Encapsulated cells to treat type 1 diabetes

描述(由申请人提供)： 转基因细胞的封装使胰岛素可以在不需要免疫抑制的情况下用于1型糖尿病。糖尿病需要严格的血糖控制，以延缓或防止晚期并发症的发生。胶囊必须允许营养物质的交换以维持细胞的活力，并允许胰岛素外流，但保护细胞免受免疫攻击。利用Theracyte免疫隔离装置，将转导表达大鼠促红细胞生成素(EPO)的血管平滑肌细胞(VSMC)包裹起来，移植到致敏受体大鼠体内。血球压积增加了75%，并在长达两年的时间里保持在高水平。重要的是，在移除Theracyte装置并植入新装置后，血球再次持续增加。因此，Theracyte设备可以维持细胞，保护同种异体细胞免受免疫攻击，并允许二次植入。 在第一个目的中，我们建议使用微囊化VSMC转导表达葡萄糖调节的胰岛素来治疗糖尿病大鼠。转导表达葡萄糖调节胰岛素的VSMC将被克隆并种植在Theracyte设备中，并植入糖尿病大鼠体内。在第二个目标中，我们将使用Theracyte设备研究转基因胰岛植入糖尿病大鼠体内。糖尿病大鼠将接受同种异体胰岛的包埋装置，胰岛基因修饰的慢病毒载体可防止细胞凋亡，并与转导高血糖素样多肽-1(GLP-1)或促红细胞生成素(EPO)的VSMC共同种植，以延长其功能和治疗寿命。我们还将与转导的克隆VSMC共同种子胰岛，表达在AIM 1中产生的葡萄糖调节的胰岛素。 这项提议的长期目标是(1)开发克隆的、特征良好的细胞系，可以移植到治疗糖尿病的大鼠身上；(2)开发允许移植同种异体胰岛的方法，以便在不需要免疫抑制的情况下长期存活和治疗。这种方法的好处是，只会产生一种人类细胞系，并将其特征用于所有患者的治疗。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，这些信息可能被应用于1型糖尿病患者的治疗。

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.