Islet Allograft Gene Therapy for Primate Diabetes

描述（由申请人提供）： 本申请是为了响应RFA DK-03-001“1型糖尿病及其并发症的台架到床边研究”而编写的。该应用程序代表了两个小组的共同努力，一个在迈阿密，一个在匹兹堡。迈阿密小组在非人灵长类动物和人类胰岛移植方面有着很强的专业知识和成就，在胰岛移植免疫学方面也很流利。匹兹堡研究小组在使用转基因和病毒向胰岛输送生长因子方面有着良好的记录。因此，本申请与RFA的目标雅阁，汇集了具有β细胞分子和细胞生物学、β细胞基因治疗和β细胞免疫学专业知识的基础科学家，胰岛转基因小鼠发育、啮齿动物胰岛移植和非人灵长类动物胰岛移植专家的动物生理学家，以及具有人类胰岛移植和糖尿病临床管理专业知识的临床医生。 具体而言，匹兹堡小组表明：1）在胰岛移植之前将肝细胞生长因子（HGF）转基因或腺病毒基因递送至啮齿动物胰岛显著改善了移植结果和胰岛移植物功能，2）这显著减少了在啮齿动物中实现成功移植结果所需的胰岛数量，和3）使用基因转移技术可以容易地将HGF递送至非人灵长类动物胰岛。迈阿密小组已经证明，埃德蒙顿小组为人类开发的无类固醇免疫抑制方案可以成功应用于非人灵长类动物，并在非人灵长类动物中开发了理想的边缘胰岛块移植模型。 这种方法学和专业知识的融合允许组合的组测试以下假设：将HGF递送至非人灵长类动物胰岛将非常显著地增强这些胰岛的植入和性能，并且因此将非常显著地减少实现正常血糖控制所需的胰岛数量。我们乐观地认为，这些研究可能会实现他们的目标，并将在短期内作为糖尿病患者类似研究所需的第三个也是最后一个临床前步骤。

DESCRIPTION (provided by applicant): This application is written in response to RFA DK-03-001, "Bench to Bedside Research in Type 1 Diabetes and Its Complications". The application represents a joint effort of two groups, one in Miami and one in Pittsburgh. The Miami group has a strong record of expertise and achievement in non-human primate and human islet transplantation, as well as fluency in islet transplant immunology. The Pittsburgh group has a strong track record using the transgenic and viral delivery of growth factors to the pancreatic islet. This application, therefore, in accord with the goals of the RFA, brings together basic scientists with expertise in beta cell molecular and cellular biology, beta cell gene therapy, and beta cell immunology, with animal physiologists expert in islet transgenic mouse development, rodent islet transplant, and non-human primate islet transplant, with clinicians with expertise in human islet transplantation and clinical management of diabetes. Specifically, the Pittsburgh group has shown that: 1) transgenic or adenoviral gene delivery of hepatocyte growth factor (HGF) to rodent islets prior to islet transplantation markedly improves transplant outcomes and islet graft function, 2) that this markedly reduces the number of islets required to achieve successful transplant outcomes in rodents, and 3) that HGF can be readily delivered to non-human primate islets using gene transfer techniques. The Miami group has demonstrated that the steroid-free immunosuppression protocol developed by the Edmonton group for humans can be successfully applied to non-human primates, and have developed an ideal marginal islet mass transplant model in non-human primates. This confluence of methodology and expertise allow the combined groups to test the hypothesis that delivery of HGF to non-human primate islets will very significantly enhance the engraftment and performance of these islets, and will therefore very significantly reduce the number of islets required to achieve normal glycemic control. We are optimistic that these studies will likely achieve their goal, and will serve in the near term as the third and final preclinical step required for similar studies in humans with diabetes.