PROFILING OF HUMAN IPSC-DERIVED SENSORY NEURONS AS AMODEL FOR NON-OPIOID PAIN THERAPEUTIC DRUG DISCOVERY

Aims: The recent FDA approval of Vertex’s compound Suzetrigine, a highly selective pain inhibitor targeting the NaV1.8 sodium channel, has renewed interest in non-opioid analgesic. While rodent models have historically supported preclinical research, significant biological and translational gap persists when moving from animal studies into human trials. To improve predictability human-relevant models are required. In this study, we report the large-scale, directed differentiation of human iPSC-derived sensory neurons (a.k.a., iCell® Sensory Neurons) and established a baseline transcriptomic characterization of these cells compared to dorsal root ganglion (hDRG) and alternative published iPSC-derived sensory neuron protocols.
Methods: iCell® Sensory Neurons (iCell SNC) were generated via directed differentiation and cultured for 21 days post-thaw. Bulk and single-cell RNA sequencing were performed to characterize transcriptional profiles and compared with hDRG tissue and published iPSC-sensory neuron protocols. Functional phenotyping included calcium influx assays and microelectrode array (MEA) electrophysiology.
Results: Using 173 sensory neuron markers, iPSC-derived sensory neuron protocols clustered distinctly from hDRG, with protocol dependent subcluster variation. iCell® SNC showed the highest expression of key non-opioid pain-related genes (SCN9A, SCN10A, TRPV1, PIEZO2, P2RX3). Single-cell RNA sequencing confirmed broad expression of TRPV1, SCN9A, and P2RX3, with a substantial portion expressing SCN10A. These neurons exhibited increased expression of neural maturation signature with lower progenitor marker expression, elevated calcium responses to sensory agonist and electrophysiological activity on MEA.
Conclusion: iPSC-derived iCell® Sensory Neurons demonstrate advanced transcriptional maturation and robust sensory function, supporting their utility as a human-relevant in vitro model for non-opioid pain discovery and neuropathy-related mechanisms.