Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia (IEM), a pain disorder caused by gain-of-function mutations in NaV1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different IEM mutations, NaV1.7-S241 T and NaV1.7-I848 T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.