Author ORCID Identifier

https://orcid.org/0000-0002-4042-4890

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Greg A. Gerhardt

Second Advisor

Dr. Craig G. van Horne

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of the degenerating dopaminergic cells in the SNpc. The main goal of our studies is to determine if implantation of peripheral nerve tissue into SNpc in combination with DBS surgeries is safe, feasible, and can possibly slow the loss of the midbrain dopamine neurons. First, RNA sequencing was used to validate the repair phenotype of human sural nerve tissue two weeks after transaction injury. The transcriptomic analysis showed that 3641 genes were differentially expressed in conjunction with the upregulation of multiple neurotrophic factors and the enhancement of axonogenesis. Secondly, to study the neurobiology of the implant, we grafted human nerve implants into the dorsal striatum of athymic nude rats (called Neuro-Avatars). Immunostaining studies showed a remarkable survival of the implanted human SCs up to 6 months post-implantation in Neuro-Avatar animals. In addition, there were significant increases in the numbers of surviving human-derived cells in the Neuro-Avatar's using pre-degenerated human sural nerve tissue as compared to the same sural nerve tissue that was harvested in its normal state.

Finally, we studied data from 27 human subjects with PD that had received DBS plus autologous nerve-implants. The safety of the combined intervention and the progression of the motor symptoms were evaluated at baseline, 12, and 24 months using the Unified Parkinson’s Disease Rating Scale part III (UPDRS). The safety of the studies at 2 years post-implantation showed adverse events (AE’s) that were similar to those seen with standard DBS therapy. In addition, there was a significant motor improvement on the side contralateral to the tissue implantation in comparison to the ipsilateral one. Taken together, our data support that combining DBS with in vivo pre-degenerated peripheral nerve tissue containing SCs can serve as a safe and promising disease-modifying therapy to alter the progression of PD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.312

Available for download on Saturday, July 24, 2021

Share

COinS