Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.
Identifieur interne : 000A17 ( PubMed/Corpus ); précédent : 000A16; suivant : 000A18Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.
Auteurs : Y P Goldberg ; S N Pimstone ; R. Namdari ; N. Price ; C. Cohen ; R P Sherrington ; M R HaydenSource :
- Clinical genetics [ 1399-0004 ] ; 2012.
English descriptors
- KwdEn :
- Analgesics (metabolism), Analgesics (therapeutic use), Drug Discovery (methods), Erythromelalgia (genetics), Humans, Mutation (genetics), NAV1.7 Voltage-Gated Sodium Channel (genetics), NAV1.7 Voltage-Gated Sodium Channel (metabolism), Pain Insensitivity, Congenital (drug therapy), Pain Insensitivity, Congenital (genetics), Voltage-Gated Sodium Channel Blockers.
- MESH :
- chemical , genetics : NAV1.7 Voltage-Gated Sodium Channel.
- chemical , metabolism : Analgesics, NAV1.7 Voltage-Gated Sodium Channel.
- chemical , therapeutic use : Analgesics.
- drug therapy : Pain Insensitivity, Congenital.
- genetics : Erythromelalgia, Mutation, Pain Insensitivity, Congenital.
- methods : Drug Discovery.
- Humans, Voltage-Gated Sodium Channel Blockers.
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.
DOI: 10.1111/j.1399-0004.2012.01942.x
PubMed: 22845492
Links to Exploration step
pubmed:22845492Le document en format XML
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Cohen</name></author><author><name sortKey="Sherrington, R P" sort="Sherrington, R P" uniqKey="Sherrington R" first="R P" last="Sherrington">R P Sherrington</name></author><author><name sortKey="Hayden, M R" sort="Hayden, M R" uniqKey="Hayden M" first="M R" last="Hayden">M R Hayden</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2012">2012</date><idno type="RBID">pubmed:22845492</idno><idno type="pmid">22845492</idno><idno type="doi">10.1111/j.1399-0004.2012.01942.x</idno><idno type="wicri:Area/PubMed/Corpus">000A17</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000A17</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.</title><author><name sortKey="Goldberg, Y P" sort="Goldberg, Y P" uniqKey="Goldberg Y" first="Y P" last="Goldberg">Y P Goldberg</name><affiliation><nlm:affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada. pgoldberg@xenon-pharma.com</nlm:affiliation></affiliation></author><author><name sortKey="Pimstone, S N" sort="Pimstone, S N" uniqKey="Pimstone S" first="S N" last="Pimstone">S N Pimstone</name></author><author><name sortKey="Namdari, R" sort="Namdari, R" uniqKey="Namdari R" first="R" last="Namdari">R. Namdari</name></author><author><name sortKey="Price, N" sort="Price, N" uniqKey="Price N" first="N" last="Price">N. Price</name></author><author><name sortKey="Cohen, C" sort="Cohen, C" uniqKey="Cohen C" first="C" last="Cohen">C. Cohen</name></author><author><name sortKey="Sherrington, R P" sort="Sherrington, R P" uniqKey="Sherrington R" first="R P" last="Sherrington">R P Sherrington</name></author><author><name sortKey="Hayden, M R" sort="Hayden, M R" uniqKey="Hayden M" first="M R" last="Hayden">M R Hayden</name></author></analytic><series><title level="j">Clinical genetics</title><idno type="eISSN">1399-0004</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Analgesics (metabolism)</term><term>Analgesics (therapeutic use)</term><term>Drug Discovery (methods)</term><term>Erythromelalgia (genetics)</term><term>Humans</term><term>Mutation (genetics)</term><term>NAV1.7 Voltage-Gated Sodium Channel (genetics)</term><term>NAV1.7 Voltage-Gated Sodium Channel (metabolism)</term><term>Pain Insensitivity, Congenital (drug therapy)</term><term>Pain Insensitivity, Congenital (genetics)</term><term>Voltage-Gated Sodium Channel Blockers</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>NAV1.7 Voltage-Gated Sodium Channel</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Analgesics</term><term>NAV1.7 Voltage-Gated Sodium Channel</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Analgesics</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Pain Insensitivity, Congenital</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Erythromelalgia</term><term>Mutation</term><term>Pain Insensitivity, Congenital</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Discovery</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Voltage-Gated Sodium Channel Blockers</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22845492</PMID><DateCreated><Year>2012</Year><Month>09</Month><Day>12</Day></DateCreated><DateCompleted><Year>2013</Year><Month>01</Month><Day>07</Day></DateCompleted><DateRevised><Year>2012</Year><Month>09</Month><Day>12</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1399-0004</ISSN><JournalIssue CitedMedium="Internet"><Volume>82</Volume><Issue>4</Issue><PubDate><Year>2012</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Clinical genetics</Title><ISOAbbreviation>Clin. Genet.</ISOAbbreviation></Journal><ArticleTitle>Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.</ArticleTitle><Pagination><MedlinePgn>367-73</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1111/j.1399-0004.2012.01942.x</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© 2012 John Wiley & Sons A/S.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Goldberg</LastName><ForeName>Y P</ForeName><Initials>YP</Initials><AffiliationInfo><Affiliation>Department of Clinical Development, Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada. pgoldberg@xenon-pharma.com</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pimstone</LastName><ForeName>S N</ForeName><Initials>SN</Initials></Author><Author ValidYN="Y"><LastName>Namdari</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Price</LastName><ForeName>N</ForeName><Initials>N</Initials></Author><Author ValidYN="Y"><LastName>Cohen</LastName><ForeName>C</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Sherrington</LastName><ForeName>R P</ForeName><Initials>RP</Initials></Author><Author ValidYN="Y"><LastName>Hayden</LastName><ForeName>M R</ForeName><Initials>MR</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>08</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>Denmark</Country><MedlineTA>Clin Genet</MedlineTA><NlmUniqueID>0253664</NlmUniqueID><ISSNLinking>0009-9163</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000700">Analgesics</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D062556">NAV1.7 Voltage-Gated Sodium Channel</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C486866">SCN9A protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D061567">Voltage-Gated Sodium Channel Blockers</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000700" MajorTopicYN="N">Analgesics</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055808" MajorTopicYN="N">Drug Discovery</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004916" MajorTopicYN="N">Erythromelalgia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D062556" MajorTopicYN="N">NAV1.7 Voltage-Gated Sodium Channel</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000699" MajorTopicYN="N">Pain Insensitivity, Congenital</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D061567" MajorTopicYN="N">Voltage-Gated Sodium Channel Blockers</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>06</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2012</Year><Month>07</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>07</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>8</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>8</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>1</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22845492</ArticleId><ArticleId IdType="doi">10.1111/j.1399-0004.2012.01942.x</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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