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葡萄糖转运蛋白2(GLUT2)启动子介导的转基因胰岛素产生可降低糖尿病小鼠的高血糖水平。

Glucose transporter-2 (GLUT2) promoter mediated transgenic insulin production reduces hyperglycemia in diabetic mice.

作者信息

Burkhardt Brant R, Parker Mathew J, Zhang Y Clare, Song Sihong, Wasserfall Clive H, Atkinson Mark A

机构信息

Department of Pathology, University of Florida College of Medicine, Gainesville, 32610, USA.

出版信息

FEBS Lett. 2005 Oct 24;579(25):5759-64. doi: 10.1016/j.febslet.2005.09.060. Epub 2005 Oct 5.

Abstract

Insulin production afforded by hepatic gene therapy (HGT) retains promise as a potential treatment for type 1 diabetes, but successful approaches have been limited. We employed a novel and previously untested promoter for this purpose, glucose transporter-2 (GLUT2) to drive insulin production via delivery by recombinant adeno-associated virus (rAAV). In vitro, the GLUT2 promoter was capable of robust glucose-responsive expression in transduced HepG2 human hepatoma cells. Therefore, rAAV constructs were designed to express the furin-cleavable human preproinsulin B10 gene, under the control of the murine GLUT2 promoter and packaged for delivery with rAAV expressing the type 5 capsid. Streptozotocin-induced diabetic mice were subjected to hepatic portal vein injection immediately followed by implantation of a sustained-release insulin pellet to allow time for transgenic expression. All mice injected with the rAAV5-GLUT2-fHPIB10 virus remained euglycemic for up to 35 days post-injection, with 50% euglycemic after 77 days post-injection. In contrast, mock-injected mice became hyperglycemic within 15 days post-injection following dissolution of the insulin pellet. Serum levels of both human insulin and C-peptide further confirmed successful transgenic delivery by the rAAV5-GLUT2-fHPIB10 virus. These findings indicate that the GLUT2 promoter may be a potential candidate for regulating transgenic insulin production for hepatic insulin gene therapy in the treatment of type I diabetes.

摘要

肝脏基因疗法(HGT)所产生的胰岛素有望成为1型糖尿病的潜在治疗方法,但成功的方法有限。我们为此采用了一种新颖且此前未经测试的启动子,即葡萄糖转运蛋白2(GLUT2),通过重组腺相关病毒(rAAV)递送驱动胰岛素生成。在体外,GLUT2启动子能够在转导的HepG2人肝癌细胞中实现强大的葡萄糖应答性表达。因此,设计了rAAV构建体,在小鼠GLUT2启动子的控制下表达可被弗林蛋白酶切割的人胰岛素原B10基因,并包装成用表达5型衣壳的rAAV进行递送。链脲佐菌素诱导的糖尿病小鼠接受肝门静脉注射,随后立即植入缓释胰岛素微丸,以便有时间进行转基因表达。所有注射rAAV5 - GLUT2 - fHPIB10病毒的小鼠在注射后长达35天内保持血糖正常,注射后77天有50%的小鼠血糖正常。相比之下,注射安慰剂的小鼠在胰岛素微丸溶解后注射后15天内血糖升高。人胰岛素和C肽的血清水平进一步证实了rAAV5 - GLUT2 - fHPIB10病毒成功进行了转基因递送。这些发现表明,GLUT2启动子可能是调节转基因胰岛素生成用于1型糖尿病治疗的肝脏胰岛素基因疗法的潜在候选者。

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