Lay summary by Abdelaziz Khalil, reviewed by Dr Monika Myszczynska and an MND lay panel
Background
Motor neuron disease (MND), is a progressive condition where the nerve cells that control movement, called motor neurons, gradually stop working and die. This leads to muscle weakness, paralysis, and eventually death.
Most MND cases are sporadic, meaning they happen without a known inherited (genetic) cause. This creates a major challenge for researchers as sporadic disease can be harder to model in the laboratory, and many treatments that look promising early on do not go on to succeed in clinical trials.
One approach to this problem is to use induced pluripotent stem cells (iPSCs). iPSCs are made from adult donor cells, often blood or skin, then transformed into stem cells and turned into motor neurons. This allows researchers to study human motor neurons in the lab and test medicines directly on the disease-relevant cells.
Why is the study important?
Instead of focusing on a small number of cell lines (cells grown in the lab from a particular person or sample), the researchers built an iPSC ‘library’ from over 100 people living with sporadic MND, aiming to capture the real-world diversity in the population of people living with MND, as well as the variability of the disease.
The researchers also tested an important idea: Is it possible to create a lab system that mirrors what happens in human disease well enough to help identify better treatments? By screening medicines that have already been tried in MND trials, the researchers could check whether this new model ‘behaves’ in a realistic way.
What did the authors do and how did they do it?
Researchers generated iPSCs from over 100 people living with sporadic MND and turned them into motor neurons. They then measured disease-related features across this group of people, for example, how well the neurons survived and how their neurites (branch-like extensions important for communication) changed over time.
Next, they performed a large-scale drug screen using all medicines that had previously been tested in clinical trials as potential disease-modifying treatments for ALS/MND, where those medicines were commercially available for laboratory screening. The researchers identified 169 candidate interventions from trial databases, and were able to source 107 drugs to test in this study. In the drug screen, they looked for medicines that improved survival or reduced motor neuron damage in these iPSC-derived motor neurons.
After identifying drugs with beneficial effects in these iPSC-derived motor neurons, they tested some of the drugs in combination with others to see whether targeting multiple pathways at once could improve outcomes further. This included testing a three-drug combination of baricitinib, memantine, and riluzole.
What are the results?
The first key finding was that these patient-derived motor neurons showed problems consistent with disease in the lab, including poorer survival over time and changes suggesting faster degeneration. This supports the idea that iPSCs can reproduce key features of sporadic MND in laboratory experiments.
When the team tested drugs that had already been tried in MND clinical trials, they found that 97% did not reduce motor neuron damage in their model, an outcome that, unfortunately, mirrors the fact that most MND drug trials have not yet delivered effective treatments. The authors speculate that the model may be capturing something meaningful as to why drug discovery for MND has been marred by failures.
When they tested combinations of the most promising drugs, the authors identified baricitinib + memantine + riluzole as a particularly promising mix, showing improved protection of iPSC-derived motor neurons compared with individual drugs alone.
What do the findings mean going forward for people with the disease?
It is true that the findings from the three-drug combination were promising, but a full clinical trial will need to be performed to see if it can work in people as well as in lab-grown human motor neurons. What this study does provide is something the MND field urgently needs: a realistic, scalable way to test treatments for the sporadic form of the disease, using human cells that carry the biology of MND.
What makes the work so exciting is that it represents a shift. Instead of testing one idea at a time in small models, this approach can screen broadly, learn from what fails, and then rationally build towards combination therapies that may have a better chance against this complex disease. Going forward, if treatments move towards clinical trials, researchers would typically recruit volunteers through specialist MND clinics and research networks and choose participants based on clear criteria (such as diagnosis stage and medical history), to ensure results are reliable and fair.
This study can be found at https://www.nature.com/articles/s41593-025-02118-7
Paper title
Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy.
Lead author
Christopher R. Bye & Bradley J. Turner
Publication details including date of publication
Nature Neuroscience, 24th November 2025