The mucopolysaccharidoses (MPS) are lysosomal storage diseases that result from deficiencies in specific genes involved in the degradative pathway of glycosaminoglycans (GAGs). Deficiencies in the gene encoding he lysosomal enzyme -glucuronidase (GUSB) result in Sly disease or MPS type VII (MPS VII). The central nervous system (CNS) pathology associated with the murine model of MPS VII is essentially the same as that seen in Sly disease patients, thus the murine system can serve as a neurodegenerative disease model. MPS treatment strategies are based on the ability of defective cells to take up secreted lysosomal enzyme. In the brain, the impact of therapeutic strategies on the global neurological disease associated with MPS VII relies on three variables: 1) the migration of the cells or viral-vectors in the brain parenchyma; 2) the level and spread of GUSB across the brain; and 3) the spread of correction mediated by the enzyme. We have previously shown that neural progenitor cells fulfill these requirements. These cells migrated through the parenchyma of the neonatal brain, differentiated into normal brain cells which integrated into the recipient brain cytoarchitecture and mediated widespread correction of hallmark pathological lesion (Snyder et al., 1995). Neural progenitor cells are self-renewing that can be isolated from the CNS of adult and developing animals. When transplanted, neural progenitor cells migrate in the recipient brain, giving rise to multiple neuronal cell lineages including neurons, astrocytes, and oligodendrocytes. We have generated primary neural progenitor cells from MPS VII mice and normal littermates by propagating neonatal cerebellar tissue in FGF-2. We will determine the usefulness of primary neural progenitor cells to treat global CNS disease. Using neural progenitor cells, we will study the relationship between the three variables that affect the therapeutic effectiveness of treatment strategies variables: 1) the migration and engraftment of PNP cells after transplantaton; 2) the sphere of enzyme secretion and lysosomal correction from PNP cells stably expressing different levels of GUSB enzyme; and 3) the stability of expression from mutant PNP cells engineered with viral vectors after transplantation. We believe this study will lead to a better understanding of neural progenitor cell biology; MPS VII disease, and molecular treatment strategies
