Discovery of a drug candidate for GLIS3-associated diabetes

作者：Amin Sadaf; Cook Brandoch; Zhou Ting; Ghazizadeh Zaniar; Lis Raphael; Zhang Tuo; Khalaj Mona; Crespo Miguel; Perera Manuradhi; Xiang Jenny Zhaoying; Zhu Zengrong; Tomishima Mark; Liu Chengyang; Naji Ali; Evans Todd; Huangfu Danwei^*; Chen Shuibing^*

来源：Nature Communications, 2018, 9(1): 2681.

DOI：10.1038/s41467-018-04918-x

GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic beta-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3(-/-) beta-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 beta-like ( PP2-beta) cells. Using this differentiation platform, we discover that GLIS3(-/-) hESCs show impaired differentiation, with significant death of PP2 and PP2-beta 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 beta-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes beta-cell death, by activating the TGF beta pathway. This study establishes an optimized directed differentiation protocol for modeling human beta-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

• 出版日期2018-7-11