İnsulin Gene Therapy

Diabetes is a pandemic disease characterized by metabolic abnormalities resulting from the combined role of immune and genetic mechanisms. Insulin-dependent diabetes mellitus (T1DM) is known as a disease characterized by autoimmune destruction of pancreatic beta cells. Although insulin injection is widely used in T1DM treatment, this treatment method cannot provide ideal blood sugar control, which leads to the development of chronic complications such as nephropathy, neuropathy, and retinopathy in patients over time. The clinical prevalence of pancreatic organ transplantation and pancreatic islet transplantation, which are applied in T1DM treatment, is significantly limited due to the difficulty of finding a pancreatic organ donor. Therefore, gene therapy, which is a promising new treatment method for many diseases, needs to be developed as an alternative therapy method. Since all T1DM patients and the majority of Type 2 diabetes mellitus (T2DM) patients become insulin-dependent over time due to beta-cell loss, insulin gene transfer through gene transfer vectors could be a potential therapeutic approach that mimics the endogenous insulin synthesis profile in diabetic patients. In our project, providing permanent insulin gene expression without causing any toxic effects was one of the main goals.


Our research group developed a new insulin gene transfer vector (LentiINS) that can respond not only to basal insulin needs but also to changing blood glucose levels throughout the day, especially postprandial glucose levels, in T1DM subjects. For this purpose, natural DNA sequence that encode human proinsulin under the control of the human insulin promoter was transferred to 3rd generation lentiviral vectors that have been clinically proven for their reliability and efficacy. The use of the human insulin promoter was necessary to make insulin gene synthesis specific to pancreatic beta cells and to create a glucose response. The therapeutic efficacy of the LentiINS vector was tested in T1DM subjects, and it was found that the LentiINS vector prevented the development of T1DM and reversed the signs of developing T1DM. In addition, combined applications of LentiINS vector and lentiviruses encoding Vasoactive Intestinal Peptide (LentiVIP), newly developed in our laboratory, were applied to suppress autoimmune cellular immunity and induce immune tolerance in T1DM subjects. As a result, the newly developed insulin gene transfer method provided better benefits than insulin injections, and combined gene therapy approaches could offer an effective solution for Type 1 diabetes.


Furthermore, the therapeutic efficacy of the LentiINS vector was tested in vivo in animal models of diabetes by silencing insulin expression using the CRISPR technique, which is introduced as a new generation gene therapy method. According to our in vivo studies, the LentiINS vector reduced blood sugar in diabetic subjects by regaining insulin expression in these cells after beta-cell transplantation. This suggests that pancreas-targeted lentiviral-mediated insulin gene transfer could also be used to treat diseases caused by defects in the insulin gene, such as MODY10.