MRNA therapy for experimental beta(-like) cell transplantation

Diabetes mellitus is a pandemic treated by insulin therapy, but in need of a cure. Insulin therapy has inherent risks of glycemic variability and provides no definitive answer to the life-threatening complications of diabetes. Restoring the endogenous beta cell mass through regeneration or transplantation offers an alternative. Beta-cell replacement therapy has been applied successfully to patients with brittle type 1 diabetes, resulting in better glycemic control and less micro- and macrovascular complications. However, major hurdles, including donor scarcity, impaired graft revascularization and islet cell dedifferentiation upon transplantation, still need to be overcome for islet cell transplantation to become a universal treatment for diabetes. The current proposal aims
to tackle these hurdles by: (i) employing beta-like cell grafts derived from human inducible pluripotent stem cells (iPS-ß) and by (ii) transfection of grafts with synthetic, modified mRNA encoding the key angiogenic factor Vascular Endothelial Growth Factor-A (mRNAVEGF-A) to
enhance graft revascularization, differentiation and function. mRNA-based transfection represents a novel, attractive and clinically safe alternative to traditional gene delivery and growth factor-based treatment approaches and is currently breaching into clinical trials. The current proposal could serve as ‘proof of principle’ for mRNA therapy in the context of beta(-like) cell transplantation