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Sci Transl Med. 2016 Apr 20;8(335):335ra56. doi: 10.1126/scitranslmed.aad7653.

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

Author information

1
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
2
University of Bristol, School of Physiology, Pharmacology, and Neuroscience, Bristol BS8 1TD, UK.
3
Hatherly College of Life and Environmental Sciences, University of Exeter, Prince of Wales Road, Exeter EX4 4PS, UK.
4
Yale Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, 950 Campbell Avenue, Building 34,West Haven, CT 06516, USA.
5
Pfizer, 1 Howe Street, New Haven, CT 06511, USA.
6
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK. j.bilsland@ucl.ac.uk edward.stevens@pfizer.com.

Abstract

In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). TheSCN9Agene 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.

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