PGK1

Terazosin shows top line results in ALS treatment. Scientists from the University of Edinburgh have shown that Terazosin, a drug approved for high blood pressure and prostate enlargement, could be repurposed for another indication: amyotrophic lateral sclerosis (ALS). Terazosin is an alpha-adrenergic blocker that works by relaxing veins and arteries to improve blood flow. It is the primary compound in Abbott’s drug Hytrin (terazosin hydrochloride), which was first approved by the U.S. Food and Drug Administration in 1987 for hypertension and then again in 1993 for lower urinary tract syndrome associated with prostate enlargement. In their study, published Wednesday in eBioMedicine, the Edinburgh team found additional therapeutic potential for terazosin using stem cell, mouse and zebrafish models of ALS. Treatment with the receptor blocker leads to an uptick in the production of phosphoglycerate kinase 1, an enzyme known to be essential for glycolysis, the process by which cells break down glucose molecules to produce energy. In turn, the zebrafish models grew longer axons and had better motor function than untreated controls. Terazosin also demonstrated strong neuroprotective effects in mice models and improved survival by 5%. “Our work shows that terazosin is protective of motor neuron cell death in multiple models of MND [motor neuron disease], making it an exciting new potential therapy,” Helena Chaytow, the study’s first author and senior postdoctoral researcher at the University of Edinburgh, said in a statement. “The benefit of working with terazosin is that it is already prescribed for a different health condition, so we know that it is safe for humans and could quickly move to the clinic.” In line with this, Chaytow and the team, along with collaborators from the University of Oxford, are planning to test terazosin in 50 patients enrolled in Oxford’s MND Care and Research Center. The feasibility study will look at the drug’s effects on disease progression. “We are excited about the potential for terazosin to impact on the breakdown of motor neurons in MND. The current work illustrates the importance of bringing together scientists and clinicians in order to identify new targets for therapy suitable for taking forward into studies in human MND patients,” Tom Gillingwater, study co-lead and professor of anatomy at the University of Edinburgh, said. ALS is a progressive nerve disorder that slowly destroys neurons in the brain and spinal cord, causing weakness in the extremities, slurred speech and cognitive problems. ALS can compromise fundamental functions like eating and breathing in its most severe forms. It is still unknown exactly how or why neurons die in ALS patients. Researchers do know that energy production in these cells steadily declines during the early stages of the disease, and this is what the Edinburgh team addressed in their study. Other groups, however, target different pathways that could also potentially lead to ALS. For instance, Ionis and Biogen are using an antisense oligonucleotide to knock out mutated copies of the SOD1 protein, which aggravates ALS symptoms. The new drug application for their candidate, Tofersen, was accepted last month and is set for an FDA decision early next year. Meanwhile, Massachusetts-based Amylyx Pharmaceuticals is attempting to halt the massive nerve death by simultaneously alleviating endoplasmic reticulum stress and mitochondrial dysfunction with its candidate AMX0035 (sodium phenylbutyrate and taurursodiol). In early September, the FDA will reconvene to review AMX0035’s NDA.

A drug typically used to treat enlarged prostates and high blood pressure has shown promise as a potential new therapy for motor neuron disease (MND) -- also known as amyotrophic lateral sclerosis (ALS) -- according to a new study. A drug typically used to treat enlarged prostates and high blood pressure has shown promise as a potential new therapy for motor neuron disease (MND) -- also known as amyotrophic lateral sclerosis (ALS) -- according to a new study. MND is a group of rare diseases that destroy nerve cells known as motor neurons, causing patients to slowly lose function of their muscles. In studies using zebrafish, mice and stem cell models, experts have demonstrated that the drug terazosin protects against the death of motor neurons by increasing their energy production. Researchers say the drug could help to slow the progression of a disease that affects around 5,000 adults in the UK. The average life expectancy is three years from the onset of symptoms. The team are starting a feasibility study into the drug's effect in MND patients. If this proves successful, they will look to launch a full clinical trial. 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. Researchers from the University of Edinburgh, working with partners at the University of Oxford, targeted the energy production of motor neurons as a potential therapeutic strategy for treating MND. Using terazosin, which has previously been shown to be effective at increasing energy production in models of stroke and Parkinson's disease, the team wanted to determine if this drug could also protect motor neurons from MND. They focused on an enzyme -- an active molecule in the cells -- involved in energy production called PGK1. Zebrafish models of MND showed that either genetically increasing the amount of PGK1 in the zebrafish or treating them with terazosin to increase PGK1's activity improved the growth of motor neurons. Terazosin also protected motor neurons in a mouse model of MND, improving survival and delaying the progression of paralysis. The team also grew motor neurons in a dish and demonstrated that terazosin protects these cells by increasing energy levels. To investigate this further the teams at the Universities of Edinburgh and Oxford are inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study, which will examine the impact of terazosin on key indicators of disease progression. The study is published in eBioMedicine. It was funded by MND Scotland and the My Name'5 Doddie Foundation. Research at the University of Edinburgh was carried by a team at the Euan MacDonald Centre for Motor Neurone Disease, which was established by Euan MacDonald and his father Donald to improve the lives of people with MND. Dr Helena Chaytow, senior postdoctoral researcher at University of Edinburgh's Euan MacDonald Centre and first author of the study, said: "Our work shows that terazosin is protective of motor neuron cell death in multiple models of MND, making it an exciting new potential therapy. The benefit of working with terazosin is that it is already prescribed for a different health condition, so we know that it is safe for humans and could quickly move to the clinic." Professor Tom Gillingwater, Professor of Anatomy at University of Edinburgh's Euan MacDonald Centre and study co-lead, said: "We are excited about the potential for terazosin to impact on the breakdown of motor neurons in MND. The current work illustrates the importance of bringing together scientists and clinicians in order to identify new targets for therapy suitable for taking forward into studies in human MND patients." Professor Kevin Talbot, Professor of Motor Neuron Biology at the University of Oxford and study co-lead, said: "We urgently need to accelerate the way drugs are developed from laboratory models into trials in patients. Our work uses a combination of approaches to increase the confidence that drugs will actually work in people with MND and significantly slow disease progression. It represents an important new step in the search for therapies." Dr Jane Haley MBE, Director of Research for MND Scotland, said: "As key funders of this research study, we are delighted to see a potential new therapy for MND on the horizon. After testing in a range of models, the results of this study show us that terazosin, a drug currently used to treat enlarged prostates and high blood pressure, may be able to protect motor neurons. We are delighted that, as a result, the drug will move to a feasibility study in Oxford, involving people living with MND. This is a wonderful example of researchers, clinicians and MND charities working together to try and speed up the search for new treatments for MND -- because it's about time we found a cure." Jill Douglas, CEO of My Name'5 Doddie Foundation, said: "The Foundation is encouraged that the collaborative nature of this work will aid translation from the lab to the clinic -- it means that basic scientific research will be more meaningful in clinical practice. We are proud to have supported this collaboration and are continuing to support the first clinical trial of terazosin in people living with MND."