Intramuscular delivery of a naked DNA plasmid encoding proinsulin and pancreatic regenerating III protein ameliorates type 1 diabetes mellitus

• Published in: Pharmacological research Vol. 63; no. 4; pp. 320 - 327
• Main Authors: Hou, Wen-Rui, Xie, Sheng-Nan, Wang, Hong-Jie, Su, Yu-Yong, Lu, Jing-Li, Li, Lu-Lu, Zhang, Sha-Sha, Xiang, Ming
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.04.2011
• Subjects: Animals; Cercopithecus aethiops; COS Cells; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - therapy; DNA - administration & dosage; DNA - genetics; DNA - therapeutic use; Gene Expression; Genetic Therapy; Hyperglycemia - therapy; Injections, Intramuscular; Insulin - metabolism; Male; Mice; Mice, Inbred BALB C; Naked plasmid; Pancreas - metabolism; Pancreas - pathology; Plasmids - administration & dosage; Plasmids - genetics; Plasmids - therapeutic use; Proinsulin; Proinsulin - genetics; Proinsulin - therapeutic use; Proteins - genetics; Proteins - therapeutic use; Reg III protein; Streptozocin; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T1DM; T1DM; EF-1α; Proinsulin; NOD; MLDS; CMV; Naked plasmid; pBud; Reg; STZ; PI; Reg III protein; MCS
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2010.12.009

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β cells. Up to now, there is still no cure for this devastating disease and alternative approach should be developed. To explore a novel gene therapy strategy combining immunotherapy and β cell regeneration, we constructed a non-viral plasmid encoding proinsulin (PI) and pancreatic regenerating (Reg) III protein (pReg/PI). Therapeutic potentials of this plasmid for T1DM were investigated. Intramuscular delivery of pReg/PI resulted in a significant reduction in hyperglycemia and diabetes incidence, with an increased insulin contents in the serum of T1DM mice model induced by STZ. Treatment with pReg/PI also restored the balance of Th1/Th2 cytokines and expanded CD4 +CD25 +Foxp3 + T regulatory cells, which may attribute to the establishment of self-immune tolerance. Additionally, in comparison to the mice treated with empty vector pBudCE4.1 (pBud), attenuated insulitis and apoptosis achieved by inhibiting activation of NF-κB in the pancreas of pReg/PI treated mice were observed. In summary, these results indicate that intramuscular delivery of pReg/PI distinctly ameliorated STZ-induced T1DM by reconstructing the immunological self-tolerance and promoting the regeneration of β cells, which might be served as a promising candidate for the gene therapy of T1DM.