Impact of cell intrinsic properties on transplantation in rodent models of Parkinson's disease

Proof of concept studies for cell replacement therapy (CRT) for Parkinson’s disease (PD) were performed using fetal tissue. Post-mortem results indicated surviving grafts more than 2 decades post-transplant. However, they also showed the presence of a-synuclein (a-syn) pathology within some of the grafted cells, which was not predicted from preclinical studies in the 6-OHDA model. This model is most commonly used for preclinical assessment of CRT for PD but fails to recapitulate many features of the human condition, including progressive DA degeneration, a-syn accumulation, and inflammation. Since the discovery of cell reprogramming, e.g. iPSCs, reprogrammed cells have been proposed as an alternative source for CRT. However, further research investigating patient-derived reprogrammed cells, including their potential susceptibility to disease processes, is needed to assess their suitability moving forward to the clinic. In this study we will investigate if cell intrinsic properties affect graft survival, integrity, and functional maturation. We derived DA progenitors from a human ESC line or an a-syn triplication patient iPSC line and transplanted them into the 6-OHDA model or accelerated a-syn model. In the 6-OHDA model, we found no difference in graft volume or TH cell density, however, there was a significant difference in graft innervation. In the accelerated a-syn model, we observed behavioural recovery 24 weeks post-transplant in both groups and further histological analysis is ongoing, specifically investigating the presence of a-syn pathology. The comparison between healthy and patient-derived cells will pave the way for future research assessing reprogrammed cells’ potential for brain repair and disease modelling