A recent study by Dr. Jordan Verplank, Assistant Professor in the Department of Anatomy, Physiology, and Genetics at the Uniformed Services University of the Health Sciences (USU), and a team of scientists from USU, State University of Buffalo (New York), and Cyclerion Therapeutics, has identified a promising approach for treating hereditary peripheral neuropathies, specifically Charcot Marie Tooth disease types 1A (CMT1A) and 1B (CMT1B).

By focusing on increasing levels of cyclic guanosine monophosphate (cGMP)—a signaling molecule involved in various biological processes—the study has shown potential improvements in myelination, nerve conduction, and motor coordination in mouse models affected by these conditions. The findings were published in Cellular and Molecular Life Sciences on October 14, 2024.

Charcot Marie Tooth (CMT) disease is the most common inherited neurological disorder globally, affecting approximately 1 in every 2,500 individuals. This condition impacts the peripheral nerves—the extensive network of nerves that connect the brain and spinal cord to the rest of the body.

Over time, CMT leads to the degeneration of these nerves, resulting in weakness, loss of sensation, tingling, and, eventually, physical impairment and disability. Currently, there are no effective treatments available for this debilitating disease.

CMT encompasses various types, caused by mutations in more than 130 genes. Notably, about 75% of diagnosed cases stem from mutations in two genes: PMP22, which is associated with CMT1A, and MPZ, linked to CMT1B. In both CMT1A and CMT1B models, the research revealed a significant impairment in protein degradation by the proteasome within peripheral nerves.

The proteasome functions as the cell’s garbage disposal, responsible for breaking down old, damaged, or unwanted proteins, thereby preventing their accumulation, which could disrupt essential cellular functions.

In the context of CMT1A and CMT1B, it was found that the proteasome’s activity was insufficient, leading to the accumulation of undigested proteins, including those that contribute to the disease’s progression.

The study explored the potential of drugs that raise cGMP levels to activate the proteasome, thereby enhancing protein degradation. CMT1A and CMT1B mouse models were treated with these cGMP-boosting drugs for three weeks, and the results were encouraging: a significant reduction in the accumulation of undegraded proteins, improved nerve conduction speed, and enhanced motor coordination were observed.

One of the notable drugs used in the study was a phosphodiesterase 5 inhibitor, which is already approved by the FDA and widely used for other medical conditions. This opens up exciting possibilities for repurposing existing medications to address the challenges posed by CMT1A and CMT1B.

The findings represent a significant step forward in understanding and potentially treating these inherited neuropathies. While more research is necessary to fully establish the efficacy and safety of these treatments in humans, the prospect of improving the lives of individuals affected by CMT is both hopeful and promising.

“This research marks an exciting step forward in our understanding of Charcot Marie Tooth disease,” said Verplank, who was recently named to the “40 under 40” top researchers and clinicians by the Charcot Marie Tooth Association.

“By uncovering new ways to address the underlying causes of nerve degeneration, we’re opening up real possibilities for future treatments. It’s an encouraging development for patients and their families, bringing us closer to therapies that could significantly improve quality of life.”

Provided by Uniformed Services University of the Health Sciences (USU)