Using a transection paradigm to enhance the repair mechanisms of an investigational human cell therapy

Abstract

AbstractOne promising strategy in cell therapies for Parkinson’s Disease (PD) is to harness a patient’s own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD. Our group has pioneered the transplantation of transection-activated sural nerve fascicles into the brain of human subjects with PD. Our experience in sural nerve transplantation through FDA-regulated clinical trials has supported the safety and feasibility of this approach. We are among the first to collect human sural nerve both before and after transection and to perform single nuclei RNA sequencing to determine the cell types present. We collected nerve tissue before and approximately 2 weeks after sural nerve transection for immunoassays from 15 participants, and collected from two additional participants for single nuclei RNA sequencing. We quantified the expression of key neuroprotective and anti-apoptotic genes along with their corresponding protein levels using immunoassays. The single nuclei data clustered into 10 distinctive groups defined on the basis of previously published cell type-specific genes. Transection-induced reparative peripheral nerve tissue showed RNA expression of neuroprotective factors and anti-apoptotic factors across multiple cell types after nerve injury induction. Key proteins of interest (BDNF, GDNF, beta-NGF, PDGFB, and VEGF) were significantly upregulated in reparative tissue compared to naïve. These results provide insight on this repair tissue’s utility as a neuroprotective cell therapy.Clinical TrialClinicaltrials.gov (Trial registration number NCT02369003)https://clinicaltrials.gov/ct2/show/NCT02369003).