Encapsulated cell therapy for Parkinson`s disease: long-term, stable and efficacious targeting of the nigrostriatal dopaminergic system with GDNF

Delivering glial cell line-derived neurotrophic factor (GDNF) to the CNS is a potential treatment for Parkinson’s Disease (PD). To be effective, GDNF needs to be delivered selectively in a long-term and stable manner to the nigrostriatal system. We have developed an encapsulated cell technology that achieves these goals by providing a targeted, continuous, de novo synthesized source of very high levels of GDNF. The studies described here satisfy several pre-clinical requisites for continued clinical development of this approach. In vivo studies demonstrated sustained, stable, and selective delivery of high levels of GDNF to the rat striatum using implanted human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Long-term efficacy was evidenced by robust neuroprotection of dopaminergic neurons in the substantia nigra, preservation and regeneration of dopaminergic fibers in the striatum, and behavioral recovery in 6-OHDA lesioned rats. In the longest duration studies, these benefits were observed for over 1 year (62 weeks). Similarly impressive distribution of GDNF and positive effects on dopaminergic function were observed when larger, clinical-sized devices were implanted for 3 months into the putamen of minipigs. Implantation of 2 devices, separated by 5 mm, resulted in distribution of GDNF throughout the putamen and caudate that robustly upregulated the expression of tyrosine hydroxylase staining in the regions covered by GDNF diffusion. These results support the concept that implantation of encapsulated GDNF-secreting cells can deliver high amounts of GDNF in a sustained and targeted manner paving the way for continued evaluation of this approach in PD.