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A gain in pain control
Subtype-specific blockade of sodium channel Nav1.7, which is important for firing of peripheral pain-signaling neurons, is a major focus of pain research. In a new study, Cao et al. created iPSC-derived sensory neurons from patients with inherited erythromelalgia (IEM), a painful disorder in which gain-of-function Nav1.7 mutations produce hyperexcitability and hyperresponsiveness to warmth in peripheral sensory neurons. The investigators show that a new selective Nav1.7 sodium channel blocker normalized the phenotype of iPSC-derived sensory neurons carrying IEM mutations and blocked pain perception in human subjects with IEM. These results provide proof of principle that selective Nav1.7 blockade may be useful in pain alleviation.
Abstract
In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). The SCN9A gene encoding the sodium channel Nav1.7 expressed in the peripheral nervous system plays a critical role in IEM. A gain-of-function mutation in this sodium channel leads to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. Five patients with IEM were treated with a new potent and selective compound that blocked the Nav1.7 sodium channel resulting in a decrease in heat-induced pain in most of the patients. We derived induced pluripotent stem cell (iPSC) lines from four of five subjects and produced sensory neurons that emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the hyperexcitability of the iPSC-derived sensory neurons, we saw a trend toward 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, our approach may have broader utility for a wide range of pain and sensory conditions.
- Copyright © 2016, American Association for the Advancement of Science
