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