02702nas a2200517   4500000000100000000000100001008004100002260001500043653003400058653003500092100002300127700001900150700001800169700002300187700002000210700002400230700002000254700001300274700001700287700002200304700001800326700001000344700002300354700001900377700001700396700002100413700002000434700002300454700002200477700001900499700002300518700001700541700002100558700001900579700001600598700001800614700001800632700001900650700001700669700002200686245013300708856005500841300000900896520126500905022001402170       2025                            d  c2025-11-2410aamyotrophic lateral sclerosis10ainduced pluripotent stem cells1 aChristopher R. Bye1 aElizabeth Qian1 aKatherine Lim1 aMaciej Daniszewski1 aFleur C. Garton1 aBảo C. Trần-Lê1 aHelena H. Liang1 aTian Lin1 aJohn G. Lock1 aDuncan E. Crombie1 aSteven Morgan1 aYi Hu1 aSamantha K. Barton1 aLucy M. Palmer1 aElvan Djouma1 aSaritha Kodikara1 aKim-Anh Lê Cao1 aThanuja Dharmadasa1 aAnjali K. Henders1 aLaura A. Ziser1 aMatthew C. Kiernan1 aKevin Talbot1 aMerrilee Needham1 aSusan Fletcher1 aPaul Talman1 aSusan Mathers1 aNaomi R. Wray1 aAlex W. Hewitt1 aAlice Pébay1 aBradley J. Turner00aLarge-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy  uhttps://www.nature.com/articles/s41593-025-02118-7  a1-133 aHeterogeneous 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.  a1546-1726