Brian Wainger, MD, PhD: Motor Neuron Excitability in ALS

January 4, 2021
Brian Wainger, MD, PhD

Assistant professor in anesthesiology and neurology, Harvard Medical School; and attending physician, Massachusetts General Hospital

The assistant professor of neurology and anesthesiology at Harvard Medical School provided context on the potential of motor neuron excitability in patients with ALS.

"In basic science literature, there’s more connecting of different ALS disease processes to this abnormal excitability. Aside from the clinical diagnosis, motor and muscle weakening and things of that sort, it’s really 1 of the strongest signals. I shouldn’t over-speak, but it is definitely a consistent feature among a broad range of pathologically different ALS.”

Recently published results from a phase 2 study showed a decrease in motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) when they were receiving treatment with ezogabine. The data suggested that these neurophysiological metrics have potential and may be used a pharmacodynamic biomarker in future clinical trials.

Change in short-interval intracortical inhibition, the primary outcome of the study, increased by 53% in the 900-mg/day ezogabine group when compared to those on placebo (P = .009). This was the first study done using ezogabine—a once FDA-approved treatment for partial-onset seizures uncontrolled by medications—in patients with ALS. Strong clinical evidence that supported hyperexcitability as a prominent phenotype in both familial and sporadic ALS helped investigators move directly from induced pluripotent stem cell (iPSC) modeling to a clinical trial.

Lead investigator Brian Wainger, MD, PhD, feels as though abnormal excitability remains a consistent factor among patients with ALS. Wainger, assistant professor, neurology and anesthesiology, Harvard Medical School, and physician scientist and principal investigator, Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, sat down with NeurologyLive to provide background on the study and the importance of his results.

REFERENCE
Wainger BJ, Macklin EA, Vucic S, et al. Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol. Published online November 23, 2020. doi: 10.1001/jamaneurol.2020.4300