Axons; Electrophysiology; Ion Channels; Multiple Sclerosis; Neurology; Neurosciences; Sodium Channels; Stroke
My research program focuses on the application of molecular techniques to the study of neurological diseases, especially spinal cord injury, multiple sclerosis, and neuropathic pain. We are interested in understanding the molecular basis for functional recovery after CNS injury. Our studies on ion channels in impulse conduction in normal, demyelinated, and regenerating nerve fibers use molecular biological, immunoultrastructural, pharmacological, and patch-clamp techniques. We are also investigating the modification of conduction properties by pharmacologically altering ion channel characteristics, an approach that has led to clinical studies in multiple sclerosis and spinal cord injury.
In addition, we are studying the role of sodium channels in the regulation of excitability of pain-signaling sensory neurons. On the basis of studies of familial erythromelalgia, which provides a genetic model of neuropathic pain in humans, we have identified sodium channel Nav1.7 (encoded by gene SCN9A) as a major player in pain. Our recent paper in JAMA Neurology (Geha et al, 2016) moves us closer to personalized, genomically-guided treatment of patients with pain. The second, published recently in Science Translational Medicine (Cao et al, 2016) reports the first results, in humans, on a new class of pain medications that selectively target peripheral sodium channel Nav1.7, and thus do not have central side-effects.
Both studies were carried out in patients with inherited erythromelalgia (IEM, also known as the “Man-on-Fire” syndrome), a human genetic model of neuropathic pain. Affected individuals experience excruciating burning pain due to gain-of-function mutations in Nav1.7 that make pain-signaling neurons hyperexcitable, so that they send high-frequency pain signals in response to benign triggers such as mild warmth.
Our pharmacogenomic approach, now published in JAMA Neurology, interrogated the genomes of patients with IEM to search for gene variants that enhance responsiveness to existing medications, and used molecular modeling and functional analysis to confirm drug engagement of Nav1.7 for two patients with one particular mutation (S241T). Our double-blind, placebo-controlled study demonstrated that the drug, carbamazepine, reduced the patients’ pain. Functional imaging showed that reduction in pain was paralleled by a shift in brain activity from areas involved in emotional processing to areas encoding accurate sensation. Although these observations apply in the strictest sense only to patients carrying one unique IEM mutation, our results provide proof-of-principle that this precision medicine approach, using genomics and molecular modeling, can match patients with specific medications for relief of chronic pain.
Our second approach uses selective targeting of peripheral sodium channel Nav1.7, based on our validation of Nav1.7 as a human pain target through studies that began in 2004. In a collaboration with Pfizer that began in 2009, we studied a subtype-specific Nav1.7 blocker as a prototype of a new class of orally bioavailable compounds that may achieve pain relief without central side effects. Together with Pfizer, we now report in Science Translational Medicine that blockade of Nav1.7 reduces firing in nociceptive neurons, and provides pain relief in human subjects carrying gain-of-function mutations in Nav1.7. We also demonstrate the use of induced pluripotent stem cells (iPSC) as a patient-derived “pain-in-a-dish” model containing the patient’s entire genome that can enable rapid screening of drugs for pain. With ongoing collaborations with biopharmaceutical companies including Convergence-Biogen, we are optimistic that pain-relief through selective Nav1.7 blockade can be achieved for more common pain indications within the general population.
The Editorial accompanying our pharmacogenomic study in JAMA Neurology noted that “this study provides an intelligent practical demonstration of the growing value of molecular neurological reasoning… There are relatively few examples in medicine where molecular reasoning is rewarded with a comparable degree of success.” There is a lot of work ahead of us, but we are optimistic that our findings presage the arrival of a new generation of precision treatments for patients with chronic pain.
We hope that our work will lead to new therapies not only for neuropathic pain but also for multiple sclerosis, spinal cord injury, and related disorders.
Specialized Terms: Axons; Electrophysiology; Genes; Ion Channels; Molecular Biology; Multiple Sclerosis; Pain Syndromes; Sodium Channels; Spinal Cord Injury; Stroke; Translational Neuroscience.
