Tolerance-Inducing mRNA Nanoparticles to Treat Type 1 Diabetes

项目总结 1型糖尿病(T1D)是一种威胁生命的自身免疫性疾病，影响着100多万患者 在美国，当免疫系统攻击并破坏胰岛素时就会发生这种情况- 在胰腺中产生胰岛细胞。T1D的治疗需要终生不变 维护以避免危及生命的并发症。迫切需要一种治疗方法 可以改造免疫系统，在早期阶段防止疾病进展，防止 对胰岛细胞的损害，并对患者有长期和变革性的影响。一 获得T1D特异性耐受的方法是对抗原提呈细胞进行基因工程 (APC)递呈疾病相关抗原(S)。在存在的情况下呈递抗原 耐受信号可导致疾病特异性保护性调节性T细胞的成熟 (Tregs)。特别是，驻留在肝脏的APC表达低水平的激活共刺激 分子和周围细胞分泌免疫抑制信号，使肝脏成为 耐受性环境。我们假设APC在肝脏中的非病毒转染与 编码T1D特异性自身抗原的基因将促进安全和特异的保护性耐受，因为 一种预防和治疗自身免疫性T1D的耐受疫苗。我们将发展 可生物降解的纳米颗粒在体内安全有效地对免疫细胞进行编程，包括 APC。我们将首先创建并很好地描述新的纳米生物技术，并在 体外模型(目标1)。然后，我们将在体内评估纳米生物技术在小鼠模型中的应用 T1D(目标2)。最后，我们将用人体免疫细胞在体外和体内对这些NPs进行评估， 使这项技术更接近翻译(目标3)。这种基于纳米颗粒的生物技术是 旨在使一种安全有效的免疫细胞工程方法治疗T1D。

PROJECT SUMMARY Type 1 diabetes (T1D) is a life-threatening autoimmune disease affecting over 1 million patients in the United States that occurs when the immune system attacks and destroys insulin- producing beta islet cells in the pancreas. Treatment of T1D requires a lifetime of constant maintenance to avoid life-threatening complications. There is an urgent need for a therapy that can engineer the immune system to prevent disease progression at early stages, prevent damage to islet cells, and have a long-lasting and transformative effect on patients. One method of achieving T1D-specific tolerance is to genetically engineer antigen-presenting cells (APCs) to present disease-relevant antigen(s). Antigen presentation in the presence of tolerogenic signals can lead to the maturation of disease-specific protective regulatory T cells (Tregs). In particular, liver-resident APCs express low levels of activating co-stimulatory molecules, and surrounding cells secrete immunosuppressive signals, making the liver a tolerogenic environment. We hypothesize that non-viral transfection of APCs in the liver with genes encoding T1D-specific autoantigens will promote safe and specific protective tolerance as a tolerogenic vaccine for the prevention and treatment of autoimmune T1D. We will develop biodegradable nanoparticles to safely and effectively program immune cells in vivo, including APCs. We will first create and well-characterize the new nanobiotechnology and validate it in in vitro models (Aim 1). We will then evaluate the nanobiotechnology in vivo in mouse models of T1D (Aim 2). Finally, we will evaluate these NPs with human immune cells in vitro and in vivo, bringing this technology closer to translation (Aim 3). This nanoparticle-based biotechnology is designed to enable a safe and effective method of immune cell engineering to treat T1D.