Tolerance-Inducing mRNA Nanoparticles to Treat Type 1 Diabetes

诱导耐受的 mRNA 纳米颗粒治疗 1 型糖尿病

• 批准号: 10835326
• 负责人: Joshua Charles Doloff
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10835326
• 关键词: Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Biocompatible Materials; Biodistribution; Biological; Biotechnology; Cell secretion; Cells; Coculture Techniques; Dendritic Cells; Development; Diabetes prevention; Disease; Disease Progression; Drug Kinetics; Engineering; Ensure; Environment; Esters; Gene Delivery; Gene Expression; Genes; Genetic Engineering; Human; Immune; Immune Targeting; Immune response; Immune system; Immunosuppression; In Vitro; Inbred NOD Mice; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Kinetics; Life; Liver; Macrophage; Maintenance; Mediating; Messenger RNA; Methods; Modeling; Mus; Non obese; Nucleic Acids; Oligonucleotides; Organ; Pancreas; Patients; Phenotype; Prevention; Property; Regulatory T-Lymphocyte; Reporter; Reporter Genes; Safety; Severity of illness; Signal Transduction; Sirolimus; Specificity; Spleen; System; T cell receptor repertoire sequencing; T-Lymphocyte; Technology; Therapeutic Uses; Transfection; Transgenic Mice; Translations; United States; Vaccines; antigen-specific T cells; biophysical properties; cell type; cellular engineering; chemical property; cytokine; cytotoxicity; design; diabetic; humanized mouse; immune activation; immunoengineering; immunoregulation; in vitro Model; in vivo; innovation; mRNA delivery; monocyte; mouse model; nanobiotechnology; nanoparticle; nanoparticle delivery; particle; prevent; programs; recruit; small molecule

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.

项目概要 1 型糖尿病 (T1D) 是一种危及生命的自身免疫性疾病，影响超过 100 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β胰岛细胞。 T1D 的治疗需要终生持续 维护以避免危及生命的并发症。迫切需要一种治疗方法 可以设计免疫系统来预防疾病的早期发展，预防 对胰岛细胞造成损害，并对患者产生持久的变革性影响。一 实现 T1D 特异性耐受的方法是对抗原呈递细胞进行基因改造 (APC) 呈递疾病相关抗原。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 T 细胞成熟 （特雷格斯）。特别是，肝脏驻留 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 耐受环境。我们假设肝脏中 APC 的非病毒转染 编码 T1D 特异性自身抗原的基因将促进安全和特异性的保护性耐受 用于预防和治疗自身免疫性 T1D 的耐受性疫苗。我们将开发 可生物降解的纳米粒子，可安全有效地对体内免疫细胞进行编程，包括 装甲运兵车。我们将首先创建并充分表征新的纳米生物技术，并在 体外模型（目标 1）。然后我们将在小鼠模型中评估纳米生物技术 T1D（目标 2）。最后，我们将用人类免疫细胞在体外和体内评估这些纳米颗粒， 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 旨在提供一种安全有效的免疫细胞工程方法来治疗 T1D。