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基因疗法恢复1型糖尿病小鼠的正常血糖水平

作者:Xiangwei Xiao, Ping Guo,Chiyo Shiota,Ting Zhang

成功治疗1型糖尿病的策略需要恢复被免疫系统破坏的胰岛β细胞的功能,并克服胰岛素分泌细胞的进一步破坏。

在这里,我们注入携带PDX1和MafA的表达框的腺病毒,通过胰管,改编α细胞,导入功能β细胞,使β细胞毒素诱导的糖尿病小鼠和自身免疫性的非肥胖型糖尿病(NOD)小鼠的血糖正常化。

在自身免疫性糖尿病的重现之前,毒素诱导的糖尿病小鼠血糖正常,自身免疫NOD小鼠中新的胰岛素+细胞维持了4个月。

这种基因治疗策略也诱导了毒素治疗的人类胰岛的α-β细胞转化,在移植的NOD/SCID小鼠中恢复血糖水平。

因此,这种策略可能代表了一种新的治疗方法,可能是通过免疫抑制,来支持内源性胰岛素的产生。

因此,我们的研究为进一步研究人类1型糖尿病提供了潜在的基础。

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Intraductal Infusion of AAV-PM Corrects ALX-Induced Hyperglycemia in GCG-Cre; R26RTomato Mice

(A) Schematic for the generation of GCG-Cre; R26RTomato mice.

(B) Hyperglycemia was induced in GCG-Cre; R26RTomato mice by ALX injection. One week after ALX treatment, mice received a pancreatic intraductal infusion of either AAV-PM (red line) or control AAV-GFP (green line). Fasting blood glucose levels were measured.

(C) IPGTT was performed in these mice 4 weeks after viral infusion. Untreated mice (no ALX, no virus, in blue) were used as an additional control.

(D) Beta cell mass at 4 weeks after virus infusion. The contribution of INS+ cells without tomato red fluorescence is shown by the hatched bar contained within the red bar, compared to the beta cell mass in mice that received AAV-GFP viral infusion (green bar), and the beta cell mass of untreated mice (UT, no ALX, no virus, blue bar).

Statistics were analyzed by one-way ANOVA with a Bonferroni correction, followed by Fisher’s exact test. Data are presented as mean ± SD. p < 0.05. ∗∗p < 0.01. n = 10. Scale bars, 50 μm.

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参考文献

Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

Xiangwei Xiao, Ping Guo,Chiyo Shiota,Ting Zhang,Gina M. Coudriet,Shane Fischbach,Krishna Prasadan,Joseph Fusco,Sabarinathan Ramachandran,Piotr Witkowski,Jon D. Piganelli,George K. Gittes


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