Transplantation of human pluripotent cell derived dopaminergic neurons into a novel accelerated a-synuclein model of Parkinson's disease.

Proof of concept clinical studies for cell replacement therapy (CRT) for Parkinson’s disease (PD) were performed using fetal tissue over 30 years ago. Post-mortem results from some of these patients have indicated surviving grafts for more than two decades post-transplant. However, they also showed transfer of pathology from the host to healthy grafted cells, which was unexpected and not predicted from preclinical studies using the “gold-standard” 6-hydroxydopamine (6-OHDA) model. This model is the 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-synuclein (a-syn) accumulation, and inflammation. To model these features, we have used human preformed a-syn fibrils and viral overexpression of human a-syn co-injected into the substantia nigra. After allowing the pathology to develop for 4-8 weeks, the animals were transplanted with human pluripotent cell derived DA progenitors in the striatum. Using this model in Sprague Dawley rats we have observed a-syn pathology, inflammation and progressive loss of DA cells from the substantia nigra and terminals in the striatum. We show that cells can survive, innervate and integrate into host circuitry in this model. Moreover, there is evidence for transfer of a-syn pathology from host to grafted cells. We have now translated this into nude athymic rats in order to investigate long term survival of transplanted DA progenitors. Our new model presents a more clinically relevant tool to assess CRT for PD. In addition, it allows us to investigate a-syn pathology within a humanised system in vivo. Future studies will investigate if cell intrinsic properties, e.g. a-syn triplication mutation, could affect transfer of a-syn pathology and graft function in this novel model