eprintid: 1489388
rev_number: 36
eprint_status: archive
userid: 608
dir: disk0/01/48/93/88
datestamp: 2016-05-02 17:26:41
lastmod: 2021-09-20 22:24:48
status_changed: 2016-08-03 11:59:59
type: article
metadata_visibility: show
creators_name: Cao, L
creators_name: McDonnell, A
creators_name: Nitzsche, A
creators_name: Alexandrou, A
creators_name: Saintot, PP
creators_name: Loucif, AJ
creators_name: Brown, AR
creators_name: Young, G
creators_name: Mis, M
creators_name: Randall, A
creators_name: Waxman, SG
creators_name: Stanley, P
creators_name: Kirby, S
creators_name: Tarabar, S
creators_name: Gutteridge, A
creators_name: Butt, R
creators_name: McKernan, RM
creators_name: Whiting, P
creators_name: Ali, Z
creators_name: Bilsland, J
creators_name: Stevens, EB
title: Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F85
note: This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine 8(335), 20 April 2016, doi: http://dx.doi.org/10.1126/scitranslmed.aad7653.
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.
date: 2016-04-20
date_type: published
official_url: http://dx.doi.org/10.1126/scitranslmed.aad7653
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1125755
doi: 10.1126/scitranslmed.aad7653
pii: 8/335/335ra56
lyricists_name: Bilsland, James
lyricists_name: Whiting, Paul
lyricists_id: JGBIL70
lyricists_id: PWHIT17
full_text_status: public
publication: Science Translational Medicine
volume: 8
number: 335
article_number: 335ra56
event_location: United States
issn: 1946-6242
citation:        Cao, L;    McDonnell, A;    Nitzsche, A;    Alexandrou, A;    Saintot, PP;    Loucif, AJ;    Brown, AR;                                                         ... Stevens, EB; + view all <#>        Cao, L;  McDonnell, A;  Nitzsche, A;  Alexandrou, A;  Saintot, PP;  Loucif, AJ;  Brown, AR;  Young, G;  Mis, M;  Randall, A;  Waxman, SG;  Stanley, P;  Kirby, S;  Tarabar, S;  Gutteridge, A;  Butt, R;  McKernan, RM;  Whiting, P;  Ali, Z;  Bilsland, J;  Stevens, EB;   - view fewer <#>    (2016)    Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.                   Science Translational Medicine , 8  (335)    , Article 335ra56.  10.1126/scitranslmed.aad7653 <https://doi.org/10.1126/scitranslmed.aad7653>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1489388/7/Whiting_aad7653_ArticleContent_v1%20%283%29%20-%2004%20Feb%202016_%20AM_05%20feb%2016%20.pdf