ASTROCYTIC GDNF EXPRESSION PREVENTS DOPAMINERGIC NEURODEGENERATION IN A GENETIC MODEL OF PARKINSON’S DISEASE

Glial cell line–derived neurotrophic factor (GDNF) is a pleiotropic neurotrophin, widely expressed and secreted within the central nervous system (CNS). Under pathological conditions, GDNF expression and release by glial cells can be upregulated, exerting neuroprotective effects while also potentially modulating glial activation and neuroinflammation. The neuroprotective properties of GDNF have garnered significant interest for potential applications in neurodegenerative disorders. In this research project, we aim to develop a novel gene therapy-based approach to drive a localized and sustained release of GDNF in striatal astrocytes to reduce neurodegeneration in a mouse model of Parkinson’s Disease (PD).
We developed a lentiviral vector (LV) capable of expressing GDNF at therapeutic levels, selectively in primary astrocytes, using the GFABC1D promoter. In vivo testing confirmed specific GDNF expression in astrocytes in the mouse striatum. In order to test the therapeutic efficacy of our LV vector, we used a genetic mouse model of Juvenile Parkinsonism, the R275W mice, that was treated in a prophylactic setting with the vector harboring GDNF or a control LV. This method of intervention provided protective effects against degeneration of Tyrosine Hydroxylase+ neurons of the Substantia Nigra and improved motor performance in the R275W animal model of juvenile Parkinson's disease.