Incretin Gene Therapy

Due to the increasing prevalence of diabetes worldwide, it has become a major public health problem, and new blood sugar-lowering drugs with different mechanisms of action have been developed to treat the disease. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are two new drug classes designed for the treatment of type 2 diabetes (T2DM). Injectable GLP-1RAs, interestingly, provide superior glucose control and lead to weight loss compared to orally administered DPP-4 inhibitors. Both drug classes are well-tolerated and highly effective, with a low risk of hypoglycemia when used alone or in combination with other antidiabetic drugs.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that triggers glucose-induced insulin secretion from pancreatic beta cells, exhibiting an insulinotropic effect. It suppresses glucagon secretion from alpha cells by triggering somatostatin release from pancreatic delta cells. In addition to beneficial effects such as appetite suppression, decreased food intake, and slowing of gastric emptying resulting in weight loss, it also exhibits useful effects such as improving myocardial performance, narrowing infarct area, and regulating endothelial function in patients with T2DM. Furthermore, it has functions such as triggering beta cell proliferation and differentiation and preventing beta cell apoptosis.

Since inadequate incretin response (a 60% decrease) is one of the most fundamental impairments seen in patients with T2DM, correction of this deficiency via GLP-1 gene transfer presents an attractive experimental gene therapy approach. Initially, technical difficulties encountered in achieving effective gene transfer directly to the pancreas greatly limited the success of GLP-1-mediated in vivo gene transfer studies. However, recent advances in utilizing different techniques and various gene transfer vectors for gene transfer have enabled more effective evaluation of the therapeutic efficacy of GLP-1 gene transfer in T2DM animal models.

In conclusion, recent gene therapy studies have shown that GLP-1 peptide and analogs have many clinical benefits, such as improving glucose tolerance, correcting hyperglycemia, suppressing appetite, and causing weight loss, which has been replicated in experimental animal models. In addition, GLP-1-focused gene therapy has also been able to reduce abdominal and hepatic fat accumulation associated with obesity-induced T2DM by causing significant changes in adipokine profiles in the treated subjects, in addition to improving insulin sensitivity.

A lentivirus-mediated GLP-1 gene transfer study could be a good example for our research on type 2 diabetes (insulin-independent). Exenatide (Byetta) and Liraglutide (Victoza) are new generation drugs developed against diabetes, approved by the FDA in recent years. Diabetic patients need to use these drugs throughout their lives to benefit from them. We developed a gene therapy drug (LentiGLP-1) that has the potential to eliminate the need for patients to use these drugs throughout their lives by cloning the gene form of these drugs (GLP-1) into gene transfer vectors with a single injection. Our pioneering studies in obese diabetic animal models break insulin resistance, correct beta cell dysfunction, and even lead to weight loss by lowering blood sugar levels through beta cell regeneration, which is one of the most important findings of diabetes.