Human Mendelian pain disorders: a key to discovery and validation of novel analgesics
Identifieur interne : 000917 ( Istex/Corpus ); précédent : 000916; suivant : 000918Human Mendelian pain disorders: a key to discovery and validation of novel analgesics
Auteurs : Yp Goldberg ; Sn Pimstone ; R. Namdari ; N. Price ; C. Cohen ; Rp Sherrington ; Mr HaydenSource :
- Clinical Genetics [ 0009-9163 ] ; 2012-10.
Abstract
We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain‐of‐function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage‐dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof‐of‐concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.
Url:
DOI: 10.1111/j.1399-0004.2012.01942.x
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ISTEX:5BF4208F8F7514ADA3521D4DBA814788C58DD32ELe document en format XML
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By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain‐of‐function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage‐dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof‐of‐concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>YP Goldberg</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string><json:string>Corresponding author: Y Paul Goldberg, Department of Clinical Development, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia V5G 4 W8, Canada.Tel.: +001 604 484 3362fax: +001 604 484 3321e‐mail:</json:string><json:string>E-mail: pgoldberg@xenon-pharma.com</json:string></affiliations></json:item><json:item><name>SN Pimstone</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string></affiliations></json:item><json:item><name>R Namdari</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string></affiliations></json:item><json:item><name>N Price</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string></affiliations></json:item><json:item><name>C Cohen</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string></affiliations></json:item><json:item><name>RP Sherrington</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</json:string></affiliations></json:item><json:item><name>MR Hayden</name><affiliations><json:string>Department of Clinical Development, Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada</json:string><json:string>Department of Medical Genetics, University of British Columbia, British Columbia, Vancouver, Canada</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>congenital indifference to pain</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>erythromelalgia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Nav1.7</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pain genetics</value></json:item></subject><articleId><json:string>CGE1942</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>reviewArticle</json:string></originalGenre><abstract>We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. 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Columbia</countryPart><country>Canada</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="cge1942-aff-0002"><orgDiv>Department of Medical Genetics</orgDiv><orgName>University of British Columbia</orgName><address><city>Vancouver</city><countryPart>British Columbia</countryPart><country>Canada</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="cge1942-kwd-0001">congenital indifference to pain</keyword><keyword xml:id="cge1942-kwd-0002">erythromelalgia</keyword><keyword xml:id="cge1942-kwd-0003">Nav1.7</keyword><keyword xml:id="cge1942-kwd-0004">pain genetics</keyword></keywordGroup><abstractGroup><abstract type="main"><p>We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by <fc><i>SCN9A</i></fc>) as a critical and novel target for analgesic development. Strong human validation has emerged with <fc><i>SCN9A</i></fc> gain‐of‐function mutations causing inherited erythromelalgia (<fc>IEM</fc>) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (<fc>XEN402</fc>) that exhibits potent, voltage‐dependent block of Nav1.7. In a small pilot study, we showed that <fc>XEN402</fc> blocks Nav1.7 mediated pain associated with <fc>IEM</fc> thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof‐of‐concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.</p></abstract></abstractGroup></contentMeta><noteGroup><title type="main">Conflict of interest</title><note xml:id="cge1942-note-0001" numbered="no"><p>YPG, SNP, RN, NP, CC, RPS are employees of Xenon Pharmaceuticals and MRH is a consultant to Xenon Pharmaceuticals.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Human Mendelian pain disorders: a key to discovery and validation of novel analgesics</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Human Mendelian pain disorders</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Human Mendelian pain disorders: a key to discovery and validation of novel analgesics</title></titleInfo><name type="personal"><namePart type="given">YP</namePart><namePart type="family">Goldberg</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><affiliation>Corresponding author: Y Paul Goldberg, Department of Clinical Development, Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, British Columbia V5G 4 W8, Canada.Tel.: +001 604 484 3362fax: +001 604 484 3321e‐mail:</affiliation><affiliation>E-mail: pgoldberg@xenon-pharma.com</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">SN</namePart><namePart type="family">Pimstone</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Namdari</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Price</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Cohen</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">RP</namePart><namePart type="family">Sherrington</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, British Columbia, Burnaby, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">MR</namePart><namePart type="family">Hayden</namePart><affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada</affiliation><affiliation>Department of Medical Genetics, University of British Columbia, British Columbia, Vancouver, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="review-article" displayLabel="reviewArticle"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2012-10</dateIssued><dateCreated encoding="w3cdtf">2012-07-31</dateCreated><dateCaptured encoding="w3cdtf">2012-06-14</dateCaptured><dateValid encoding="w3cdtf">2012-07-23</dateValid><edition>Goldberg YP, Pimstone SN, Namdari R, Price N, Cohen C, Sherrington RP, Hayden MR. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.</edition><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain‐of‐function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage‐dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof‐of‐concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.</abstract><subject><genre>keywords</genre><topic>congenital indifference to pain</topic><topic>erythromelalgia</topic><topic>Nav1.7</topic><topic>pain genetics</topic></subject><relatedItem type="host"><titleInfo><title>Clinical Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Clin Genet</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>REVIEW</topic></subject><identifier type="ISSN">0009-9163</identifier><identifier type="eISSN">1399-0004</identifier><identifier type="DOI">10.1111/(ISSN)1399-0004</identifier><identifier type="PublisherID">CGE</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>82</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>367</start><end>373</end><total>7</total></extent></part></relatedItem><identifier type="istex">5BF4208F8F7514ADA3521D4DBA814788C58DD32E</identifier><identifier type="DOI">10.1111/j.1399-0004.2012.01942.x</identifier><identifier type="ArticleID">CGE1942</identifier><accessCondition type="use and reproduction" contentType="copyright">>© 2012 John Wiley & Sons A/S© 2012 John Wiley & Sons A/S</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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