2. Academic Validation
  3. Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy

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

  • Nat Neurosci. 2025 Nov 24. doi: 10.1038/s41593-025-02118-7.
Christopher R Bye 1,  Elizabeth Qian 2,  Katherine Lim 2,  Maciej Daniszewski 3 4,  Fleur C Garton 5,  Bảo C Trần-Lê 2,  Helena H Liang 3,  Tian Lin 5,  John G Lock 6,  Duncan E Crombie 2,  Steven Morgan 7,  Yi Hu 2,  Samantha K Barton 2,  Lucy M Palmer 2,  Elvan Djouma 8,  Saritha Kodikara 9,  Kim-Anh Lê Cao 9,  Thanuja Dharmadasa 2,  Anjali K Henders 5,  Laura A Ziser 5,  Matthew C Kiernan 10 11,  Kevin Talbot 12,  Merrilee Needham 13 14 15,  Susan Fletcher 14,  Paul Talman 16,  Susan Mathers 17,  Naomi R Wray 5 18,  Alex W Hewitt 3 19,  Alice Pebay 3 4 20,  Bradley J Turner 21 22
Affiliations

Affiliations

  • 1 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. [email protected].
  • 2 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • 3 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
  • 4 Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
  • 5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • 6 School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
  • 7 Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia.
  • 8 Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria, Australia.
  • 9 Melbourne Integrative Genomics, School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia.
  • 10 Neuroscience Research Australia, University of New South Wales, Sydney, New South Wales, Australia.
  • 11 Neurology Department, South Eastern Sydney Local Health District, Sydney, New South Wales, Australia.
  • 12 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
  • 13 Department of Neurology, Fiona Stanley Hospital, Perth, Western Australia, Australia.
  • 14 Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Western Australia, Australia.
  • 15 Notre Dame University, Fremantle, Western Australia, Australia.
  • 16 Neurosciences Department, University Hospital Geelong, Geelong, Victoria, Australia.
  • 17 Calvary Healthcare Bethlehem Hospital Neuro-Consultancy, South Caulfield, Victoria, Australia.
  • 18 Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • 19 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
  • 20 Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
  • 21 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. [email protected].
  • 22 Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia. [email protected].
PMID: 41286450 DOI: 10.1038/s41593-025-02118-7
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.

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