Pancreas Transporter Development and Validation

胰腺转运蛋白的开发和验证

• 批准号: 6993313
• 负责人: MICHAEL John TAYLOR
• 金额: $ 51.59万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6993313
• 关键词: athymic mouse; biomedical equipment development; clinical biomedical equipment; clinical research; cold temperature; human tissue; pancreatic islet transplantation; pancreatic islets; perfusion; swine; tissue /organ preservation

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.

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I型糖尿病临床治疗的胰岛移植重新引起人们的兴趣。然而，在这个时候，用于胰岛分离和移植的供体胰腺的采购还处于起步阶段。大多数在较远的供体部位的胰腺并没有获得，因为在运送到胰岛分离和移植中心的过程中，有理由担心死后缺血。灌注/保存技术已被证明对避免肾移植中的缺血性损伤具有重要影响。该提案旨在将这种方法应用于保存和获取可供移植的存活胰岛。该提案的主要目的是使用最先进的灌注技术和新的保存解决方案来测试机器灌注可以提高从缺血性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原型胰腺转运蛋白（PTR）。使用猪模型证明了在2-7 ℃下灌注保存24小时的可行性，该模型超过了目前临床上安全、静态冷藏供体胰腺的16小时限制。胰岛产量和功能被证明与从新鲜对照胰腺中获得的相当。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，具体目标有三个。第一步将是根据第一阶段可行性研究对PTR进行设计修改。第二步将需要将从在PTR上灌注24小时的胰腺分离的胰岛的产量和功能指数与从对照、24小时常规储存的胰腺获得的指数进行比较。然后评价冷灌注时间（24和48小时）和热缺血时间（长达60分钟）对猪胰岛分离参数的相互作用，以确定潜在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。预计胰腺转运蛋白和胰腺灌注方案的可用性将允许利用大多数（如果不是全部）适合在美国移植的胰腺。此外，PTR可以允许胰岛分离库用于长期储存。银行将允许有时间更好地进行供体与受体的HLA配型，现成的可用性，并使质量保证/控制程序能够在移植前进行。这项研究计划得到了三个主要临床中心的合作支持，这些中心对验证这种灌注技术以供未来使用感兴趣。