Gene and Cell Therapy for Diabetes

Research Seminar
Title: Gene and Cell Therapy for Diabetes
Speaker: Timothy J. Kieffer, Ph.D.
Professor
University of British Columbia
Vancouver, CANADA
Time: 13:00-14:30, Oct. 27, 2017
Location: Youcai Deng Hall，School of Life Sciences（生科院邓祐才报告厅）
Host：Chengran Xu
Abstract：
Diabetes results from insufficient production of the hormone insulin from beta cells in pancreatic islets.  Our aim is to develop an approach to re-establish automatic meal-dependent insulin production within the body.  We have investigated the therapeutic potential of pancreatic progenitor cells derived from human embryonic stem cells.  Several months following implant into diabetic rodents, these Stage 4 cells mature and secrete sufficient human insulin, in a regulated manner, and can thereby treat rodents with diabetes.  The cells also mature and function when implanted subcutaneously in retrievable macroencapsulation devices.  This approach is now in clinical trials in both the USA and Canada.  An extended differentiation protocol was produced to generate more mature cells (Stage 7) that have greater insulin content and mild glucose-responsiveness, mimicking immature beta cells.  These cells are able to reverse diabetes in rodents significantly faster and with lower doses of cells as compared to Stage 4 cells.  These cells may provide a useful model system for studying disease mechanisms and for screening for new drugs to improve beta cell function, in addition to providing an unlimited source of cells for transplant to treat diabetes.
In another approach, we have directed insulin expression to gut K-cells which secrete the hormone glucose-dependent insulinotropic polypeptide in a meal-dependent manner.  Integration of a GIP promoter driving insulin gene into gut stem cells results in long-term expression of insulin selectively in the K-cells.  Such “GIP/Ins” transgenic mice secrete sufficient amounts of insulin from the intestine to protect the animals from diabetes when beta-cells are destroyed, either by a chemical toxin (streptozotocin) or by an autoimmune mediated process, as well as in mice with congenital pancreatic insulin deficiency.  Interestingly, intestinally produced insulin does not induce gut inflammation and also dampens the immune-mediated destruction of beta-cells in a mouse model of type 1 diabetes.  Our studies further support the engineering of K-cells for insulin replacement therapy.  A chitosan based gene delivery method is being developed as means to deliver the insulin gene to gut K-cells in a clinically relevant approach.
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