Encapsulated cells to treat type 1 diabetes

封装细胞治疗 1 型糖尿病

• 批准号: 6950285
• 负责人: WILLIAM R OSBORNE
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950285
• 关键词: autoimmunity; cell transplantation; clinical research; diabetes mellitus therapy; erythropoietin; gene delivery system; gene expression; glucose tolerance test; homologous transplantation; human tissue; insulin; insulin dependent diabetes mellitus; laboratory rat; nonhuman therapy evaluation; pancreatic islets; tissue /cell preparation; vascular smooth muscle

DESCRIPTION (provided by applicant): Encapsulation of genetically modified cells permits insulin delivery for Type 1 diabetes without the need for immunosuppression. Diabetes mellitus requires tight blood glucose control to delay or prevent the onset of late complications. The encapsulation must permit the exchange of nutrients to sustain cell viability, and allow insulin to efflux, but shield cells from immune attack. Using Theracyte immunoisolation devices, we encapsulated vascular smooth muscle cells (VSMC) transduced to express rat erythropoietin (EPO) and transplanted them into allergenic recipient rats. Hematocrits increased by up to 75% and remained high for up to 2 years. Importantly, after Theracyte devices were removed and new ones implanted sustained increased hematocrits were again achieved. Thus, Theracyte devices can sustain cells, protect allogeneic cells from immune attack, and allow second implants. In the first aim we propose to use encapsulated VSMC transduced to express glucose-regulated insulin to treat diabetic rats. VSMC multiply transduced to express glucose-regulated insulin will be cloned and seeded in Theracyte devices and implanted in diabetic rats. In a second aim we will study genetically modified islets implanted in diabetic rats using Theracyte devices. Diabetic rats will receive encapsulation devices seeded with allogeneic rat islets genetically modified with lentivirus vector encoding Bcl-2 to prevent apoptosis and co-seeded with VSMC transduced to express glucagon like peptide-1 (GLP-1) or EPO to expand their function and therapeutic lifetime. We will also co-seed islets with transduced cloned VSMC expressing glucose-regulated insulin generated in aim 1. The long term goals of this proposal are (1) to develop cloned, well characterized cell lines that may be transplanted to treat rats with diabetes and (2) to develop methods to permit implantation of allogeneic islets for long term survival and therapy without the need for immunosuppression. This approach has the benefit that only one human cell line will be generated and characterized for the treatment of all patients. These studies will provide valuable preclinical information from diabetic rodents that may be applied to treat patients with type 1 diabetes.

描述（由申请人提供）： 转基因细胞的封装允许在无需免疫抑制的情况下输送胰岛素治疗 1 型糖尿病。糖尿病需要严格控制血糖以延缓或预防晚期并发症的发生。封装必须允许营养物质交换以维持细胞活力，并允许胰岛素流出，但保护细胞免受免疫攻击。使用 Theracyte 免疫隔离装置，我们将转导表达大鼠促红细胞生成素 (EPO) 的血管平滑肌细胞 (VSMC) 封装起来，并将其移植到过敏性受体大鼠体内。血细胞比容增加高达 75%，并保持高水平长达 2 年。重要的是，在移除 Theracyte 装置并植入新装置后，血细胞比容再次实现持续增加。因此，Theracyte 装置可以维持细胞，保护同种异体细胞免受免疫攻击，并允许第二次植入。 在第一个目标中，我们建议使用封装的 VSMC 转导来表达葡萄糖调节胰岛素来治疗糖尿病大鼠。经多重转导表达葡萄糖调节胰岛素的 VSMC 将被克隆并接种到 Theracyte 装置中，并植入糖尿病大鼠体内。第二个目标是，我们将研究使用 Theracyte 设备植入糖尿病大鼠体内的转基因胰岛。糖尿病大鼠将接受封装装置，其中植入了用编码 Bcl-2 的慢病毒载体进行基因修饰的同种异体大鼠胰岛，以防止细胞凋亡，并与转导表达胰高血糖素样肽 1 (GLP-1) 或 EPO 的 VSMC 共同接种，以扩展其功能和治疗寿命。我们还将与目标 1 中生成的表达葡萄糖调节胰岛素的转导克隆 VSMC 共同接种胰岛。 该提案的长期目标是（1）开发克隆的、特征明确的细胞系，可移植以治疗糖尿病大鼠；（2）开发允许植入同种异体胰岛以实现长期存活和治疗而无需免疫抑制的方法。这种方法的优点是只需生成一种人类细胞系并对其进行表征即可用于治疗所有患者。这些研究将提供来自糖尿病啮齿动物的有价值的临床前信息，可用于治疗 1 型糖尿病患者。