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The Journal of Neuroscience, October 15, 2001, 21(20):8108-8118

Neuroprotection through Delivery of Glial Cell Line-Derived Neurotrophic Factor by Neural Stem Cells in a Mouse Model of Parkinson's Disease

Peter Åkerud¹, Josep M. Canals¹, Evan Y. Snyder², and Ernest Arenas¹

¹ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-17177 Stockholm, Sweden, and ² Departments of Neurology, Pediatrics and Neurosurgery, Harvard Medical School and Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115

Neural stem cells (NSCs) have been proposed as tools for treating neurodegeneration because of their capacity to give rise to cell types appropriate to the structure in which they are grafted. In the present work, we explore the ability of NSCs to stably express transgenes and locally deliver soluble 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 grafts was tested in a mouse 6-hydroxydopamine model of Parkinson's disease. We found that GDNF-NSCs prevented the degeneration of dopaminergic neurons in the substantia nigra and reduced behavioral impairment in these animals. Thus, our results demonstrate that NSCs efficiently express therapeutic levels of GDNF in vivo, suggesting a use for NSCs engineered to release neuroprotective molecules in the treatment of neurodegenerative disorders, including Parkinson's disease.

Key words: dopaminergic neurons; glial cell line-derived neurotrophic factor; GDNF; neuroregeneration; neurotrophic factors; striatum; transplantation

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21208108-11$05.00/0

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