Establishment of the method for gene therapy of β cell regeneration by non-invasive gene delivery via pancreatic duct

点击翻译按钮获取中文摘要

This research was undertaken to establish the new therapy for diabetes mellitus especially for βcell-depleted type of diabetes. We reported that Betacellulin and Heparin-binding EGF-like growth factor (HB-EGF), both of which belong to EGF family, are expressed abundantly in human pancreas, especially developing fetal pancreas, and that recombinant human betacellulin, has a potency to induce differentiation of βcell from non-β pancreatic exocrine cell line. To confirm this effect of betacellulin in vivo, we next demonstrated that recombinant human betacellulin ameliorated glucose intolerance in diabetic mice model induced by selective perfusion of alloxan. These results indicate that betacellulin and HB-EGF may act as a growth and/or differentiation factor in the pancreas.Based on these evidence, we intend to develop the new gene therapy for βcell regeneration by non-invasive method of endoscopic retrograde injection into pancreatic duct. We tried to induce βcell neogenesis from duct ce … More lls by injecting adenovirus vector containing LacZ or genes of putative β cell differentiation factors such as Betacellulin and Heparin-binding EGF-like growth factor in mice. We succeeded in inducing the expression of LacZ mainly in duct cells by injecting LacZ-containing adenovirus into duct from the orifice of pancreatic duct in the duodenum without any serious side effect, suggesting that this method of regeneration therapy for diabetes is applicable to larger animals including human. As a next step, we tried to induce Betacellulin and HB-EGF genes in pancreatic duct cells using adenovirus vector. Both genes could be expressed in duct cells, and neogenesis of endocrine cells including β cells from ducts was observed, but expression levels of these gene products appeared to be not enough to elevate the insulin content significantly. It is necessary to improve the expression level of such genes to develop the new gene therapy for diabetes by the method of endoscopic retrograde injection of adenovirus vectors containing such genes of β cell differentiation factors into pancreatic duct. Less