Protection of pancreatic islets using theranostic silencing nanoparticles in a baboon model of islet transplantation

The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation and other factors continues to limit its efficacy. In this project we demonstrate a novel approach aimed at protection of islets prior to Tx in non-human primates (NHP, baboons) by silencing a gene (caspase 3) responsible for induction of apoptosis. This was done using small interfering RNA (siRNA, siCas-3) conjugated to magnetic nanoparticles (MN). In addition to serving as carriers for siCas-3 these nanoparticles also act as reporters for magnetic resonance imaging so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the anti-apoptotic effect of MN-siCas-3 on islets in culture resulting in a minimal islet loss. For in vivo studies donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted even with a marginal number of labeled islets compared to controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaver or living donor.