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Stephen Waxman, MD, PhD

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

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Stephen Waxman, MD, PhD

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Research Summary

My research program uses molecular genetic, biophysical, stem-cell based and pharmacological technicues, togetther with sophisticated molecular imaging and computer simulations, to study the molecular basis for neurological diseases, especially spinal cord injury, multiple sclerosis, and neuropathic pain, and to search for new treatments that will alleviate suffering in these disorder.. On major interest focuses the molecular basis for functional recovery after CNS injury. Our studies were the first to explicate how remissions (recovery of function) occur in MS, and demonstrated the remarkable molecular remodeling of sodium channels that enables demyelinated axons to recover the capability to conduct impulses. Our early studies also demonstrated the modification of conduction properties by pharmacological modulation of ion channels, an approach that has led to clinical studies in multiple sclerosis and spinal cord injury.

In our studies on neuropathic pain, we were the first to show the role of sodium channels in the regulation of excitability of pain-signaling sensory neurons. We are a world-wide hub for the study of gene mutations that prduce or alleviate pain. Our studies of inherited erythromelalgia (IEM, the "man on fire syndrome") provide a genetic model of neuropathic pain in humans and identify sodium channel Nav1.7gene SCN9A) as a major regulator of human pain. . For example, we have demonstrated (Cao et al, Science Translational Medicine 2016) 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. This research is ongoing, and w are optimistic that pain-relief through selective blockade of Nav1.7 can be achieved for more common pain indications within the general population.

A second pharmacogenomic approach, now published in JAMA Neurology (Geha et al 2016), 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.

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.

In another line of work, we are using molecular genetics and stem-cell derived models to identify pain resilience genes (Mis et al, Journal of Neuroscience, 2019

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. We have also used molecular genetics and stem-cell derived models to identify pain resilience genes.

We are using state-of-the art molecular imaging to determine how nerve cell build their excitable membranes, molecule by molecule. 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.


Research Interests

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

Selected Publications