Cai, Erica P.Ishikawa, YukiZhang, Weide Carvalho Leite, NayaraLi, JianHou, ShurongKiaf, BadrHollister-Lock, JenniferYilmaz, Nese KurtSchiffer, Celia A.Melton, DouglasKissler, StephanYi, Peng2023-05-192020-07-27Cai, Erica P., Yuki Ishikawa, Wei Zhang, Nayara C. Leite, Jian Li, Shurong Hou, Badr Kiaf, et al. 2020. “Genome-Scale in Vivo CRISPR Screen Identifies RNLS as a Target for Beta Cell Protection in Type 1 Diabetes.” Nature Metabolism 2 (9): 934–45.2522-5812https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37375273Other authors include 4 non-Harvard-affiliated individuals not subject to the Open Access policy and two authors from Harvard FAS (Leite, Nayara and Melton, Doug).Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, here we show that deleting RNLS, a GWAS candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modeling identified the FDA-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, leading to disease reversal. Further, pargyline could prevent or delay diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.en-USCell BiologyPhysiology (medical)Endocrinology, Diabetes and MetabolismInternal MedicineJournal Article2023-05-1910.1038/s42255-020-0254-1