TY - JOUR
KW - amyotrophic lateral sclerosis
KW - induced pluripotent stem cells
AU - Christopher R. Bye
AU - Elizabeth Qian
AU - Katherine Lim
AU - Maciej Daniszewski
AU - Fleur C. Garton
AU - Bảo C. Trần-Lê
AU - Helena H. Liang
AU - Tian Lin
AU - John G. Lock
AU - Duncan E. Crombie
AU - Steven Morgan
AU - Yi Hu
AU - Samantha K. Barton
AU - Lucy M. Palmer
AU - Elvan Djouma
AU - Saritha Kodikara
AU - Kim-Anh Lê Cao
AU - Thanuja Dharmadasa
AU - Anjali K. Henders
AU - Laura A. Ziser
AU - Matthew C. Kiernan
AU - Kevin Talbot
AU - Merrilee Needham
AU - Susan Fletcher
AU - Paul Talman
AU - Susan Mathers
AU - Naomi R. Wray
AU - Alex W. Hewitt
AU - Alice Pébay
AU - Bradley J. Turner
AB - 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.
BT - Nature Neuroscience
DA - 2025-11-24
DO - 10.1038/s41593-025-02118-7
LA - en
N2 - 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.
PY - 2025
SP - 1
EP - 13
T2 - Nature Neuroscience
TI - Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy
UR - https://www.nature.com/articles/s41593-025-02118-7
Y2 - 2025-12-15
SN - 1546-1726
ER -