siRNA Protection of Composite Islet Kidney Transplant in Baboons

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 DESCRIPTION (provided by applicant): The overall goal of this proposal is to combine two novel technologies in order to improve the capacity of pancreatic islet transplants to cure type 1 diabetes. The first technology involves transplantation of vascularized islets in the form of composite islet-kidneys (IK), which has the capacity to cure both diabetes and renal failure in swine and baboon model as we have recently demonstrated. In this protocol, pancreatic islets obtained after partial pancreatectomy are first transplanted under the autologous kidney capsule to allow for re- vascularization, and then the composite islet-kidney is transplanted in a recipien diabetic animal. Though composite autologous IK technology substantially reduces the extent of graft damage due to immunologic events, there is still considerable islet loss in IK composite due to hypoxia and ischemic loss ultimately requiring a 70% pancreatectomy of the living donor. To improve IK composite survival and significantly reduce the number of donor islets we propose to use the second technology that utilizes theranostic magnetic nanoparticles as carriers for siRNA, which upon accumulation in islet cells could silence genes responsible for islet damage prior to IK creation. In addition to serving as siRNA carriers these theranostic nanoparticles could be used as in vivo magnetic resonance imaging (MRI) reporters providing information about graft volume longitudinally and non-invasively. We have previously shown the applicability of this technology for improving graft survival in a mouse model of transplantation. In this application we propose to investigate pre-clinical utility of this approach in non-human primates by delivering siRNA-nanoparticle probes targeting genes implicated in apoptosis to islets prior to creating the IK composite. Specifically, we will target caspase 3, caspase 8 and Fas, alone or in combination, as the most important mediators of apoptosis. In vivo MR imaging will be used to monitor autologous IK graft volume followed by continuous imaging of the IK transplant in recipient diabetic animals since magnetic nanoparticles are retained in the islets long term. We expect that by targeting apoptotic genes we will reduce the damage to the islets in autologous IK composite and as a consequence will reduce the number of donor islets required for IK composite to correct hyperglycemia in diabetic recipients. By further minimizing the amount of excised pancreas and non-invasive assessment of islets volume by the MN-siRNA technology, the clinical applicability of this procedure will be more favorable for living donor IK transplantation.