Antiepileptic drug reduces motor neuron excitability in ALS

BOSTON – The antiepileptic drug ezogabine reduced pathologic excitability of cortical and spinal motor neuron cells that are early signs of clinical dysfunction in people with amyotrophic lateral sclerosis (ALS), according to a study conducted by the Neurological Clinical Research Institute of Massachusetts General Hospital (MGH). In addition to providing a clearer understanding of motor neuron excitability as an important disease pathway for ALS, the multi-site study, published in JAMA Neurology, involves the first clinical investigation of ALS (also known as Lou Gehrig’s disease) using a drug identified through an induced pluripotent stem cell (iPSC) model.

“The stem cell approach allowed us to capture the hyperexcitability of motor neurons -- a prominent disease phenotype -- and to then show ezogabine was able to reduce it in people with ALS,” says lead author Brian Wainger, MD, PhD, of the Healey Center for ALS at MGH. “Our findings could have important implications for the field of ALS research both by demonstrating the effect of ezogabine on excitability in people with the disease and by showing that the metrics of cortical and spinal motor neuron excitability may be used as drug biomarkers in multi-site clinical trials.”

ALS is a progressive neurodegenerative disorder that leads to the death of neurons in the brain and spinal cord that control speech, swallowing and limb movements. Named after the famous baseball player Lou Gehrig, who was diagnosed with the disease in 1939, there are around 20,000 people in the U.S. with ALS, and another 5,000 newly diagnosed cases each year. Currently, there are three approved drugs in the U.S. for treating ALS, each with limited benefit, creating an urgent need for new therapies that could change the course of the fatal disease.

The MGH study of ezogabine was not designed to assess the long-term effects of the drug on the neurodegenerative disorder, but rather to unravel the biological processes that go awry and identify novel molecular targets for drug intervention. To that end, the ten-week, phase 2 study of 65 participants with ALS at 12 U.S. sites investigated the feasibility of using neuron excitability metrics as predictors of disease progression. “We demonstrated for the first time that these neurophysiological assays can be effectively deployed across multiple study sites, which is important in trials of diseases like ALS where investigators rely on many sites for recruitment,” explains Wainger. “That finding could be useful in evaluating other drugs to treat ALS, or even for other diseases where motor neuron metrics could serve as key biomarkers.”

Ezogabine (also known as retigabine) had been previously approved by the U.S. Food and Drug Administration (FDA) for treating epilepsy with a unique mechanism of action: facilitating potassium channels in cell membranes that play a central role in controlling neuron excitability, particularly important in the control of seizures. Researchers from MGH’s Neurological Clinical Research Institute began evaluating the drug’s potential in the context of ALS, using transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS) to measure the effects of ezogabine on motor neuron excitability. They learned that ezogabine did indeed calm the excitability of motor neurons.

“Further studies are needed to determine if longer treatment will sustain the effects of reduced excitability and, if so, whether that may slow disease progression,” says Wainger. “Through our study we’ve hopefully established a new research paradigm for using iPSC-based in vitro models for identifying novel disease targets and compounds, and rapidly repurposing drugs for clinical trials.”

Wainger is assistant professor in Neurology, Anesthesia, Critical Care and Pain Medicine at Harvard Medical School (HMS). Senior author Merit Cudkowicz, MD, MSc, is chief of Neurology at MGH, director of the MGH Neurological Clinical Research Institute, and the Julieanne Dorn Professor of Neurology at HMS. Co-author Eric Macklin, PhD, is a biostatistician at the MGH Biostatistics Center.

The study was supported by the ALS Association, GlaxoSmithKline, the Harvard Stem Cell Institute and the MGH Neurological Clinical Research Institute.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of "America’s Best Hospitals."

About the Sean M. Healey & AMG Center for ALS at Mass General
At the Sean M. Healey & AMG Center for ALS at Mass General, we are on a quest to discover life-saving therapies for all people who are affected by ALS. Launched in November 2018, we are a diverse group of researchers and clinicians determined to accelerate the pace of ALS therapy development.

Under the leadership of Merit Cudkowicz, MD, chief of Neurology, and a Science Advisory Council of international experts, we partner with other experts around the globe to reimagine how to develop the right novel therapies for the right people at the right time. We are grounded in our strong belief in the partnership between people with ALS, caregivers and our team. Together we can design more efficient and more effective clinical trials and broaden access for people with ALS. For more information, please email healeycenterforals@mgh.harvard.edu and visit the center’s website https://www.massgeneral.org/neurology/als/.

About the Northeast ALS Consortium
The Northeast ALS Consortium (NEALS) is an international, independent, non-profit group of 134 research sites around the world that collaboratively conduct clinical research in Amyotrophic Lateral Sclerosis (ALS) and other motor neuron diseases. The mission of NEALS is to translate scientific advances into new treatments for people with ALS and motor neuron disease as rapidly as possible. The NEALS member sites are committed to the principles of open scientific communication, peer review, and democratic governance of the Consortium’s organization and activities. Governed by an Executive Committee, the Consortium’s research activities are advised by an experienced Scientific Advisory Board. The NEALS Science Advisory Board also regularly guides academic and industry partners on ALS targets, trial design, and conduct.

NEALS is dedicated to educating people with ALS on clinical research and therapy development and empowering them to be advocates for clinical research, along with encouraging the opportunity to influence and improve the ALS research process.