Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease

Neural stem cells (NSCs) have been proposed as tools for treating neurodege neration because of their capacity to give rise to cell types appropriate t o the structure in which they are grafted. In the present work, we explore the ability of NSCs to stably express transgenes and locally deliver solubl e molecules with neuroprotective activity, such as glial cell line-derived neurotrophic factor (GDNF). NSCs engineered to release GDNF engrafted well in the host striatum, integrated and gave rise to neurons, astrocytes, and oligodendrocytes, and maintained stable high levels of GDNF expression for at least 4 months. The therapeutic potential of intrastriatal GDNF-NSCs gra fts was tested in a mouse 6-hydroxydopamine model of Parkinson's disease. W e found that GDNF-NSCs prevented the degeneration of dopaminergic neurons i n the substantia nigra and reduced behavioral impairment in these animals. Thus, our results demonstrate that NSCs efficiently express therapeutic lev els of GDNF in vivo, suggesting a use for NSCs engineered to release neurop rotective molecules in the treatment of neurodegenerative disorders, includ ing Parkinson's disease.