Evaluation of a beta cell replacement therapy combined product that avoids the need for immunosuppression via localized induction of immune tolerance

项目摘要/摘要 糖尿病是世界范围内一个日益重要的健康问题。尽管糖尿病治疗最近取得了进展， 包括长效胰岛素制剂、胰岛素泵和连续血糖监测仪，大多数糖尿病患者 患者无法达到目前推荐的血糖控制目标。虽然移植了 有供体胰岛或完整胰腺的糖尿病患者有效地恢复血糖 在控制方面，由于来源材料有限以及对终身的要求，这种程序仍然很少 免疫抑制。为了绕过第一个障碍，再生医疗解决方案(RMS) 开发了一种专利协议，用于转化诱导多能干细胞(IPSC)，这是一种几乎无限的细胞 来源是胰岛样细胞群(ILC)，其中包括产生胰岛素的β-样细胞。为了消除这种需要 在免疫抑制方面，iTerance，Inc.已经推出了一种由Fas配体结合的产品 微粒(iTOL-100)，当与啮齿动物或灵长类胰岛共同移植时，产生局部免疫 在糖尿病动物模型中提供耐受性和防止同种异体移植排斥反应的长期保护。在本建议中 项目中，RMS将与迈阿密大学糖尿病研究所合作测试一种联合产品 由ILC和iTOL-100混合作为基于细胞的糖尿病治疗候选药物组成，将缓解 终身免疫抑制。为了确定这种组合产品的可行性，我们将首先演示 两种产物(ILC和iTOL-100)的体外细胞相容性。接下来，体内细胞相容性和 联合产品的治疗效果将在免疫低下的小鼠模型中得到验证。 糖尿病。最后，联合产物在免疫中延缓异种移植排斥反应的能力 合格的糖尿病小鼠将被确定。总之，这些研究将为第二阶段项目奠定基础 其中组合产品将在重组的小鼠身上测试其逃避同种异体移植排斥反应的能力 人类免疫系统，以及将使临床翻译成为可能的其他基本研究。可得性 一种丰富的β细胞替代疗法，不需要慢性免疫抑制药物治疗 长期的同种异体移植耐受将把这种治疗形式的范围扩大到越来越多的 可能从中受益的患者。

Project Summary/Abstract Diabetes is an increasingly important health problem worldwide. Despite recent advances in diabetes care, including long-acting insulin formulations, insulin pumps, and continuous glucose monitors, a majority of diabetic patients cannot achieve currently recommended targets for blood glucose control. Although transplantation of diabetic patients with donor-derived pancreatic islets or intact pancreas effectively restores blood glucose control, such procedures remain rare due to limited source material and the requirement for life-long immunosuppression. To circumvent the first of these obstacles, Regenerative Medical Solutions (RMS) has developed a proprietary protocol for converting induced pluripotent stem cells (iPSC), a virtually unlimited cell source, into islet-like clusters (ILC) of cells that include insulin-producing beta-like cells. To eliminate the need for immunosuppression, iTolerance, Inc, has advanced a product consisting of Fas ligand conjugated microparticles (iTOL-100) that, when co-transplanted with rodent or primate islets, create localized immune tolerance and provide long-term protection from allograft rejection in animal models of diabetes. In this proposed project, RMS will work with the Diabetes Research Institute at the University of Miami to test a combined product consisting of ILC mixed with iTOL-100 as a candidate cell-based diabetes therapeutic that will alleviate the need for life-long immunosuppression. To establish the feasibility of such a combined product, we will first demonstrate in vitro cytocompatibility of the two products (ILC and iTOL-100). Next, the in vivo cytocompatibility and therapeutic efficacy of the combined product will be verified in an immunocompromised mouse model of diabetes. Finally, the ability of the combined product to delay the xenograft rejection response in immune competent diabetic mice will be determined. Together, these studies will lay the groundwork for a Phase II project in which the combined product will be tested for its ability to evade allograft rejection in mice reconstituted with a human immune system, along with other essential studies that will enable clinical translation. The availability of an abundant beta cell-replacement therapy that does not require chronic immunosuppressive medication for long-term allograft tolerance will extend the reach of this form of treatment to the ever-growing numbers of patients who may benefit from it.