Pancreas Transporter Development and Validation

描述（由申请人提供）：由于使用“埃德蒙顿方案”获得的结果，用于临床治疗I型糖尿病的朗格汉斯胰岛移植重新引起了人们的兴趣。然而，目前，用于胰岛分离和移植的供体胰腺的采购尚处于起步阶段。大多数偏远供体的胰腺都不能获得，因为有理由担心在运往胰岛隔离和移植中心的过程中会出现死后缺血。灌注/保存技术已被证明在肾移植中避免缺血性损伤方面具有重要作用。本提案旨在将这种方法应用于保存和获取可移植的胰岛。本提案的主要目的是使用最先进的灌注技术和新的保存溶液来验证机器灌注可以提高由缺血胰腺制备的胰岛的产量和活力的假设。为此，在I期研究中设计并构建了胰腺转运蛋白（PTR）原型。用猪模型证明了在2-7℃条件下24小时灌注保存的可行性，该模型超过了16小时，这是目前供体胰腺安全、静态冷藏的临床极限。胰岛产量和功能与新鲜对照胰腺相当。这项新技术的安全性和有效性将在II期研究中进一步研究，有三个具体目标。第一步是根据第一阶段可行性研究对PTR进行设计修改。第二步将比较胰岛在PTR上灌注24小时的产量和功能指数，与从常规储存24小时的对照胰腺中获得的指数。然后评估冷灌注时间（24和48h）和热缺血时间（最长60min）对胰岛分离参数的相互作用，确定潜在的临床范围和技术限制。最后，不适合移植的人类胰腺将用于该技术的临床前验证。预计胰腺转运体和胰腺灌注方案的可用性将允许在美国使用大多数（如果不是全部的话）适合移植的胰腺。此外，PTR可能允许胰岛分离库进行长期储存。储存将为供体和受体更好地匹配HLA提供时间，提供现成的可用性，并在移植前进行质量保证/控制程序。该研究项目得到了三家主要临床中心的合作支持，这些中心对该灌注技术的验证感兴趣，以供未来使用。

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) was designed and constructed in the Phase I study. The feasibility of 24h perfusion preservation at 2-7¿C was demonstrated using a porcine model that exceeds the 16h documented to be the present clinical limits of safe, static cold storage of donor pancreatic. Islet yield and function was demonstrated to be equivalent to that obtained from fresh control pancreases. The safety and efficacy of this new technology will be further investigated during this Phase II study with three specific aims. The first step will be to implement design modifications to the PTR ensuing from the Phase I feasibility study. The second step will entail a comparison of the yield and function indices for islets isolated from pancreata perfused for 24h on the PTR with indices obtained from control, 24h conventionally stored pancreata. 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 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.