Engineered Regulatory T cells with Enhanced Stability and Suppression for Autoimmunity

具有增强稳定性和抑制自身免疫功能的工程调节性 T 细胞

• 批准号: 10314662
• 负责人: MICHAEL GREGORY CHAVEZ
• 金额: $ 3.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314662
• 关键词: Engineered; Regulatory; cells; Enhanced; Stability

PROJECT SUMMARY Autoimmune diseases are characterized by the immune system attacking the body, adversely affecting over 23 million Americans a year. Current standards of care often only alleviate symptoms, leave patients dependent on therapies, and increase their susceptibility to infection, necessitating new treatment paradigms. The recent development of engineered cell-based therapies has allowed us to harness a suppressive T cell phenotype known as regulatory T cells (Tregs) and design them to target sites of autoimmunity. However, instability of the Treg phenotype and inability to drive immunosuppressive functions have hindered their therapeutic potential and widespread adoption in the clinic. We seek to harness novel technologies from genome and receptor engineering to build a platform for engineering of highly stable and suppressive Tregs that become the basis for future cell- based therapies against autoimmunity. This platform is enabled by two novel cell engineering techniques that I recently developed, including a highly efficient and specific knock-in strategy that stabilizes transgene expression and a receptor platform that activates customized cytokine pathways. Specifically, we aim to 1) generate a highly stable Treg phenotype by leveraging the knock-in strategy to express the Treg driving transcription factor, FOXP3, in CD4+ T cells, 2) identify and characterize suppression enhancement pathways by high-throughput cell-based screens utilizing my receptor platform, and 3) assess the therapeutic benefit of these novel engineered Tregs in a mouse model of Graft-vs-Host Disease. This work results in a novel discovery and engineering platform that creates Tregs that can be adapted for targeted cell-based therapies against a plethora of autoimmune diseases. The completion of the proposed work creates new data, new pathways, and new technologies to improve the survival and the function of Treg therapies, improving their translation potential and bringing them closer to helping the people who need it most.

项目总结 自身免疫性疾病的特征是免疫系统攻击身体，对23%以上的人产生不利影响 每年有数百万美国人。目前的护理标准往往只缓解症状，让患者依赖 这可能会增加他们对感染的易感性，从而需要新的治疗模式。最近的 基于细胞的工程疗法的发展使我们能够利用抑制性T细胞表型 被称为调节性T细胞(Tregs)，并将它们设计为自身免疫的靶点。然而，经济的不稳定 Treg表型和无法驱动免疫抑制功能阻碍了它们的治疗潜力和 在临床上被广泛采用。我们寻求利用基因组和受体工程的新技术 为设计高度稳定和抑制的Tregs建立一个平台，成为未来细胞的基础- 针对自身免疫力的基础疗法。该平台是由两种新的细胞工程技术实现的，即 最近开发的，包括一种高效和特定的稳定转基因表达的敲入策略 和一个受体平台，激活定制的细胞因子途径。具体地说，我们的目标是1)产生高度的 稳定的Treg表型通过利用敲入策略表达Treg驱动转录因子FOXP3， 在CD4+T细胞中，2)通过高通量细胞为基础的识别和表征抑制增强通路 利用我的受体平台进行筛查，以及3)评估这些新型工程Tregs在 移植物抗宿主病小鼠模型的建立。这项工作产生了一种新的发现和工程平台 创造出可用于针对过多自身免疫性疾病的靶向细胞疗法的Treg。 拟议工作的完成创造了新的数据、新的途径和新的技术，以改善 Treg疗法的生存和功能，提高其翻译潜力并使其更接近于帮助 最需要它的人。