HSCI Retreat 2020 Abstract 3

Genome Scale In Vivo CRISPR Screen Identifies RNLS as a Target for Beta Cell Protection in Type 1 Diabetes

Erica P. Cai,#*1 Yuki Ishikawa,#2 Wei Zhang,#2 Nayara C. Leite,3 Jian Li,1 Shurong Hou,4 Badr Kiaf,2 Jennifer Hollister-Lock,1 Nese Kurt Yilmaz,4 Celia A. Schiffer,4 Doug A. Melton,3 Stephan Kissler,**2 and Peng Yi**1
1 Section for Islet Cell and Regenerative Biology, Harvard Medical School, Boston, MA, USA
2 Section for Immunobiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
3 Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
4 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA      

 These authors contributed equally to this work
*   Presenting author
** Corresponding authors (these authors jointly supervised the study): stephan.kissler@joslin.harvard.edu; peng.yi@joslin.harvard.edu

Submitted: Jun 11, 2020; Published online: Jul 27, 2020



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, we discovered 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.