SA-FasL-engineered human islets as a novel product for the treatment of type 1 diabetes

项目摘要 1型糖尿病（T1 D）是一种慢性自身免疫性疾病，影响全球约1%的人口。外源 胰岛素治疗是T1 D的标准治疗，但通常会对生活质量产生负面影响，并且无效 预防复发性高血糖发作和慢性并发症。最近的研究表明，人类 同种异体胰岛移植可以恢复长期的正常血糖和胰岛素依赖性， 低血糖和免疫抑制T1 D患者微血管病变进展缓慢。然而，在这方面， 免疫排斥和连续使用免疫抑制来控制排斥是两个主要限制 临床胰岛移植。标准的免疫抑制对移植物的长期存活是无效的 并且对移植物和移植物受体也具有显著的不利影响。因此，小说的发展 在没有慢性免疫抑制的情况下防止胰岛移植物排斥的方法是一个重要的目标。 FasCure Therapeutics专注于开发具有所需免疫调节作用的生物制剂， 针对目标适应症的活动。该公司拥有专有的新免疫组合的独家权利， 作为免疫调节平台组分的抑制性配体 自身免疫性疾病和移植排斥。该公司的领先治疗平台包括胰岛工程 一种新的Fas配体免疫调节蛋白SA-FasL。T细胞是T1 D的罪魁祸首， 以及同种异体胰岛移植排斥反应。抗原诱导T细胞表面Fas受体表达上调 激活，并变得对Fas/FasL介导的凋亡敏感。重要的是，FasL诱导的细胞凋亡起着重要的作用。 在T细胞稳态和对自身抗原的耐受性中起重要作用。因此，SA-FasL具有显著的 诱导对自身和同种异体抗原耐受的潜力。与此概念相一致，瞬态 在胰岛上展示SA-FasL蛋白在克服免疫排斥方面显示出强大的功效， 各种同种异体和异种啮齿动物移植模型。第一阶段STTR的主要目标是 i）评估用SA-FasL蛋白工程化人胰岛的可行性， ii）测试SA-FasL工程化的胰岛在克服其功能方面的功效， 在不存在连续免疫抑制的情况下，在人源化小鼠模型中的排斥。如果可行 尽管在人源化小鼠模型中显示了SA-FasL工程化的人胰岛和功效， 在II期STRR申请中作为新产品开发用于临床。

PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However, immune rejection and continuous use of immunosuppression to control rejection are two major limitations of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. FasCure Therapeutics is focused on the development of biologics with desired immune modulatory activities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immune inhibitory ligands as components of an immunomodulatory platform for prevention and treatment of autoimmune diseases and graft rejection. The Company’s lead therapeutic platform includes islets engineered with a novel form of Fas ligand immunomodulatory protein, SA-FasL. T cells are the main culprits of T1D as well as allogeneic islet graft rejection. T cells upregulate Fas receptor on their surface following antigen activation, and become sensitive to Fas/FasL-mediated apoptosis. Importantly, FasL-induced apoptosis plays an important role in T cell homeostasis and tolerance to self-antigens. As such, SA-FasL has significant potential for the induction of tolerance to auto and alloantigens. Consistent with this notion, the transient display of SA-FasL protein on pancreatic islets have shown robust efficacy in overcoming immune rejection in various allogeneic and xenogeneic rodent transplantation models. The major goals of this phase I STTR application is to: i) assesses the feasibility of engineering human islets with SA-FasL protein without negatively impacting their function, and ii) test the efficacy of SA-FasL-engineered islets in overcoming rejection in a humanized mouse model in the absence of continuous immunosuppression. If feasibility and efficacy are shown in the humanized mouse model, the SA-FasL-engineered human islets will be further developed as a novel product in a Phase II STRR application for translation into clinic.