Objective: In this study, we assess how transplanted human embryonic stem cell (hESC) derived dopaminergic (DA) neurons survive, mature, integrate and innervate the host circuitry in a novel accelerated model of Parkinson’s disease (PD), whereby a mixture of preformed human a-synuclein (asyn) fibrils and AAV6 human asyn are unilaterally injected into the rat substantia nigra (SN).

Background: Preclinical studies to assess the therapeutic potential of hESC DA neurons have mostly been performed in the 6-hydroxydopamine (6-OHDA) DA depletion model of PD. However, this model does not reflect the pathological features or progressive nature of PD.

Method: After induction of the model, and allowing the model to develop for 4-8 weeks, we transplanted hESC-derived DA neurons into the striatum and assessed their survival, maturation, integration and innervation at 6- and 12-weeks post-transplant.

Results: This model gives rise to inflammation, DA cell dysfunction and progressive loss of DA cells from the SN and terminals in the striatum. Additionally, the model shows extensive asyn pathology in both the SN and striatum making it an interesting model in which to examine cell transplantation. Post mortem histology revealed that transplanted cells were capable of innervating the DA depleted striatum in a similar, biologically-relevant pattern previously seen in the 6-OHDA model. We used monosynaptic tracing based on modified rabies virus to assess that the pathology present in this model did not inhibit the ability of the graft to integrate into the host circuitry, meaning that the grafted cells are able to receive appropriate and sufficient synaptic contact with the host central nervous system. Finally, on closer examination, we found evidence of asyn pathology in the form of phosphorylated asyn inclusions in the grafted TH+ cells, indicating host-to-graft transfer of asyn pathology.

Conclusion: Further studies to examine a longer time-point where we can assess the maturation and function of the transplanted cells, and if this is affected by the pathology transfer, are currently underway. This will give us a better understanding of the performance of these cells in a more clinically relevant, albeit accelerated, novel asyn model of PD, thus adding to the body of knowledge required as this cell replacement therapy progresses to clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-impact-of-a-synuclein-pathology-on-human-embryonic-stem-cell-derived-dopaminergic-neurons-transplanted-in-an-accelerated-a-synuclein-rat-model-of-parkinsons-disease/