Discovery of a drug candidate for GLIS3-associated diabetes

Sadaf Amin, Brandoch Cook, Ting Zhou, Zaniar Ghazizadeh, Raphael Lis, Tuo Zhang, Mona Khalaj, Miguel Crespo, Manuradhi Perera, Jenny Zhaoying Xiang, Zengrong Zhu, Mark Tomishima, Chengyang Liu, Ali Naji, Todd Evans, Danwei Huangfu () and Shuibing Chen ()
Additional contact information
Sadaf Amin: Weill Graduate School of Medical Sciences of Cornell University
Brandoch Cook: Department of Surgery
Ting Zhou: Department of Surgery
Zaniar Ghazizadeh: Department of Surgery
Raphael Lis: Ansary Stem Cell Institute
Tuo Zhang: Genomics Resources Core Facility
Mona Khalaj: Weill Graduate School of Medical Sciences of Cornell University
Miguel Crespo: Department of Surgery
Manuradhi Perera: Department of Surgery
Jenny Zhaoying Xiang: Genomics Resources Core Facility
Zengrong Zhu: Sloan Kettering Institute
Mark Tomishima: Sloan Kettering Institute
Chengyang Liu: University of Pennsylvania School of Medicine
Ali Naji: University of Pennsylvania School of Medicine
Todd Evans: Department of Surgery
Danwei Huangfu: Sloan Kettering Institute
Shuibing Chen: Weill Graduate School of Medical Sciences of Cornell University

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3−/− β-like cells have been unsuccessful. Here, we develop a “minimal component” protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3−/− hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

Date: 2018
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DOI: 10.1038/s41467-018-04918-x

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