Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia

Abstract

One sentence summary: Bench to bedside translation using iPSC to characterise phenotype and pharmacology in primary erythromelalgia, an inherited chronic pain condition. ABSTRACTIn common with other chronic pain conditions, inherited erythromelalgia (IEM) represents a significant unmet medical need. The peripherally expressed SCN9A encoded sodium channel Nav1.7 plays a critical role in IEM with gain-of-function leading to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. In five carefully phenotyped IEM patients, a novel highly potent and selective Nav1.7 blocker reduced heat-induced pain in the majority of subjects. In four of the five subjects we used induced pluripotent stem cell (iPSC) technology to create sensory neurons which uniquely emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the iPSC-derived sensory neuron hyperexcitability we saw a trend towards a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, this translational approach is likely to have broader utility to a wide range of pain and sensory conditions. This emphasizes the use of iPSC approaches to bridge between clinical and preclinical studies, enabling greater understanding of a disease and the response to a therapeutic agent in defined patient populations.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

“…While efficacy in the OD1 model, as well as emerging positive clinical trial results with small molecule aryl sulfonamides56, suggest that Na V 1.7 inhibitors may be efficacious in IEM or PEPD, our results reveal that acute administration of peripherally restricted Na V 1.7 inhibitors alone may not have broad efficacy in inflammatory pain. The efficacy of peripherally restricted Na V 1.7 inhibitors in other pain types, such as neuropathic pain, remains to be determined, and underscores the need for further studies to determine how, or whether, Nav1.7 blockade will reduce pain in humans.…”

Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor

“…However, although several selective Nav1.7 inhibitors have been described in the literature101112, none have fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects1112 and clinical progress has been slow1314. While the absence of efficacy has discouraged many in the field, and led some to question the drugabililty of Nav1.7, one possible explanation is that the pharmacological tools utilized provided sub-optimal block of Nav1.7.…”

Patient-derived induced pluripotent stem cells in cancer research and precision oncology

“…iPSCs can be used to draw associations between genotype and drug responses and to identify biomarkers to inform patient selection for enrollment in clinical trials 109–111 . For example, the pharmacological reversal, using a selective sodium-channel blocker, of a hyperexcitability phenotype in sensory neurons derived from iPSCs from patients with the pain disorder inherited erythromelalgia was found to correlate with patient responses and specific patient mutations 111 .…”

“…For example, the pharmacological reversal, using a selective sodium-channel blocker, of a hyperexcitability phenotype in sensory neurons derived from iPSCs from patients with the pain disorder inherited erythromelalgia was found to correlate with patient responses and specific patient mutations 111 . For such applications to materialize, large and diverse collections of cancer-derived iPSCs, capturing a range of cancer types and genotypes, will need to be assembled.…”