Transient striatal delivery of GDNF via encapsulated cells leads to sustained behavioral improvement in a bilateral model of Parkinson disease

Abstract

Numerous studies have shown the neuroprotective and regenerative benefits of glial cell line-derived neurotrophic factor (GDNF) in animal models of PD. Brain delivery of GDNF can, however, be associated with limiting side-effects in both primates and PD patients, rendering the duration of delivery a critical factor. In the present study, the effects of transient vs. sustained GDNF delivery by encapsulated cells were evaluated in a bilateral animal model, closely mimicking advanced PD. One week following bilateral striatal 6-hydroxydopamine injections in rats, capsules loaded with human fibroblasts genetically engineered to release GDNF were bilaterally implanted in the striatum. GDNF delivery resulted in a significant improvement of movement initiation and swimming performance in the lesioned animals, associated with striatal reinnervation of dopaminergic fibers. To test the sustainability of the behavioral improvement, GDNF-secreting capsules were withdrawn in a subgroup of animals, 7 weeks post-implantation. Strikingly, both the behavioral and morphological improvements were maintained until the sacrifice of the animals 6 weeks post-GDNF withdrawal. The sustained cellular and behavioral benefits after GDNF washout suggest the need for temporary delivery of the trophic factor in PD. Retrievable encapsulated cells represent an attractive delivery tool to achieve this purpose.

Keywords

• Parkinson disease
• Glial cell line-derived neurotrophic factor
• Neurotrophic factor withdrawal
• Bilateral 6-OHDA model
• Encapsulated cells
• Dopamine fiber regeneration