ParkinsonCanadaV1, PascalFrancis, Corpus, bibRecord, 000171

Human Mendelian pain disorders: a key to discovery and validation of novel analgesics

Identifieur interne : 000171 ( PascalFrancis/Corpus ); précédent : 000170; suivant : 000172

Human 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. Hayden

Source :

Clinical genetics [ 0009-9163 ] ; 2012.

RBID : Pascal:12-0366791

Descripteurs français

Pascal (Inist)
- Erythromélalgie, Homme, Douleur, Validation test, Analgésique, Congénital, Génétique.

English descriptors

KwdEn :
- Analgesic, Congenital, Erythromelalgia, Genetics, Human, Pain, Test validation.

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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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A02	`01`			`@0 CLGNAY`
A03		`1`		`@0 Clin. genet.`
A05				`@2 82`
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A08	`01`	`1`	`ENG`	`@1 Human Mendelian pain disorders: a key to discovery and validation of novel analgesics`
A11	`01`	`1`		`@1 GOLDBERG (Y. P.)`
A11	`02`	`1`		`@1 PIMSTONE (S. N.)`
A11	`03`	`1`		`@1 NAMDARI (R.)`
A11	`04`	`1`		`@1 PRICE (N.)`
A11	`05`	`1`		`@1 COHEN (C.)`
A11	`06`	`1`		`@1 SHERRINGTON (R. P.)`
A11	`07`	`1`		`@1 HAYDEN (M. R.)`
A14	`01`			`@1 Department of Clinical Development, Xenon Pharmaceuticals Inc @2 Burnaby, British Columbia @3 CAN @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 4 aut. @Z 5 aut. @Z 6 aut. @Z 7 aut.`
A14	`02`			`@1 Department of Medical Genetics, University of British Columbia @2 Vancouver, British Columbia @3 CAN @Z 7 aut.`
A20				`@1 367-373`
A21				`@1 2012`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 15185 @5 354000504493890080`
A44				`@0 0000 @1 © 2012 INIST-CNRS. All rights reserved.`
A45				`@0 54 ref.`
A47	`01`	`1`		`@0 12-0366791`
A60				`@1 P`
A61				`@0 A`
A64	`01`	`1`		`@0 Clinical genetics`
A66	`01`			`@0 GBR`
C01	`01`		`ENG`	@0 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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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.
C02	`01`	`X`		`@0 002A04`
C02	`02`	`X`		`@0 002A07`
C02	`03`	`X`		`@0 002B23`
C02	`04`	`X`		`@0 002B08G`
C03	`01`	`X`	`FRE`	`@0 Erythromélalgie @5 01`
C03	`01`	`X`	`ENG`	`@0 Erythromelalgia @5 01`
C03	`01`	`X`	`SPA`	`@0 Eritromelalgia @5 01`
C03	`02`	`X`	`FRE`	`@0 Homme @5 09`
C03	`02`	`X`	`ENG`	`@0 Human @5 09`
C03	`02`	`X`	`SPA`	`@0 Hombre @5 09`
C03	`03`	`X`	`FRE`	`@0 Douleur @5 10`
C03	`03`	`X`	`ENG`	`@0 Pain @5 10`
C03	`03`	`X`	`SPA`	`@0 Dolor @5 10`
C03	`04`	`X`	`FRE`	`@0 Validation test @5 11`
C03	`04`	`X`	`ENG`	`@0 Test validation @5 11`
C03	`04`	`X`	`SPA`	`@0 Validación prueba @5 11`
C03	`05`	`X`	`FRE`	`@0 Analgésique @5 12`
C03	`05`	`X`	`ENG`	`@0 Analgesic @5 12`
C03	`05`	`X`	`SPA`	`@0 Analgésico @5 12`
C03	`06`	`X`	`FRE`	`@0 Congénital @5 13`
C03	`06`	`X`	`ENG`	`@0 Congenital @5 13`
C03	`06`	`X`	`SPA`	`@0 Congénito @5 13`
C03	`07`	`X`	`FRE`	`@0 Génétique @5 14`
C03	`07`	`X`	`ENG`	`@0 Genetics @5 14`
C03	`07`	`X`	`SPA`	`@0 Genética @5 14`
C07	`01`	`X`	`FRE`	`@0 Acrosyndrome @5 37`
C07	`01`	`X`	`ENG`	`@0 Acrosyndrome @5 37`
C07	`01`	`X`	`SPA`	`@0 Acrosíndrome @5 37`
C07	`02`	`X`	`FRE`	`@0 Pathologie de l'appareil circulatoire @5 38`
C07	`02`	`X`	`ENG`	`@0 Cardiovascular disease @5 38`
C07	`02`	`X`	`SPA`	`@0 Aparato circulatorio patología @5 38`
C07	`03`	`X`	`FRE`	`@0 Pathologie des capillaires sanguins @5 39`
C07	`03`	`X`	`ENG`	`@0 Capillary vessel disease @5 39`
C07	`03`	`X`	`SPA`	`@0 Capilar sanguíneo patología @5 39`
C07	`04`	`X`	`FRE`	`@0 Pathologie de la peau @5 40`
C07	`04`	`X`	`ENG`	`@0 Skin disease @5 40`
C07	`04`	`X`	`SPA`	`@0 Piel patología @5 40`
C07	`05`	`X`	`FRE`	`@0 Pathologie des vaisseaux sanguins @5 41`
C07	`05`	`X`	`ENG`	`@0 Vascular disease @5 41`
C07	`05`	`X`	`SPA`	`@0 Vaso sanguíneo patología @5 41`
N21				`@1 282`
N44	`01`			`@1 OTO`
N82				`@1 OTO`

