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

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

doi:10.1038/s41593-025-02118-7

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

Journal article

Open access

Peer reviewed

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

Christopher R Bye, Elizabeth Qian, Katherine Lim, Maciej Daniszewski, Fleur C Garton, Bảo C Trần-Lê, Helena H Liang, Tian Lin, John G Lock, Duncan E Crombie, …

Nature neuroscience

2025

DOI: https://doi.org/10.1038/s41593-025-02118-7

PMID: 41286450

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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.

Details

Title: Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy
Authors/Creators: Christopher R Bye - Florey Institute of Neuroscience and Mental Health
Elizabeth Qian - Florey Institute of Neuroscience and Mental Health
Katherine Lim - Florey Institute of Neuroscience and Mental Health
Maciej Daniszewski - Centre for Eye Research Australia
Fleur C Garton - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Bảo C Trần-Lê - Florey Institute of Neuroscience and Mental Health
Helena H Liang - Centre for Eye Research Australia
Tian Lin - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
John G Lock - UNSW Sydney
Duncan E Crombie - Florey Institute of Neuroscience and Mental Health
Steven Morgan - Melbourne Bioinformatics
Yi Hu - Florey Institute of Neuroscience and Mental Health
Samantha K Barton - Florey Institute of Neuroscience and Mental Health
Lucy M Palmer - Florey Institute of Neuroscience and Mental Health
Elvan Djouma - La Trobe University
Saritha Kodikara - Melbourne Genomics Health Alliance
Kim-Anh Lê Cao - Melbourne Integrative Genomics, School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia
Thanuja Dharmadasa - Florey Institute of Neuroscience and Mental Health
Anjali K Henders - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Laura A Ziser - The University of Queensland
Matthew C Kiernan - Neuroscience Research Australia
Kevin Talbot - University of Oxford
Merrilee Needham - Murdoch University, Personalised Medicine Centre
Susan Fletcher - Murdoch University, Personalised Medicine Centre
Paul Talman - Deakin University
Susan Mathers - Calvary Health Care Bethlehem
Naomi R Wray - Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
Alex W Hewitt - University of Tasmania
Alice Pebay - Centre for Eye Research Australia
Bradley J Turner - Perron Institute for Neurological and Translational Science
Publication Details: Nature neuroscience
Publisher: Springer Nature
Number of pages: 33
Grant note: 1137024 / Department of Health | National Health and Medical Research Council (NHMRC) 2021 / Department of Health | National Health and Medical Research Council (NHMRC)
Identifiers: 991005831941707891
Murdoch Affiliation: Health Futures Institute; Personalised Medicine Centre; Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 ALS Mechanisms
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior