From Targets to Therapies for Neuropathic Pain

Our goal is to develop improved therapies for neuropathic pain. To this end, our investigations range from molecular studies in vitro and in animal models to translational studies in humans, and from rare genetic model diseases to common disorders affecting the population-at-large. We have, for example, identified and characterized sodium channel Nav1.7 as a highly suitable target for neuropathic pain (Dib-Hajj et al., 2010, 2013; Black et al., 2008). Nav1.7 is preferentially expressed in peripheral neurons (Rush et al., 2006), and expressed only at very low levels in the central nervous system and heart. Targeted blockade of Nav1.7 would thus be predicted to carry minimal risk of abuse or addiction, and few, if any, CNS or cardiac side effects. This prediction is further supported by the observation that individuals lacking functioning Nav1.7 are appear normal except for their insensitivity to pain and anosmia. Our research has provided impetus to the pharmaceutical/biotech sectors to develop Nav1.7-specific blockers for the treatment of neuropathic pain (McDonnell et al., 2016; Cao et al., 2016).

Personalized treatments, guided by the patient’s unique genetic blueprint, also hold promise for optimal pain-relief in patients with neuropathic pain. We are studying individual-to-individual genetic variations in Nav1.7 that may affect a person’s response to neuropathic pain medications (Fischer et al., 2009). We have, for example, developed molecular modeling tools that can interrogate the interplay between individual genetic variations and available pain medications, so as to predict the most appropriate line of treatment for each individual patient (Yang et al., 2012). Informed by such in silico interrogations of a genetic variant that responds more favorably to carbamazepine, we were able to successfully tailor a treatment plan with improved clinical outcomes for a patient with the debilitating and painful condition, inherited erythromelalgia (Geha et al., 2016). We are currently building on this approach to define subgroups within the general population in their ability to respond to specific pain medications.

Publications

Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325-47.

Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Nav1.7 sodium channel: from molecule to man. Nat Rev Neurosci. 2013 Jan;14(1):49-62.

Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol. 2008 Dec; 64(6):644-53.

Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8245-50.

McDonnell A, Schulman B, Ali Z, Dib-Hajj SD, Brock F, Cobain S, Mainka T, Vollert J, Tarabar S, Waxman SG. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile. Brain. 2016 Feb 26. 

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, Bisland J, Stevens EB.  Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci. Transl Med. 2016 Apr 20:8(335). 

Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib-Hajj SD, Waxman SG. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol. 2009 Jun; 65(6):733-41.

Yang Y, Dib-Hajj SD, Zhang J, Zhang Y, Tyrrell L, Estacion M, Waxman SG. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel. Nat Commun. 2012;3:1186.

Geha P, Yang Y, Estacion M, Schulman BR, Tokuno H, Apkarian AV, Dib-Hajj SD, Waxman SG. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. JAMA Neurol. 2016 Jun 1:73(6):659-67.