RNA Technology Improves Islet Transplantation Outcomes
A new RNA-based method may help insulin-producing cells survive transplantation more effectively. In a study from Karolinska Institutet, published in the journal Signal Transduction and Targeted Therapy, treated cells restored their blood supply more rapidly, and fewer donor islets were required to re-establish normal blood glucose control.
Researchers at Karolinska Institutet have developed a targeted RNA technology to prepare pancreatic islet cells for transplantation. The technology briefly boosts a gene that drives blood vessel growth, prompting grafts to re-establish their blood supply sooner and shortening the vulnerable, low-oxygen window that normally follows transplantation. In studies using both mouse and human islets, treated cells engrafted more effectively and required fewer donor islets to restore normal blood sugar control. The findings, published in Signal Transduction and Targeted Therapy (a Nature journal), may eventually contribute to better outcomes for patients with insulin dependent diabetes.
Transplanting pancreatic islets with their insulin-producing cells can relieve patients with insulin dependent diabetes from daily insulin injections. However, the procedure faces a significant challenge in that many transplanted cells fail to survive, so a larger number of donor islets than would otherwise be needed must be transplanted to offset the losses that occur during the early phase of transplantation. These losses are largely driven by the avascular phase immediately after transplantation, before new blood vessels have formed, when grafts are starved of oxygen and nutrients. Understanding how to improve cell survival during this vulnerable period is crucial to making this therapy available to more patients.
Researchers at the Rolf Luft Research Center for Diabetes and Endocrinology at Karolinska Institutet have now developed a technique using targeted RNA to prepare islet cells before transplantation. In studies using both mouse and human cells, the team found that this pre-treatment improved cell survival and function after transplantation.
A Targeted Approach to Cell Preparation
The researchers combined cell-type-specific RNA aptamers (molecular tags that recognize markers on the surface of insulin-producing β-cells) with small activating RNAs (saRNAs) that briefly switch on a gene called VEGF-A. Because VEGF-A drives the growth of new blood vessels, this brief activation helps the graft re-establish its blood supply more quickly and shortens the avascular window in which most early cell loss occurs. The activation is transient, taking place only during the initial preparation phase and returning to normal levels after transplantation, allowing the researchers to strengthen the cells without permanently altering their genetics.
“This RNA platform allows us to reprogram cell behavior in a precise, temporary, and fully reversible way. By delivering gene activation directly to β-cells, we can precondition islets to better withstand the stress of transplantation before it occurs,” says Dimitri Van Simaeys, Research Specialist at the Department of Molecular Medicine and Surgery, and corresponding author of the study.
Better Outcomes with Fewer Donor Islets
When the RNA-treated islets were transplanted into mice with diabetes, the grafts re-established their blood supply more rapidly and accumulated less cellular stress, preserving significantly more functional β-cells. When the animals were challenged with induced diabetes, recipients of preconditioned islets showed markedly delayed disease onset and better glucose control. Most significantly, the same level of blood sugar control was achieved using fewer transplanted islets than in untreated control groups. This finding has direct implications for clinical practice, where donor pancreases are scarce.
“Importantly, our work introduces an RNA-guided preconditioning strategy that is compatible with donor islets, engineered cellular therapies, and stem cell-derived replacement tissue,” says Per-Olof Berggren, senior author of the study. He adds, “As regenerative medicine approaches in diabetes move towards a cure, technologies that improve the efficiency and reliability of early engraftment will be essential. Rather than replacing intrinsic adaptive responses, our treatment preconditions the islet graft to better withstand the physiological stresses associated with engraftment and integration. For patients with insulin dependent diabetes, who suffer from hypoglycemic unawareness or brittle diabetes, blood sugar that is difficult to control, islet transplantation offers hope. Improving transplant success rates brings this life-changing therapy closer to wider clinical use.”
Towards General Clinical Translation
The modular design of this RNA approach means it could potentially be adapted to improve other types of cell transplantation beyond islet therapy: the targeting component can be directed at different cell types, and the activating RNA at different genes. The team is now focused on optimizing the method for use in human patients and exploring how similar strategies might enhance outcomes in other emerging cell therapies.
Publication
β-cell-targeted RNA activation of vascular endothelial growth factor-A improves islet transplantation.
Van Simaeys D, Berggren PO
Signal Transduct Target Ther 2026 Aug;11(1):