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Journal article
Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy
Nature neuroscience
2025
PMID: 41286450
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 HealthElizabeth Qian - Florey Institute of Neuroscience and Mental HealthKatherine Lim - Florey Institute of Neuroscience and Mental HealthMaciej Daniszewski - Centre for Eye Research AustraliaFleur C Garton - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, AustraliaBảo C Trần-Lê - Florey Institute of Neuroscience and Mental HealthHelena H Liang - Centre for Eye Research AustraliaTian Lin - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, AustraliaJohn G Lock - UNSW SydneyDuncan E Crombie - Florey Institute of Neuroscience and Mental HealthSteven Morgan - Melbourne BioinformaticsYi Hu - Florey Institute of Neuroscience and Mental HealthSamantha K Barton - Florey Institute of Neuroscience and Mental HealthLucy M Palmer - Florey Institute of Neuroscience and Mental HealthElvan Djouma - La Trobe UniversitySaritha Kodikara - Melbourne Genomics Health AllianceKim-Anh Lê Cao - Melbourne Integrative Genomics, School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, AustraliaThanuja Dharmadasa - Florey Institute of Neuroscience and Mental HealthAnjali K Henders - Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, AustraliaLaura A Ziser - The University of QueenslandMatthew C Kiernan - Neuroscience Research AustraliaKevin Talbot - University of OxfordMerrilee Needham - Murdoch University, Personalised Medicine CentreSusan Fletcher - Murdoch University, Personalised Medicine CentrePaul Talman - Deakin UniversitySusan Mathers - Calvary Health Care BethlehemNaomi R Wray - Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, AustraliaAlex W Hewitt - University of TasmaniaAlice Pebay - Centre for Eye Research AustraliaBradley 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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