Neuroscience
Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy
Researchers create the first validated model of sporadic ALS using patient-derived stem cells, identifying a promising three-drug combination therapy after screening over 100 compounds.
Imagine if scientists could take a small sample of your skin, turn those cells into the exact type of brain cells that are dying in ALS, and then test hundreds of potential medicines on them in a lab dish. That's essentially what this research accomplished. Scientists took skin cells from 100 people with ALS, converted them into motor neurons (the brain cells that control muscle movement), and discovered that these lab-grown neurons died in the same way as they do in actual ALS patients. When they tested over 100 drugs that had failed in human trials, 97% also failed in their lab model - proving their system works like the real disease. Most importantly, they found a combination of three drugs that kept the neurons alive longer, offering new hope for treatment.
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Generated an iPSC library from 100 patients with sporadic ALS and demonstrated that motor neurons derived from these patients showed reduced survival and accelerated neurite degeneration compared to controls
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Screening of over 100 drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration in the SALS model, reflecting real clinical trial outcomes
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Identified a promising therapeutic combination of baricitinib, memantine and riluzole that significantly increased survival of SALS motor neurons
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Demonstrated that SALS motor neurons exhibited transcriptional dysregulation consistent with postmortem spinal cord tissues from ALS patients and showed pharmacological rescue by riluzole
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Established the first validated model of sporadic ALS using patient-derived iPSCs that recapitulates key disease features and correlates with donor survival
Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.