title: Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.
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.
authors: Department of Clinical Development, Xenon Pharmaceuticals Inc, Burnaby, British Columbia, Canada. pgoldberg@xenon-pharma.com
authors: Y P
authors: YP
authors: Goldberg
authors: S N
authors: SN
authors: Pimstone
authors: R
authors: R
authors: Namdari
authors: N
authors: N
authors: Price
authors: C
authors: C
authors: Cohen
authors: R P
authors: RP
authors: Sherrington
authors: M R
authors: MR
authors: Hayden
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000627:therapeutic use*; D055808:Drug Discovery / Q000379:methods; D004916:Erythromelalgia / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D000699:Pain Insensitivity, Congenital / Q000188:drug therapy* / Q000235:genetics*; D061567:Voltage-Gated Sodium Channel Blockers
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D061567:Voltage-Gated Sodium Channel Blockers