Encapsulated Porcine Islets into Rhesus Macaques

将猪胰岛封装入恒河猴体内

• 批准号: 7280849
• 负责人: INGRID STUIVER
• 金额: $ 57.63万
• 依托单位: MICROISLET, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280849
• 关键词: Encapsulated; Porcine; Islets; into; Rhesus

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.

描述（由申请人提供）：胰岛同种异体移植作为I型糖尿病治疗的概念已被过去五年中在埃德蒙顿、迈阿密、明尼阿波利斯、费城和其他地点进行的开创性工作证明是可行的。然而，用于移植的组织仍然存在相当大的短缺。Microlslet，Inc的重点是通过提供免疫分离的成年猪胰岛异种移植物来满足对内分泌组织日益增长的需求。到目前为止，我们已经开发了新的冷藏和胰岛处理解决方案，并产生了改良的胰岛培养条件。在撰写本文时，我们已经处理了超过87个胰腺，并且我们的平均产量已经增加到437，000 q34，000 lEq/胰腺，纯度约为90%（>90%的胰岛成功分离率）。虽然在第1阶段的目标中没有提出，但在该提议的第1阶段期间产生的胰岛被封装在2种类型的Ca 2 +-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其功能。在4个实验中，裸和封装的猪胰岛移植到47个免疫缺陷，糖尿病小鼠（NOD/SCID）的腹腔。动物接受不同量的移植组织，范围为每只动物500至104 IE，在移植后2天内100%的动物恢复正常。迄今为止，这些动物在移植后保持移植物功能超过6个月。在第二系列研究中，将包封的胰岛移植到免疫活性小鼠（C57 BL/6）中，在没有任何免疫抑制的情况下，100%的动物在2天内恢复到正常水平。目前，3组链脲佐菌素诱导的糖尿病C57 BL/6移植了用我们的核心技术包被的胰岛，凝胶核心Ca 2 +-藻酸盐珠，其中40%的动物血糖正常超过200天。这些数据表明，当腹膜内移植到糖尿病啮齿动物模型中时，包裹的成年猪胰岛具有功能性和生物相容性。为了确定这种异种移植物是否具有在人类中发挥作用的潜力，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，II期的目的是证明包封的猪胰岛在非人灵长类动物中的长期功能。具体目标1：证明藻酸盐微囊化猪胰岛异种移植物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。目的I的目的是确定包封在基于藻酸盐的专利制剂中的成年猪胰岛异种移植物在糖尿病恒河猴中的安全性、有效性和结局。特定目的2：确认用于制备END的胰岛分离、微囊化和移植的方法和材料。目标2的目的是确认和鉴定药物非临床研究质量管理规范（GLP）标准中描述的方法和材料，以准备研究性新药/器械（IND）申请。