Extensive Research Description
My laboratory focuses on functional recovery in diseases of the brain and spinal cord. In particular, we use a spectrum of methods including molecular biology and genetics, cell biology, electrophysiology, computer simulations, molecular modeling etc. to understand how the nervous system responds to injury, and how we can induce functional recovery. Approaching these issues from a molecule- and mechanism-driven standpoint, we have a special interest in spinal cord injury, multiple sclerosis, and neuropathic pain. Our early studies demonstrated the molecular basis for remissions in MS. We have a major interest in the role of ion channels in diseases of the brain and spinal cord. We have demonstrated, for example, that following injury to their axons, spinal sensory neurons turn off some sodium channel genes, while turning others on. This results in the production of different types of sodium channels (with different kinetics and voltage-dependencies) in these neurons, causing them to become hyperexcitability and thereby contributing to neuropathic pain.
We are also interested in hereditary neuropathic pain and have delineated, for the first time, the molecular basis for a hereditary pain syndrome (inherited erythromelalgia; OMIM #133020;#603415). We have identified mutations in ion channel genes that cause painful peripheral neuropathy, and are moving toward pharmacogenomically-guided pain pharmacotherapy.
My laboratory is also examining the role of abnormal sodium channel expression in spinal cord injury (SCI) and multiple sclerosis (MS). Specific projects focus on molecular mechanisms of recovery of conduction along demyelinated axons, and on molecular substrates of axonal degeneration. We are also studying neuroprotection, and have demonstrated that it is possible to pharmacologically protect axons, so they don't degenerate in SCI and MS.
- Gain-of-function NaV1.8 mutations in painful neuropathy. Faber, C.G., Lauria, G., Merkies, I.S.J., Cheng, X., Han, C., Ahn, H-S., Persson, A-K., Hoeijmakers, J.G.J., Gerrits, M.M., Pierro, T., Lombardi, R., Kapetis, D., Dib-Hajj, S.D., and Waxman, S.G. Gain-of-function NaV1.8 mutations in painful neuropathy. PNAS, 109:19444-19449, 2012. PMID: 23115331
- The NaV1.7 sodium channel: from molecule to man. Dib-Hajj, S.D., Yang, Y., Black, J.A., Waxman, S.G. The NaV1.7 sodium channel: from molecule to man. Nat Rev Neurosci, 14(1): 49-62, 2012. PMID: 23232607
- Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel. Yang, Y., Dib-Hajj, S.D., Zhang, J., Zhang, Y., Tyrrell, L., Estacion, M., and Waxman, S.G. Structural modeling and mutant cycle analysis predict pharmacoresponsiveness of a NaV1.7 mutant channel, Nature Comm., 3: 1186, 2012. PMID 23149731
- Sodium Channels and neuroprotection in MS: current status Waxman, S.G. (2008) Sodium Channels and neuroprotection in MS: current status., Nature Clinical Neurology, 4, 159-170
- Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Black, J.A., Nikolajsen, L., Kroner, K., Jensen, T.S., and Waxman, S.G., Multiple sodium channel isoforms and MAP kinases are present in painful human neuromas. Annals of Neurology, 64(6): 644-53, 2008. PMID: 19107992.
- Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. Rush, A.M., Cummins, T.R., Waxman, S.G. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J. Physiol. 579:1-14, 2007. PMID: 17158175
- Channel, neuronal, and clinical function in sodium channelopathies: From genotype to phenotype. Waxman, S.G., Channel, neuronal, and clinical function in sodium channelopathies: From genotype to phenotype. Nature Neuroscience, 10:405-410, 2007. PMID: 17387329
- Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Waxman, S.G. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nature Rev. Neurosci., 5: 932-942, 2006. PMID: 17115075
- Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. Geha, P., Yang, Y., Estacion, M., Schulman, B.R., Tokuno, H., Apkarian, A.V., Dib-Hajj, S.D., Waxman, S.G. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. JAMA Neurol., in press, 2016. PMID: 27088781
- Cao, L., Nitzsche, N., McDonnell, A., Alexandrou, A., Saintot, P-P., Loucif, A.J.C., Brown, A.R., Young, G., Mis, M., Randall, A., Waxman, S.G., Stanley, P., Kirby, S., Tarabar, S., Gutteridge, A., Butt, R., McKernan, R.M., Whiting, R., Ali, Z., Bilsland, J., Stevens, E.B. Pharmacological reversal of pain phenotype in iPSC-derived sensory neurons and human subjects with inherited erythromelalgia, Science Translational Medicine, 8(335): 335ra56, 2016. PMID: 27099175