The results of research by scientists at the University of Edinburgh and at the University of Oxford have found that a drug typically used to treat enlarged prostates and high blood pressure could also have promise as a potential new therapy for amyotrophic lateral sclerosis (ALS), the most prevalent form of motor neuron disease (MND).

Their studies in stem cell models, zebrafish, and mice demonstrated that the FDA-approved drug, terazosin, protects against the death of motor neurons by increasing their energy production. The team is now starting a feasibility study into the drug’s effect in patients with MND, and say if this proves successful, they will look to launch a full clinical trial. The University of Edinburgh’s Helena Chaytow, PhD, is first author of the team’s published paper in eBioMedicine, which is titled, “Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.” In their paper, the authors concluded, “Since terazosin is acting on the glycolysis pathway and therefore downstream of the cause of disease, it has the potential to benefit patients with all forms of ALS, irrespective of disease cause.”

MND is a group of rare diseases that destroy nerve cells known as motor neurons, causing patients to slowly lose function of their muscles. ALS is the most common form of motor neuron disease. “This devastating disease, characterized by the loss of upper and motor neurons leading to progressive weakness, is uniformly fatal,” the authors noted. In fact, 50% of patients die within three years from first symptoms, and 80–90% will die within five years, they noted.

And as the majority of patients have no known genetic cause, MND therapy development has been “challenging,” the researchers continued. “Crucially, there are currently no treatment options for patients that meaningfully alter the disease course, with the only approved drugs, riluzole and edavarone, increasing lifespan by a few months.”

It is still unclear why motor neurons die, but experts know that a decrease in their energy production takes place at an early stage of the disease. Motor neurons need to produce energy to carry the brain’s instructions to the muscles. If there is not enough energy, the messages cannot be transferred effectively and movement is affected. The University of Edinburgh-led team targeted the energy production of motor neurons as a potential therapeutic strategy for treating MND. “Dysregulated energy metabolism is common across both familial and sporadic forms of ALS, and so targeting energy production has the potential to be therapeutic for multiple patient groups,” they wrote.

Terazosin is an FDA-approved drug that has previously been identified as targeting the glycolysis enzyme phosphoglycerate kinase 1 (PGK1), which is involved in energy production, and increasing its activity, the researchers pointed out. The authors explained, “PGK1 activity can be increased using an off-target effect of the FDA-approved small molecule terazosin, which is normally prescribed for benign prostatic hyperplasia or hypertension.” The drug had also been shown to be neuroprotective in models of stroke and Parkinson’s disease. “We, therefore, asked whether this neuroprotective effect could translate to ALS, a disease where novel therapeutic approaches are desperately needed,” they wrote.

Their experiments in zebrafish models of MND showed that either genetically increasing the amount of PGK1 in the animals, or treating them with terazosin to increase the activity of PGK1 improved the growth of motor neurons. “Importantly, this then correlated with significant improvements in motor performance and behavior,” they wrote. Terazosin also protected motor neurons in a mouse model of MND, improving survival and delaying the progression of paralysis. The team separately grew motor neurons in a dish and demonstrated that terazosin protected these cells by increasing energy levels.

“Treatment with terazosin improved motor neuron phenotypes in zebrafish models which correlated with improved motor behavior,” the investigators summarized. “… it also increased survival and clinical phenotypes in a mouse model of ALS and protected against cell death in response to oxidative stress in motor neurons in culture … The neuroprotective action of terazosin is likely due to the observed increase in glycolysis, as well as potentially through a recovery of stress granule formation seen in motor neuron cultures.”

The teams at the Universities of Edinburgh and Oxford are now inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study that will examine the impact of terazosin on key indicators of disease progression. “Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation,” they stated, in reference to their preclinical study. “Repurposing terazosin, therefore, has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.”

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