CMT patients have nerve-muscle communication deficits: Study

ESTABLISH study findings tie severity of impairment to severity of disease

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The transmission of signals between the nerves and muscles is impaired in people with Charcot-Marie-Tooth (CMT) type 1 or 2, and the severity of this impairment appears to be related to the disease’s.

That’s according to findings from ESTABLISH (NCT04980807), an observational study launched by NMD Pharma in 2021 to learn how CMT manifests at the neuromuscular junction (NMJ), the point of contact between nerves and muscles.

“We are excited to report the identification of an aspect of the disease that could represent a breakthrough in the identification of novel treatments for CMT,” William David Arnold, MD, the trial’s principal investigator at Ohio State University, said in a NMD Pharma press release. Arnold is also the executive director at the University of Missouri’s NextGen Precision Health.

The study has provided important information about how to measure NMJ transmission reliably, which could inform future clinical trial outcomes and to develop new treatments.

The ESTABLISH results were presented by NMD Pharma in the poster “Neuromuscular Junction Transmission Dysfunction in Patients with Charcot-Marie-Tooth Disease − The ESTABLISH Study,” (abstract P 074) at this year’s Peripheral Nerve Society meeting, June 17-20, in Copenhagen, Denmark.

“With no currently approved treatments or therapies for this debilitating disease, uncovering NMJ transmission failure as a new disease mechanism in CMT represents a significant milestone for the development of new therapies including our novel ClC-1 inhibitor treatment approach,” said Jorge A. Quiroz, NMD Pharma’s chief medical officer.

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Measuring NMJ signal transmission

NMD670 is an experimental, orally available small molecule that’s designed to suppress ClC-1, a channel protein in muscles that’s involved in voluntary movement. Preclinical work has suggested blocking ClC-1 improves NMJ transmission and muscle function.

Plus, data from an early, small trial with myasthenia gravis, a neuromuscular disease, showed NMD670 safely and effectively improved muscle function and strength.

CMT is an inherited disease that damages the peripheral nerves outside the brain and spinal cord. These nerves control movement and relay sensory information, such as the sense of touch, to the brain. When they become damaged, a range of symptoms can result, from muscle weakness to loss of sensation or numbness.

While previous preclinical evidence suggested NMJ problems contribute to CMT’s motor deficits, this hadn’t been confirmed, leading NMD Pharma to launch the ESTABLISH study where researchers examined the NMJ signal transmission of 21 people with CMT type 1 or type 2, the most common forms of the disease, and 10 healthy people. The two groups were about the same average age (46.4 vs. 43.3).

To measure NMJ transmission, the researchers used two different electrophysiological tests — single fiber electromyography and repetitive nerve stimulation. The first measures an individual muscle fiber’s response to electrical stimulation. The second assesses a nerve cell’s ability to transmit a signal over multiple rounds of stimulation.

Because the researchers wanted to determine the tests’ reliability, they were given multiple times to see if the results remained consistent. The healthy group performed the tests once.

The researchers also analyzed potential associations between electrophysiological and clinical outcomes — including a measure of muscle strength called dynamometry, the six-minute walk test (a measure of exercise capacity), and the Berg balance scale, which measures balance.

Results showed that jitter, a measure of NMJ transmission variability, was significantly higher, by nearly two times, in CMT patients relative to healthy people (median, 56.3 vs. 29.4 microseconds). The CMT group also showed significantly higher blocking, a measure of NMJ transmission failure than the healthy group (median, 13.4% vs. 0%).

CMT type 2 patients showed higher jitter and blocking values than type 1 patients.

In the CMT group, both jitter and blocking correlated with measures of strength, mobility, fatigue, and balance, meaning they were linked to how severe the disease was.

This means NMJ may fail to “effectively transmit signals from nerves to muscles and that the level of transmission failure correlates with the functional capabilities of the patients,” said Henning Andersen, MD, PhD, the trial’s principal investigator at Aarhus University Hospital, Denmark. “This opens the door for pharmacologically targeting the transmission failure to improve symptoms in patients with CMT.”

Both single fiber electromyography and repetitive nerve stimulation were well tolerated and produced consistent results, but single fiber electromyography was more accurate and reliable in measuring NMJ transmission.

NMD Pharma plans to publish the study’s full data in a peer-reviewed journal.