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

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posted on 27.08.2020 by Ada Admin, Thomas Pomposelli, Ping Wang, Kazuhiro Takeuchi, Katsunori Miyake, Yuichi Ariyoshi, Hironosuke Watanabe, Xiaojuan Chen, Akira Shimizu, Neil Robertson, Kazuhiko Yamada, Anna Moore
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.

Funding

This work was supported in part by R01DK105503 and R01DK105468 to A.M. and K.Y.

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