Diabetes mellitus is a pandemic metabolic disorder characterized by chronic hyperglycemia. The pathogenic process is the result of insulin insufficiency. Insulin is a peptide hormone produced in the beta cells of the pancreatic islets. Current diabetes treatments strive for glycemic control but fail to solve the underlying beta cell defect. This approach has increased the life expectancy and quality of most patients with diabetes but has turned diabetes into a chronic disease. Curative strategies should aim at restoring and protecting the functional beta cell mass which in turn would self-regulate a fine-tuned glucose homeostasis. Beta cell transplantation has already proven its therapeutic value and is clinically applied in a selected group of patients with diabetes. However, the procedure suffers from a large islet cell loss immediately following transplantation. This cellular loss is at least partly due to insufficient graft revascularization. To tackle this hurdle, we devised a novel approach based on the transfection of islet cells with mRNA encoding the proangiogenic factor VEGF-A immediately before transplantation. Such an approach using in vitro transcribed mRNA for gene delivery has important advantages over classic gene therapy: (i) the overexpression is transient thus avoiding side effects of chronic VEGF-A overexpression such as increased vascular permeability and inflammation, and (ii) the inherent risks of viral-vector-based methods, such as insertional mutagenesis or vigorous immune reaction are absent. We provide proof-of-concept for the ability of VEGF-A mRNA-therapy to enhance the vascularization of both mouse and human beta cell grafts.
Key learning points
- Beta cell transplantation has provided proof of concept of its potential to cure diabetes.
- Beta cell transplantation suffers from a major cell loss post-transplantation due to insufficient graft revascularization
- Vegf-A mRNA transfection of beta cells before transplantation improves graft revascularization and is a promising strategy to improve engraftment success in clinical islet transplantation protocols.
22 Sep 2021 - 26 Sep 2021