Electrical spinal stimulation reduces toxic protein clumps in ALS mice
Study findings support continued development of neuromodulation device
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- Electrical spinal stimulation can reduce toxic TDP-43 protein aggregates in preclinical ALS mouse models, a study reports.
- These findings support the continued development of Pathmaker Neurosystems' MyoRegulator device.
- Clinical trials are currently testing this noninvasive neuromodulation device to evaluate its feasibility and safety in humans.
Delivering gentle electrical stimulation to the spinal cord can reduce the buildup of toxic TDP-43 protein clumps in a mouse model of amyotrophic lateral sclerosis (ALS), according to a new study.
The specific type of stimulation used in the study is known as multisite direct current stimulation (DCS). The findings support the continued development of MyoRegulator, a neuromodulation device from Pathmaker Neurosystems that uses the same type of stimulation to treat ALS.
“For the first time, we have shown that our non-invasive Multi-Site DCS technology can reduce toxic … TDP-43 protein aggregates in spinal [nerve cells],” Nader Yaghoubi, MD, PhD, co-founder and CEO of Pathmaker, said in a company press release.
The study, “Multisite Anodal Direct Current Stimulation Preserves Motor Function and Modulates Key Cellular Pathways in TDP-43 and SOD1 Mouse Models of Amyotrophic Lateral Sclerosis,” was published in Neuromodulation: Technology at the Neural Interface. The research was conducted by a trio of scientists at City University of New York (CUNY), including Zaghloul Ahmed, PhD, a CUNY professor and scientific founder of Pathmaker.
MyoRegulator device being tested in 15 people
After an early feasibility study involving five participants, Pathmaker launched a larger clinical trial, called CALM (NCT06649955), to test its noninvasive MyoRegulator device in about 15 people with ALS.
The main goal is to determine the feasibility and safety of active MyoRegulator treatment for four weeks, but researchers will also gather preliminary evidence of potential effectiveness. The open-label trial is recruiting participants at Beth Israel Deaconess Medical Center in Boston.
“With our second ALS clinical trial now nearing full enrollment, we are building the clinical evidence base to bring this therapy to people with ALS,” Yaghoubi said.
Mice given electrical stimulation had better motor function scores
ALS is marked by the progressive dysfunction and death of motor neurons, nerve cells that control movement. Exactly what causes the disease is not fully understood, but researchers have shown that nearly all patients have toxic clumps of the TDP-43 protein in their motor neurons. For this reason, reducing TDP-43 clumps is widely seen as a promising strategy for ALS treatment.
A potential noninvasive way of doing so is by reducing hyperexcitability — excessive nerve cell activation — which is also an important driver of motor neuron damage in the disease. By restoring the normal patterns of motor neuron activity, approaches such as multisite DCS may make motor neurons less vulnerable to other neurodegenerative mechanisms.
“TDP-43 aggregation and motor neuron hyperexcitability are increasingly understood to reinforce each other in a cycle that accelerates ALS progression,” Yaghoubi said. “This study demonstrates that Multi-Site DCS can intervene on both sides of that cycle, suppressing spinal motor neuron excitability while simultaneously reducing toxic TDP-43 protein accumulation.”
In the new study, this type of electrical stimulation was explored in two mouse models of ALS caused by genetic mutations. One of the models is caused by mutations in the TDP-43 gene itself, while the other is associated with mutations in a different gene called SOD1. The electrical signals were delivered through electrodes placed on the skin on different regions of the spine, as well as the lower back and abdominal regions.
Together, these findings support the potential of multisite [direct current stimulation] as a neuromodulatory strategy capable of targeting disease-relevant mechanisms that contribute to ALS progression.
In both mouse models, mice given the electrical stimulation had better motor function scores, particularly at later timepoints. In the TDP-43 model, the stimulation also led to a significant reduction in the amount of TDP-43 protein in motor neurons.
“Together, these findings support the potential of multisite DCS as a neuromodulatory strategy capable of targeting disease-relevant mechanisms that contribute to ALS progression,” the researchers concluded, noting that “the consistency [of the results] across SOD1 and TDP-43 models highlights the potential of this approach to target shared mechanisms of neurodegeneration.”
Last year, the MyoRegulator device, which delivers this type of stimulation, was granted breakthrough status in the U.S. This designation is aimed at speeding the development of promising therapies for serious disorders.
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