Format Inist (serveur)

NO :	PASCAL 12-0366791 INIST
ET :	Human Mendelian pain disorders: a key to discovery and validation of novel analgesics
AU :	GOLDBERG (Y. P.); PIMSTONE (S. N.); NAMDARI (R.); PRICE (N.); COHEN (C.); SHERRINGTON (R. P.); HAYDEN (M. R.)
AF :	Department of Clinical Development, Xenon Pharmaceuticals Inc/Burnaby, British Columbia/Canada (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 6 aut., 7 aut.); Department of Medical Genetics, University of British Columbia/Vancouver, British Columbia/Canada (7 aut.)
DT :	Publication en série; Niveau analytique
SO :	Clinical genetics; ISSN 0009-9163; Coden CLGNAY; Royaume-Uni; Da. 2012; Vol. 82; No. 4; Pp. 367-373; Bibl. 54 ref.
LA :	Anglais
EA :	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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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.
CC :	002A04; 002A07; 002B23; 002B08G
FD :	Erythromélalgie; Homme; Douleur; Validation test; Analgésique; Congénital; Génétique
FG :	Acrosyndrome; Pathologie de l'appareil circulatoire; Pathologie des capillaires sanguins; Pathologie de la peau; Pathologie des vaisseaux sanguins
ED :	Erythromelalgia; Human; Pain; Test validation; Analgesic; Congenital; Genetics
EG :	Acrosyndrome; Cardiovascular disease; Capillary vessel disease; Skin disease; Vascular disease
SD :	Eritromelalgia; Hombre; Dolor; Validación prueba; Analgésico; Congénito; Genética
LO :	INIST-15185.354000504493890080
ID :	12-0366791

