Testing the treatment efficacy of adenovirus mediated TRAIL gene therapy approach in type 1 diabetic animal models

Type 1 Diabetes (T1D), characterized by permanent destruction of insulin-producing beta cells is lethal unless exogenous-insulin therapy or whole-organ transplantation is employed. While pancreatic islet transplantation is a safer and less invasive method compared to whole-organ transplant surgery, its treatment efficacy has been limited by islet graft malfunction and graft failure. Thus, ex vivo genetic engineering of beta cells is necessary to prolong islet graft survival.For this reason, a novel gene therapy approach involving adenovirus-mediated TRAIL gene delivery into pancreatic islets was tested to determine whether this approach would defy auto-reactive T-cell assault in streptozotocin (STZ)-induced diabetic rats. To test this, genetically-modified rat pancreatic islets were transplanted under the kidney capsule of STZ induced diabetic rats.The diabetic status (blood sugar and body weight) was followed up to 90 days after islet transplantation. Animals carrying Ad5hTRAIL-infected islets experienced prolonged normoglycemia compared to animals grafted with mock-infected or AdCMVLacZ infected islets in STZ-induced diabetic rats. While severe insulitis was detected in animals transplanted with AdCMVLacZ-infected or mock-infected islets; the severity of insulitis was reduced in animals engrafted with Ad5hTRAIL-infected islets. Thus, TRAIL over-expression in pancreatic islets extends allograft survival and function leading to a therapeutic benefit in STZ induced diabetic rats.