Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Abstract

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. I n vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.

Cytokine-, Neurotrophin-, and Motor Rehabilitation-Induced Plasticity in Parkinson’s Disease

“…Furthermore, these same animals demonstrated a slow and steady improvement in motor performance when evaluated on 3 separate neurological tests (cylinder, placing, and stepping tests). Our data demonstrated also that a part of the motor recovery is explained by the germination or regeneration of residual dopaminergic terminals postinjury [ 170 ]. Beneficial effects were observed when the same therapeutic approach was investigated into the hippocampus of pilocarpine-treated rats [ 171 , 172 ].…”

From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson's Disease

“…Long-term efficacy was evidenced by robust neuroprotection of dopaminergic neurons in the substantia nigra and fibers in the striatum in 6-OHDA lesioned rats. In the longest duration studies, GDNF implants produced a significant improvement in motor performance that persisted for over 1 year (62 weeks; [73]). Similarly, impressive distribution of GDNF and positive effects on dopaminergic function were observed when larger, clinicalsized devices were implanted for 3 months into the putamen of Göttingen minipigs.…”

Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders

“…Similarly, impressive distribution of GDNF and positive effects on DA function were observed when larger, clinical-sized devices were implanted for three months into the putamen of minipigs. Implantation of two 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 (Wahlberg et al, 2020).…”