Approaches for the Cure of Type 1 Diabetes by Cellular and Gene Therapy

Abstract

Type 1 diabetes results from insulin deficiency caused by autoimmune destruction of insulin-producing pancreatic beta cells. Islet transplantation, beta cell regeneration, and insulin gene therapy have been explored in an attempt to cure type 1 diabetes. Major progress on islet transplantation includes substantial improvements in islet isolation technology to obtain viable and functionally intact islets and less toxic immunosuppressive drug regimes to prevent islet graft failure. However, the availability of human islets from cadaveric pancreata is limited. Regeneration of pancreatic beta cells from embryonic or adult stem cells may overcome the limited source of islets and transplant rejection if beta cells are regenerated from endogenous stem cells. However, it is difficult to overcome the persisting hostile beta cell-specific autoimmune response that may destroy the regenerated beta cells. Insulin gene therapy might overcome the weakness of islet transplantation and beta cell regeneration with respect to their vulnerability to autoimmune attack. This method replaces the function of beta cells by introducing various components of the insulin synthetic and secretory machinery into non- beta cells, which are not targets of beta cell-specific autoimmune responses. However, there is no regulatory system that results in the expression and release of insulin in response to glucose with satisfactory kinetics. Although there is no perfect solution for the cure of type 1 diabetes at the present time, research on a variety of potential approaches will offer the best choices for the cure of human type 1 diabetes.

Adenovirus Transduction is Required for the Correction of Diabetes Using Pdx-1 or Neurogenin-3 in the Liver

“…2,3 The delivery of insulin via gene therapy has been attempted by several groups with varying degrees of success, but the main caveat of this method is the difficulty in achieving tightly regulated and glucose-responsive expression of insulin. 4 It seems likely that the only method of achieving endogenous glucose-responsive secretion of insulin would be to have insulin secreted from normal insulin-producing beta cells present in the islets of Langerhans. Indeed, the transplantation of islets in humans has resulted in the successful lifelong correction of diabetes, but is limited by the extremely scarce number of islet donors.…”

Ectopic PDX-1 expression in liver ameliorates type 1 diabetes

“…However, the simple replacement of the insulin gene expression by genetic engineering is not likely to result in continuous normoglycemia, unless the hormone secretion is tightly regulated by glucose within a narrow physiological range [3,4].…”

Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin-induced diabetes in rats

“…Compared with the injection of exogenous insulin, islet transplantation provides relatively long-term restoration of euglycemia and dynamic insulin secretion in response to glucose level [1][2][3] . Clinical application of islet transplantation is severely hampered by a scarcity of islet donors.…”

“…Despite the unclear nature of islet generation, these results suggest the possibility that functional islet or islet-like cells could be expanded from pancreatic tissues. Isolation and in vitro differentiation of islet progenitor cells have been reported by many groups [1,2] . The isolation strategies included clonal identification [14] , flow-cytometric cell sorting [15] , and selective cultivation [5,[16][17][18][19] .…”