminoglycansprincipally in the central nervous systemCNSA 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 CNSThis proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIBa disease with severe neurodegenerative symptoms but no current therapies due to poor transport across the blood brain barrierWe have tested our approach on a similar diseaseMPSIwhich is missing a different key enzyme called iduronidaseIDUAUsing iduronidaseIDUAconjugated to guanidinoneomycinGNeoa molecular transporterwe 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 brainThe purpose of this grant is conjugate NAGLU with GNeoGNeo NAGLUand assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS IIIB mouse model using intracerebroventricular administrationDose dependent biodistribution of GNeo NAGLU and effects on biochemical and histological pathologyand 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 IIIBa lysosomal storage disorder with severe neurological symptoms for which there is currently no available treatment