Promising ALS Therapy M102 Shows Disease-Slowing Potential in Preclinical Trials
Sheffield, UK – A novel oral therapy, M102, has demonstrated encouraging results in preclinical studies, suggesting a potential to slow the progression of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. Research conducted by scientists at the University of Sheffield’s Institute for Translational Neuroscience (SITraN) and Aclipse indicates that M102 activates key cellular pathways – NRF2 and HSF1 – and offers neuroprotective benefits across multiple models of the disease.
The findings, recently presented, detail experiments using two ALS mouse models: one with mutations in the SOD1 gene and another with mutations in the TDP-43 gene. While most ALS cases aren’t linked to specific genetic mutations, these genes are frequently implicated in both familial and sporadic forms of the disease.In the TDP-43 model, M102 treatment improved muscle activity and motor function. The therapy also preserved motor neurons in the SOD1 model and improved body weight – an indirect measure of disease progression – in both.
Researchers further tested M102 on astrocytes derived from ALS patients, including those with genetic mutations and those with sporadic ALS where no genetic cause is known. Astrocytes, star-shaped cells supporting nerve function, often exhibit oxidative stress and protein misfolding in ALS. M102 treatment demonstrably reduced both of these features. Importantly, when these treated astrocytes were grown alongside motor neurons, the survival rate of the motor neurons increased.
“We have demonstrated that M102, a combined activator of NRF2 and HSF1 signalling pathways, has positive therapeutic effects in two different ALS transgenic mouse models and improves motor neuron survival and multiple pathological markers … in a range of human ALS cellular model systems,” the researchers stated. “Importantly, these neuroprotective effects are seen across multiple subtypes of ALS, including the two most common genetic subtypes caused by mutations in the C9orf72 and SOD1 genes, as well as sporadic ALS cases.”
The team also performed pharmacological tests to determine safe and possibly effective doses for human trials, concluding that predicted therapeutic doses fall “well within the safety margin” based on existing toxicology data.
ALS is a progressive neurodegenerative disease affecting motor neurons, leading to muscle weakness, paralysis, and eventually, respiratory failure. Currently, treatments primarily focus on managing symptoms and slowing disease progression modestly. These preclinical results with M102 represent a significant step toward developing a more effective oral therapy that could truly make a difference for people living with ALS.
