Substrate Reduction Therapy Strategies for Treatment of Mucopolysaccharidoses

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Mucopolysaccharidoses (MPS) are genetically inheritable diseases defined by the inability of the cell to catabolize glycosaminoglycan sugars, causing intra-lysosomal accumulation of the undegraded metabolite. MPS disorders that store the glycosaminoglycan heparan sulfate result in severe neuropathology and are usually lethal within the first few decades of life. The cause of neuropathology in these diseases is unclear but may be associated with the storage of secondary metabolites. Indeed, the secondary accumulation of gangliosides in the brains of MPS disease models deficient in heparan sulfate catabolism has been previously described. Further, preliminary analysis in our lab has revealed a novel mechanism by which heparan sulfate storage in MPSIIIa cells results in the dramatic secondary accumulation of chondoitin/dermatan sulfate. In the first aim of this project we will further characterize the secondary storage of chondroitin/dermatan sulfate by analyzing fibroblasts from additional heparan sulfate storage disorders. Further, we will use the analytical facilities available through Glycotechnology Core at UCSD to screen for the secondary accumulation of additional metabolites such as N- or O-glycans in MPS fibroblasts. To assess whether secondary metabolite storage might contribute to neuropathology, we will characterize the accumulation of known and novel metabolites in the MPSIIIa mouse brain at early-, mid-, and late-stages of disease and determine whether storage correlates with established pathological indicators. The second aim of this study will determine whether strategies to reduce the accumulation of primary or secondary metabolites could be used to ameliorate neuropathology. To this end, genetic strategies will be used to reduce heparan sulfate biosynthesis either systemically or in specific cell types in the brain. Pharmacological treatment or intracerebral enzyme administration will be used to reduce the secondary storage of gangliosides or chondroitin sulfate/dermatan sulfate in the MPSIIIa mouse brain, respectively. The significance of this work lies in our ability to identify novel therapeutic targets for treating MPS disease pathology in the brain.