The neuroglia of CNS are in intimate contact with the surfaces of neurons and are thus strategically placed for the delivery of secreted therapeutic agents. However, in vivo delivery of transforming agents such as DNA or liposomes to these cells is problematic because of the extremely narrow intracellular space of the CNS. Recent evidence from retroviral marking experiments indicates that both astrocytes and oligodendrocytes or their progenitors migrate over substantial distances during development; thus, progenitors isolated and transformed in vitro, or strategic populations transformed locally in vivo, might by subsequent migration colonize widely. This product will test the hypothesis that migrating neuroglia can deliver therapeutic agents. In the first place, the extent and patterns of migration of transgenically marked populations of astrocytes and microglia transplanted into murine CNS at various pre- and postnatal stages. These data, along with similar information on native oligodendrocytes currently being generated in an ongoing project, will at once reveal principles of organization of normal neural development and will underpin attempts to use these populations, after genetic modification, as delivery vehicles for secreted therapeutic agents. In addition, we have recently discovered that immature neuroglia transplanted into the cerebral ventricles will migrate into the brain parenchyma. we will determine the identity of the migrating neuroglia and their eventual fate to determine if this route of administration might be effective for the delivery of genetically modified neuroglia. The second phase of this project will explore the utility of implanted neuroglia as in vivo secretors of engineered proteins, by transplanting transgenically marked cells into murine lysosomal storage disease models to analyze the effect of these disorders on neuroglial cell migration. Finally, neuroglial cells secreting modified, putative therapeutic lysosomal proteins will be obtained from transgenic mouse lines or by transfection of neuroglia from normal mice. These cells will be implanted in the same lysosomal storage disease models in an attempt to develop a cell-transplant based model for lysosomal storage disease therapy.
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