Prolonged control of insulin-dependent diabetes via intramuscular expression of plasmid-encoded single-strand insulin analogue  

作　　者：Lu Deng Ping Yang Caixia Li Lifang Xie Wanling Lu Yanhan Zhang Ming Liu Gang Wang 

机构地区：[1]National Engineering Research Center for Biomaterials,Sichuan University,Chengdu,Sichuan 610064,China [2]Chengdu Institute of Biology,Chinese Academy of Sciences,Chengdu,Sichuan 610041,China [3]Department of Abdominal Oncology,West China Hospital,Sichuan University,Chengdu,Sichuan 610044,China

出　　处：《Genes & Diseases》2023年第3期1101-1113,共13页基因与疾病（英文）

基　　金：supported by the National Natural Science Foundation of China(No.31971390);the International Cooperative Project of Sichuan Province on Science and Technology Innovation(China)(No.2021YFH0142).

摘　　要：Daily insulin injection is necessary for the treatment of the insulin-dependent diabetes. However, the process is painful and inconvenient. Accordingly, we have made exploratory efforts to establish an alternative method for continuous insulin supply via intramuscular injection of a designed plasmid encoding the single-strand insulin analogue (SIA), which provides safe, effective and prolonged control of insulin-dependent diabetes. To generate a SIA, a short flexible peptide was alternatively introduced into the natural proinsulin to replace its original long and rigid C-peptide. Then, the synthetic promoter SP301 was used to drive potent and specific expression of SIA in skeletal muscle cells. By combining the Pluronic L64 and low-voltage electropulse (L/E), the specialized gene delivery technique was applied to efficiently transfer the constructed plasmid into skeletal muscle cells via intramuscular injection. Through these efforts, a plasmid-based intramuscular gene expression system was established and improved, making it applicable for gene therapy. The plasmid-expressed SIA showed biological functions that were similar to that of natural insulin. A single L/E-pSP301-SIA administration provided sustained SIA expression in vivo for about 1.5 months. In addition, the diabetic mice treated with L/E-pSP301-SIA were much healthier than those with other treatments. This plasmid-based system was safe for the treatment of diabetes and did not cause immune responses or pathological damage. The results confirmed that, in a mouse model, long-term positive effects were achieved by a single intramuscular L/E-pSP301-SIA injection, which consequently provided reliable experimental basis for its clinical application for the treatment of diabetes mellitus with promising prospects.

关 键 词：Diabetes Gene therapy Intramuscular injection PLASMID Single-strand insulin analogue(SIA) Synthetic promoter 

分 类 号：R587.1[医药卫生—内分泌]