When pieces come together, progress is made: how terazosin moved from bench to clinical trial

At MND Scotland, we know that investment in fundamental research is crucial in the hunt for potential MND therapies. Sometimes it takes a number of small discoveries to come together for progress to occur. A powerful example is our investment in early-stage research, which helped Professor Tom Gillingwater, at the University of Edinburgh, launch terazosin on its path to clinical trial. 

In 2017, MND Scotland awarded £147,000 to Professor Gillingwater to explore energy-related genes in motor neurons, focusing on PGK1 (phosphoglycerate kinase 1), an enzyme that plays a key role in how cells produce energy. His lab wanted to find out whether boosting energy production in cells could protect them from the damage caused by MND.

As part of this project, his team began testing a class of drugs that interact with PGK1. Among them was terazosin, a medication already used to treat high blood pressure and prostate conditions. Researchers believed that by activating PGK1, terazosin could help boost energy levels inside motor neurons, making them more resilient to the stress and damage caused by MND. This early-stage research revealed that terazosin significantly improved the survival and function of motor neurons in cell-based and animal models of MND. 

MND Scotland’s initial funding of Tom’s work was crucial to enabling this discovery, but it would not have been possible without even earlier funding investment from MND-Scotland.  

In 2009, we awarded a £73,000 PhD studentship to Dr Catherina Becker at the University of Edinburgh. Her student successfully developed a model that used zebrafish to study motor neuron axon degeneration and regeneration – zebrafish are unusual in that they are able to regrow motor neurons. This model has been further developed over the years and was used by Tom’s lab to test the effect of terazosin on motor neuron degeneration. Zebrafish are now also being used at the University of Edinburgh to screen for drugs that slow or reverse motor neuron death, using robotically controlled and analysed systems. 

In 2010 we also provided £77,500 for a PhD studentship in Tom’s lab to develop an in vitro model of neuromuscular junctions using human stem cells. Although not using quite the same technique, motor neurons grown from mouse stem cells were used to test terazosin in Tom’s more recent study.  

The journey towards finding new treatments requires many different pieces and these often happen at different times and places. In order for Tom’s lab to be able to look at whether PGK1 is involved in MND, the following things needed to happen: 

• The PGK1 enzyme had to be discovered, in 1955. It has subsequently been implicated in a variety of conditions including cancer and, more recently, the neurodegenerative conditions stroke and Parkinson’s. 
• Inhibitors of PGK1 enzyme needed to be developed – terazosin was made in 1975 but its ability to activate PGK1 was only identified in 2015. 
• The zebrafish model of MND needed to be developed, which required the identification, in 2011, of a key change in the C9orf72 gene which can lead to the development of MND in humans. This was then re-created in the motor neurons of zebrafish in 2021.  
• A mouse model of MND also needed be developed. For the model used by Tom’s lab, this required the discovery, in 2006, that TDP-43 protein clumping occurs in most cases of MND. A mouse model was then created in 2010 that showed this same protein clumping and displayed MND-like symptoms. 
• The knowledge and technology to successfully grow mouse motor neurons with human MND-associated changes in a dish so they can be used in experiments. This process began in 2006 and was perfected, for the model used here, in 2019.

Only once all these pieces were in place, was Tom’s lab in a position to undertake the studies in human stem cells, zebrafish and animal models that showed terazosin enhances energy metabolism, reduces oxidative stress, and protects motor neurons from degeneration. 

Thanks to this strong pre-clinical data, additional funding from partners like the My Name’5 Doddie Foundation, the Medical Research Council, and the Academy of Medical Sciences helped continue to drive this research forward. Together, this support has ensured that terazosin could progress to the next stage: a small clinical trial. 

Today, terazosin is being trialled in a small number of people living with MND. In collaboration with Tom’s lab, the University of Oxford is leading a pilot clinical trial to assess whether terazosin can safely and effectively slow the progression of the disease. The study is examining how well the drug is tolerated by people, its impact on energy metabolism, and whether it can preserve motor function over time. If results are positive, then this research has provided a real step toward potentially offering a new treatment option for people with by MND. 

Terazosin’s journey from lab bench to clinical trial shows how MND Scotland has been able to impact the future of MND research by investing in early-stage research, to better understand the mechanisms behind MND. It also demonstrates how important each small step is and how collaboration is crucial, between not only researchers but also funding organisations, as we all strive towards the goal of a world without MND. 

For more information, please click here. 

The original paper from Professor Tom Gillingwater’s laboratory can be found here.