Guo Ping, Zhang Ting, Lu Aiping, Shiota Chiyo, Huard Matthieu, Whitney Kaitlyn E, Huard Johnny
Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA.
Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80526, USA.
Mol Ther Methods Clin Dev. 2023 Feb 11;28:355-365. doi: 10.1016/j.omtm.2023.02.003. eCollection 2023 Mar 9.
Endogenous reprogramming of pancreas-derived non-beta cells into insulin-producing cells is a promising approach to treat type 1 diabetes (T1D). One strategy that has yet to be explored is the specific delivery of insulin-producing essential genes, Pdx1 and MafA, to pancreatic alpha cells to reprogram the cells into insulin-producing cells in an adult pancreas. In this study, we used an alpha cell-specific glucagon (GCG) promoter to drive Pdx1 and MafA transcription factors to reprogram alpha cells to insulin-producing cells in chemically induced and autoimmune diabetic mice. Our results showed that a combination of a short glucagon-specific promoter with AAV serotype 8 (AAV8) can be used to successfully deliver Pdx1 and MafA to pancreatic alpha cells in the mouse pancreas. Pdx1 and MafA expression specifically in alpha cells were also able to correct hyperglycemia in both induced and autoimmune diabetic mice. With this technology, targeted gene specificity and reprogramming were accomplished with an alpha-specific promotor combined with an AAV-specific serotype and provide an initial basis to develop a novel therapy for the treatment of T1D.
将胰腺来源的非β细胞内源性重编程为胰岛素生成细胞是治疗1型糖尿病（T1D）的一种有前景的方法。一种尚未探索的策略是将胰岛素生成必需基因Pdx1和MafA特异性递送至胰腺α细胞，以便在成年胰腺中将这些细胞重编程为胰岛素生成细胞。在本研究中，我们使用α细胞特异性胰高血糖素（GCG）启动子驱动Pdx1和MafA转录因子，从而在化学诱导的糖尿病小鼠和自身免疫性糖尿病小鼠中将α细胞重编程为胰岛素生成细胞。我们的结果表明，短的胰高血糖素特异性启动子与8型腺相关病毒（AAV8）的组合可用于成功地将Pdx1和MafA递送至小鼠胰腺中的胰腺α细胞。Pdx1和MafA在α细胞中的特异性表达也能够纠正诱导性糖尿病小鼠和自身免疫性糖尿病小鼠的高血糖症。利用这项技术，通过α特异性启动子与AAV特异性血清型的组合实现了靶向基因特异性和重编程，并为开发治疗T1D的新疗法提供了初步依据。
