New Solutions to Improve Islet Recovery after Machine Preservation of Pancreas

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DESCRIPTION (provided by applicant): Transplantation of islets of Langerhans for the clinical treatment of Type I diabetes has had a resurgence of interest due to results obtained using the "Edmonton protocol". However, at this time, procurement of donor pancreases for islet isolation and transplantation is in its infancy. Most pancreases at more remote donor sites are not procured due to justified concerns about post-mortem ischemia during transport to the islet isolation and transplant center. Perfusion/preservation technology has been shown to have a major impact in circumventing ischemic injury in kidney transplantation. This proposal seeks to apply this approach to the preservation and procurement of viable islets for transplantation. The primary objective of this proposal is to use state-of-the-art perfusion technology and new preservation solutions to test the hypothesis that machine perfusion can improve the yield and viability of islets prepared from ischemic pancreases. To this end, a prototype pancreas transporter (PTR) has been designed and constructed in a previous study that demonstrated the feasibility of 24h perfusion preservation at 2-7 degrees C using a porcine model. This exceeds the 16h documented to be the present clinical limits of safe, static cold storage of donor pancreata. Here we propose a complimentary study to address the second important factor for further development of this technology, namely the design and optimization of the perfusate to maximize the yield and viability of isolated islets after hypothermic machine perfusion preservation. More specifically, in the Phase I study a new proprietary solution (Unisol) will be compared with current standard organ preservation solutions (KPS1 and UW Viaspan) for 24h preservation of fresh porcine pancreata. The safety and efficacy of this new technology will be further investigated during a Phase II study in which the design of the solution used to perfuse the pancreas in the PTR will be optimized in four specific aims. The first step will be to use a system of high throughput assays to select cytoprotective additives to be incorporated into the base perfusates. The second step will entail a comparison of pancreas perfusates with the addition of the cytoprotective cocktail for machine preservation of fresh pancreata with no warm ischemia. Then the interaction between cold perfusion time (24 and 48h) and warm ischemia time (up to 60 min) on porcine islet isolation parameters will be evaluated using the optimized perfusate for the definition of the potential clinical scope and technology limits. Finally, human pancreases that are unsuitable for transplantation will be employed for pre-clinical validation of this technology. It is anticipated that the availability of a pancreas transporter and pancreas perfusion protocols will permit utilization of most, if not all, pancreases suitable for transplantation in the U.S. Furthermore, the PTR may permit islet isolation banking for long-term storage. Banking would allow time for better HLA matching of donors to recipients, off-the-shelf availability, and enable quality assurance/control procedures to be conducted prior to transplantation. This research program is supported by collaboration with three major clinical centers interested in validation of this perfusion technology for their future use. Project Narrative: Insulin-dependent diabetes is one of the major health problems worldwide and there is now a great deal of interest in developing an option for a potential cure by transplantation of islet cells isolated from a donor pancreas. A critical component of this approach is the availability of sufficient high quality islets to reverse diabetes in the patient. This research is focused on the development of new technologies (a perfusion machine and protective solutions) for improving the quality of pancreas preservation to yield larger numbers of high functioning islet cells.