Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy

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.

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Publication Details

Journal
Nature Neuroscience
Published
2025-11-24
DOI
https://doi.org/10.1038/s41593-025-02118-7
Citations
4
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
5.56

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article

Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy

Helena H. Liang, Thanuja Dharmadasa, John G. Lock, Kevin Talbot et al.
4 citations
Nature Neuroscience
Amyotrophic Lateral Sclerosis Research
5.56
article

Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy

Helena H. Liang, Thanuja Dharmadasa, John G. Lock, Kevin Talbot, Fleur C. Garton, Tian Lin, Duncan E. Crombie, Lucy M. Palmer, Maciej Daniszewski, Alex William Hewitt, Samantha K. Barton, Alice Pébay, Christopher R. Bye, Merrilee Needham, Elvan Djouma, Paul Talman, Matthew C. Kiernan, Bradley J. Turner, Naomi R. Wray, Laura Ziser, Sue Fletcher, Elizabeth L. Qian, Saritha Kodikara, Steven Morgan, Susan Mathers, Kim‐Anh Lê Cao, Anjali K. Henders, Katherine Lim, Yi Hu, Bảo C. Trần-Lê
article en
4 citations

Abstract

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.

Nature NeuroscienceVol. 29(1)
University of Tasmania (AU), The Royal Melbourne Hospital (AU), The University of Queensland (AU), The University of Melbourne (AU), Murdoch University (AU), La Trobe University (AU), Florey Institute of Neuroscience and Mental Health (AU), Geelong Hospital (AU), Fiona Stanley Hospital (AU), UNSW Sydney (AU), Melbourne Bioinformatics (AU), University of Oxford (GB), Centre for Eye Research Australia (AU), Calvary Health Care Bethlehem (AU), Perron Institute for Neurological and Translational Science (AU), South Eastern Sydney Local Health District (AU), Melbourne Genomics Health Alliance (AU), Neuroscience Research Australia (AU), The University of Notre Dame Australia (AU)
Motor Neurone Disease Research Institute of Australia, FightMND, Strong, Motor Neurone Disease Research Australia, State Government of Victoria, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 4%
Amyotrophic Lateral Sclerosis Research
5.56
DOIOpen Access PDFOpenAlex
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