Links to Exploration step

Pascal:12-0366791

Le document en format XML

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<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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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>
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<fA14 i1="01"><s1>Department of Clinical Development, Xenon Pharmaceuticals Inc</s1>
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<fA21><s1>2012</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
</fA23>
<fA43 i1="01"><s1>INIST</s1>
<s2>15185</s2>
<s5>354000504493890080</s5>
</fA43>
<fA44><s0>0000</s0>
<s1>© 2012 INIST-CNRS. All rights reserved.</s1>
</fA44>
<fA45><s0>54 ref.</s0>
</fA45>
<fA47 i1="01" i2="1"><s0>12-0366791</s0>
</fA47>
<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
</fA61>
<fA64 i1="01" i2="1"><s0>Clinical genetics</s0>
</fA64>
<fA66 i1="01"><s0>GBR</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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.</s0>
</fC01>
<fC02 i1="01" i2="X"><s0>002A04</s0>
</fC02>
<fC02 i1="02" i2="X"><s0>002A07</s0>
</fC02>
<fC02 i1="03" i2="X"><s0>002B23</s0>
</fC02>
<fC02 i1="04" i2="X"><s0>002B08G</s0>
</fC02>
<fC03 i1="01" i2="X" l="FRE"><s0>Erythromélalgie</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="ENG"><s0>Erythromelalgia</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Eritromelalgia</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Homme</s0>
<s5>09</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Human</s0>
<s5>09</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Hombre</s0>
<s5>09</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Douleur</s0>
<s5>10</s5>
</fC03>
<fC03 i1="03" i2="X" l="ENG"><s0>Pain</s0>
<s5>10</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Dolor</s0>
<s5>10</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Validation test</s0>
<s5>11</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Test validation</s0>
<s5>11</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Validación prueba</s0>
<s5>11</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Analgésique</s0>
<s5>12</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Analgesic</s0>
<s5>12</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Analgésico</s0>
<s5>12</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Congénital</s0>
<s5>13</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Congenital</s0>
<s5>13</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Congénito</s0>
<s5>13</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Génétique</s0>
<s5>14</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Genetics</s0>
<s5>14</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>Genética</s0>
<s5>14</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Acrosyndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Acrosyndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Acrosíndrome</s0>
<s5>37</s5>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Pathologie de l'appareil circulatoire</s0>
<s5>38</s5>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Cardiovascular disease</s0>
<s5>38</s5>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Aparato circulatorio patología</s0>
<s5>38</s5>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Pathologie des capillaires sanguins</s0>
<s5>39</s5>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Capillary vessel disease</s0>
<s5>39</s5>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Capilar sanguíneo patología</s0>
<s5>39</s5>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Pathologie de la peau</s0>
<s5>40</s5>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Skin disease</s0>
<s5>40</s5>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Piel patología</s0>
<s5>40</s5>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Pathologie des vaisseaux sanguins</s0>
<s5>41</s5>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Vascular disease</s0>
<s5>41</s5>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Vaso sanguíneo patología</s0>
<s5>41</s5>
</fC07>
<fN21><s1>282</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
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<server><NO>PASCAL 12-0366791 INIST</NO>
<ET>Human Mendelian pain disorders: a key to discovery and validation of novel analgesics</ET>
<AU>GOLDBERG (Y. P.); PIMSTONE (S. N.); NAMDARI (R.); PRICE (N.); COHEN (C.); SHERRINGTON (R. P.); HAYDEN (M. R.)</AU>
<AF>Department of Clinical Development, Xenon Pharmaceuticals Inc/Burnaby, British Columbia/Canada (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 6 aut., 7 aut.); Department of Medical Genetics, University of British Columbia/Vancouver, British Columbia/Canada (7 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Clinical genetics; ISSN 0009-9163; Coden CLGNAY; Royaume-Uni; Da. 2012; Vol. 82; No. 4; Pp. 367-373; Bibl. 54 ref.</SO>
<LA>Anglais</LA>
<EA>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 Nav 1.7 (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 Navl.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 Navl.7. In a small pilot study, we showed that XEN402 blocks Navl.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.</EA>
<CC>002A04; 002A07; 002B23; 002B08G</CC>
<FD>Erythromélalgie; Homme; Douleur; Validation test; Analgésique; Congénital; Génétique</FD>
<FG>Acrosyndrome; Pathologie de l'appareil circulatoire; Pathologie des capillaires sanguins; Pathologie de la peau; Pathologie des vaisseaux sanguins</FG>
<ED>Erythromelalgia; Human; Pain; Test validation; Analgesic; Congenital; Genetics</ED>
<EG>Acrosyndrome; Cardiovascular disease; Capillary vessel disease; Skin disease; Vascular disease</EG>
<SD>Eritromelalgia; Hombre; Dolor; Validación prueba; Analgésico; Congénito; Genética</SD>
<LO>INIST-15185.354000504493890080</LO>
<ID>12-0366791</ID>
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Human Mendelian pain disorders: a key to discovery and validation of novel analgesics

Human Mendelian pain disorders: a key to discovery and validation of novel analgesics

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