I037 Generating a hESC-derived medium spiny neuron cell therapy product for clinical application

<h3>Background</h3> Early atrophy within the basal ganglia, particularly the medium spiny neurons of the striatum (MSNs), represents a key neuropathological feature of Huntington’s disease (HD). Proof-of-concept that cell replacement therapy can alleviate or halt progression of some motor and cognitive features of the disease has been established using fetal-derived MSNs in both preclinical rodent models and in early clinical trials. Stem cell-derived MSNs are required for widespread clinical application and, to date, some <i>in vitro</i> differentiation strategies have been established that are capable of generating high proportions of MSN progenitors. <h3>Aim</h3> To develop a stem cell-derived MSN progenitor cell product to repair the neural circuitry affected by HD. <h3>Methods/Results</h3> Here, we report a novel human stem cell derived cell therapy product (RHD001), which is generated using a modification to the Activin-A protocol and which has been optimised for <i>in vivo</i> transplantation. We have conducted single-cell RNAseq on our RHD001 progenitor cells to confirm expression of key markers of authentic MSN progenitor cells at the point of cryopreservation. Post-transplantation, we have confirmed survival, integration and expression of key MSN markers by immunocytochemistry. Using the monosynaptic tracing technology, we have demonstrated host-to-graft synapse formation. Slice electrophysiology and behavioural assays (apomorphine-induced drug rotation, cognitive testing using the lateralised reaction time task) establish the functional efficacy of the RHD001 cell therapy product <i>in vivo</i>. <h3>Conclusion</h3> Going forward, we aim to complete safe and toxicity testing, in order to bring our cells forward for clinical application.