Summary by Dr Alannah Mole, reviewed by Dr Lydia Castelli, Dr Scott Allen and an MND lay panel including Dr Rick Nelms
Background
Repurposing approved drugs is an attractive concept in motor neuron disease. If successful, this could increase cost effectiveness and accelerate the route for drugs to become available in the clinic. Much work is therefore underway to examine the therapeutic potential of drugs that have not been considered in the context of treating neurodegenerative diseases.
Terazosin is an FDA-approved drug that is used to treat enlarged prostate and high blood pressure. Studies have shown that terazosin can also protect neurons (nerve cells) – the basic working unit of the nervous system that is responsible for transferring information – in models of stroke, Parkinson’s disease, and Spinal Muscular Atrophy (a childhood motor neuron disease). This study assesses whether terazosin also has protective effects in models of Amyotrophic Lateral Sclerosis (ALS). ALS is the most common form of motor neuron disease. It is characterised by progressive muscle weakness and motor neuron loss that leads to paralysis and ultimately death within 3-5 years from symptom onset. Crucially, there are no treatment options that can meaningfully alter the course of disease, with the only approved drugs, riluzole and edavarone, increasing lifespan by just a few months.
The complexity of ALS is well-recognised; several causes have been identified, and many biological pathways implicated. There is growing evidence to support that defects in a cell’s ability to generate energy are common across different forms of ALS. A key catalyst of energy production is called phosphoglycerate kinase 1 (PGK1), with PGK1 levels found to be reduced in mouse models of motor neuron disease. Since terazosin increases PGK1 activity, here, the authors asked if treatment with terazosin could improve outcomes in animal or cell models of ALS.
Why is the study important?
Identifying drugs that target common aspects of disease across different forms of ALS could provide an opportunity to treat ALS irrespective of cause. Repurposing approved drugs with unrecognised therapeutic potential in ALS may expedite and reduce costs to take this drug into the clinic.
What did the authors do and how did they do it?
Here, the author’s assess whether targeting PGK1 is effective in ALS. Using zebrafish models with ALS-linked genetic changes, they demonstrate that directly increasing PGK1 improves motor neuron health. They then show that treatment with terazosin also improves motor neuron health and survival, with improved structure (length/number of processes that allow cells to communicate with each other) and function (ability of the fish to swim away following tail touching).
In mouse models with ALS-linked genetic changes, terazosin improved survival. Treated mice had increased body weight and decreased symptom severity, with reduced leg weakness and/or paralysis. Treatment with terazosin increased the remaining number of motor neurons in the spinal cord by 40% when compared to untreated mice. Overall, terazosin protected against motor neuron death, reduced symptom severity and increased survival.
Next, this study investigated how terazosin provides such protection. In stem cells with ALS-linked genetic changes, terazosin reduced oxidative stress. Oxidative stress occurs due to an imbalance between reactive oxygen species and antioxidant defences in the body. Here, terazosin treatment prior to a stressful stimulus that normally causes cells to die, rescued survival by 100%. The authors suggest that terazosin works by improving the cell’s response to stress and increasing energy production. Finally, this group demonstrate that treatment with terazosin rescues the cell’s ability to form particles that may help it to deal with stress.
What are the results?
Terazosin improved motor neuron health, reduced disease severity and increased survival in models of ALS with different causes. This drug is thought to work by protecting the cell from stress-induced death, modulating energy production, and rescuing the cell’s ability to form stress particles. Terazosin is a candidate to be repurposed for clinical trials in ALS.
What do the finding mean going forward for people with the disease?
Overall, this work highlights terazosin as a candidate for clinical trials in ALS. Terazosin can cross the blood-brain-barrier, which is important if this drug is to reach the central nervous system. It should be noted that at very high doses, protective effects may be lost, therefore this must be considered if this drug is to move into the clinic. Since terazosin is already approved, side effects are known; these include mild dizziness and transient increases in serum aminotransferase levels, a sign of liver damage, however this is not long-term, and there is unlikely to be safety profile issues for terazosin. As a repurposed drug, the translation of this drug as a therapeutic option for ALS patients would be accelerated.
This study can be found at: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00384-X/fulltext
Paper title: Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis
Author list: Helena Chaytow, Emily Carroll, David Gordon, Yu-Ting Huang, Dinja van der Hoorn, Hannah Louise Smith, Thomas Becker, Catherina Gwynne Becker, Kiterie Maud Edwige Faller, Kevin Talbot, Thomas Henry Gillingwater
Publication details including date of publication: eBioMedicine (part of THE LANCET), volume 83, 104202, September 01, 2022