Stephen George Waxman, MD, PhD

Bridget M. Flaherty Professor of Neurology; Director, Center for Neuroscience and Regeneration Research

Research Interests

Axons; Electrophysiology; Ion Channels; Multiple Sclerosis; Neurology; Neurosciences; Sodium Channels; Stroke

Research Organizations

Neurology

Center for Neuroscience and Regeneration Research

Interdepartmental Neuroscience Program

Neuropharmacology

Office of Cooperative Research

Research Summary

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.

Selected Publications

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Contact Info

Stephen George Waxman, MD, PhD
Office Location
Center for Neuroscience & Regeneration ResearchVA Connecticut Healthcare
950 Campbell Avenue, Ste BLDG. 34

West Haven, CT 06516
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Mailing Address
Neurosci. Res. Ctr. (BLDG. 34)VA Hospital
950 Campbell Ave

West Haven, CT 06516

Curriculum Vitae

Waxman Lab/Center for Neuroscience & Regeneration Research