Encapsulated Porcine Islets into Rhesus Macaques

描述（由申请人提供）：在过去的五年中，在埃德蒙顿、迈阿密、明尼阿波利斯、费城和其他地方进行的开创性工作证明，胰岛异体移植作为1型糖尿病治疗的概念是可行的。然而，用于移植的组织仍然存在相当大的短缺。Microlslet公司的重点是通过提供免疫分离的成年猪胰岛异种移植来满足对内分泌组织日益增长的需求。迄今为止，我们已经开发了新的冷藏和胰岛处理解决方案，并产生了改进的胰岛培养条件。在撰写本文时，我们已经处理了超过87个胰岛，我们的平均产量已增加到437,000 q34,000 lEq每个胰腺，纯度约为90%（>90%胰岛分离成功率）。虽然没有在I期目标中提出，但在该提议的I期期间产生的胰岛被封装在2种Ca2+-海藻酸盐微胶囊中，并在两种链脲佐菌素诱导的糖尿病小鼠模型中测试了功能。在4个实验中，将裸露和包封的猪胰岛移植到47只免疫缺陷糖尿病小鼠（NOD/SCID）的腹膜腔中。每只动物接受不同数量的移植组织，从500到104 IE不等，100%的动物在移植后2天内恢复正常血糖。迄今为止，这些动物在移植后能维持移植功能6个月以上。在第二个系列研究中，将包封的胰岛移植到免疫能力小鼠（C57BL/6）中，100%的动物在2天内恢复正常血糖，没有任何免疫抑制。目前，3组链脲佐菌素诱导的糖尿病C57BL/6移植胰岛，其中40%的动物在200天以上的时间内血糖正常。这些数据表明，在糖尿病啮齿动物模型中腹腔移植时，封装的成年猪胰岛具有功能和生物相容性。为了确定这种异种移植物是否有可能在人类中发挥作用，下一步是在糖尿病非人灵长类动物中进行测试，这是一种已建立的大型动物临床前模型。因此，第二阶段的目标是证明封装猪岛在非人灵长类动物中的长期功能。特异性目的1：证明海藻酸盐微胶囊猪胰岛异种移植在链脲佐菌素诱导的糖尿病非人灵长类动物中的安全性和有效性。Aim I的目的是确定以海藻酸盐为基础的专有配方封装的成年猪胰岛异种移植物在糖尿病恒河猴中的安全性，有效性和命运。特异性目标2：确定用于END制备的胰岛分离、微胶囊化和移植的方法和材料。Aim 2的目的是验证和限定良好实验室规范（GLP）标准中描述的方法和材料，以备试验性新药/器械（IND）申请。

DESCRIPTION (provided by applicant): The concept of islet allotransplantation as a treatment for Type I Diabetes has been demonstrated as feasible by the pioneering work done in Edmonton, Miami, Minneapolis, Philadelphia and other sites during the last five years. However, there still exists a considerable shortage of tissue for transplantation. The focus of Microlslet, Inc is to meet the increased demand for endocrine tissue by providing immune-isolated adult porcine islet xenografts. To date we have developed novel cold storage and islet processing solutions and generated modified islet culturing conditions. We have processed over 87 pancreata at the time of this writing and our average yields have increased to 437,000 q34,000 lEq per pancreas with approximately 90% purity (>90% successful islet isolation rate). Though not proposed in the Phase 1 aims, islets generated during Phase I of this proposal were encapsulated in 2 types of Ca2+-alginate microcapsules and were tested for function in two streptozotocin-induced diabetic mouse models. In 4 experiments, naked and encapsulated porcine islets were transplanted into the peritoneal cavities of 47 immunodeficient, diabetic mice (NOD/SCID). Animals received varying amounts of graft tissue ranging from 500 to 104 IE per animal, with a return to normoglycemia occurring in 100% of the animals within 2 days of transplantation. To date, these animals have maintained graft function for more than 6 months post-transplantation. In the second series of studies, encapsulated islets were transplanted into immune competent mice (C57BL/6) with a return to normoglycemia achieved within 2 days in 100% of animals without any immunosuppression. Presently, 3 groups of streptozotocin-induced diabetic C57BL/6 transplanted with islets coated with our core technology, a gelled-core Ca2+-alginate bead, where 40% of the animals have been normoglycemic for over 200 days. These data demonstrate that encapsulated adult porcine islets are functional and biocompatible when transplanted intraperitoneally in a diabetic rodent model. To ascertain whether this xenograft has the potential to function in humans, the next step is to test it in diabetic nonhuman primates, an established large animal preclinical model. Therefore, the objective of Phase II is to demonstrate the long-term function of encapsulated porcine islets in non-human primates. SPECIFIC AIM 1: Demonstrate the safety and efficacy of alginate microencapsulated pig islet xenografts in streptozotocin-induced diabetic non-human primates. The goal of Aim I is to determine the safety, efficacy and fate of adult porcine islet xenografts encapsulated in a proprietary alginate-based formulation, in diabetic rhesus macaques. SPECIFIC AIM 2: Qualification of methods and materials for islet isolation, microencapsulation and transplantation for END preparation. The objective of Aim 2 is to validate and qualify the methods and materials described by Good Laboratory Practice (GLP) standards in preparation for an Investigative New Drug/Device (IND) application.