Work

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

Year: 2024

Type: conference-abstract

Abstract: Background 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 in vitro differentiation strategies have been established that are capable of generating high proportions of MSN progenitors. Aim To develop a stem cell-derived MSN progenitor cell product to repair the neural circuitry affected by HD. Methods/Results 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 in vivo 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 in vivo. Conclusion Going forward, we aim to complete safe and toxicity testing, in order to bring our cells forward for clinical application.

DOI: 10.1136/jnnp-2024-ehdn.319