Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.
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.
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Lishuang
L
Cao
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Aoibhinn
A
McDonnell
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Anja
A
Nitzsche
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Aristos
A
Alexandrou
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Pierre-Philippe
PP
Saintot
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Alexandre J C
AJ
Loucif
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Adam R
AR
Brown
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Gareth
G
Young
University of Bristol, School of Physiology, Pharmacology, and Neuroscience, Bristol BS8 1TD, UK.
Malgorzata
M
Mis
Hatherly College of Life and Environmental Sciences, University of Exeter, Prince of Wales Road, Exeter EX4 4PS, UK.
Andrew
A
Randall
Yale Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, 950 Campbell Avenue, Building 34,West Haven, CT 06516, USA.
Stephen G
SG
Waxman
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Philip
P
Stanley
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Simon
S
Kirby
Pfizer, 1 Howe Street, New Haven, CT 06511, USA.
Sanela
S
Tarabar
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Alex
A
Gutteridge
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Richard
R
Butt
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Ruth M
RM
McKernan
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Paul
P
Whiting
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
Zahid
Z
Ali
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK. j.bilsland@ucl.ac.uk edward.stevens@pfizer.com.
James
J
Bilsland
Pfizer Neuroscience and Pain Research Unit, The Portway Building, Granta Park, Cambridge CB21 6GS, UK. j.bilsland@ucl.ac.uk edward.stevens@pfizer.com.
Edward B
EB
Stevens
D000328:Adult; D004916:Erythromelalgia / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism*; D010647:Phenyl Ethers / Q000627:therapeutic use*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
D062556:NAV1.7 Voltage-Gated Sodium Channel; D010647:Phenyl Ethers; D013449:Sulfonamides; C000618268:PF-05089771; D000096926:Benzenesulfonamides; C486866:SCN9A protein, human