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.

项目摘要 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， 在胰腺中产生β胰岛细胞。T1D的治疗需要持续的 避免危及生命的并发症。迫切需要一种治疗方法， 可以工程免疫系统，以防止疾病的进展在早期阶段， 对胰岛细胞的损害，并对患者产生持久和变革性的影响。一 获得T1D特异性耐受性的方法是对抗原呈递细胞进行遗传工程改造 （APCs）来呈递疾病相关抗原。存在以下物质时的抗原呈递 致耐受性信号可导致疾病特异性保护性调节性T细胞的成熟 （Tennis）.特别地，肝脏驻留的APC表达低水平的活化共刺激因子。 分子和周围的细胞分泌免疫抑制信号，使肝脏 耐受性环境我们假设，非病毒转染的APC在肝脏中， 编码T1D特异性自身抗原的基因将促进安全和特异性保护性耐受， 用于预防和治疗自身免疫性T1D的致耐受性疫苗。我们将开发 可生物降解的纳米颗粒，以安全有效地在体内编程免疫细胞，包括 装甲运兵车。我们将首先创建和良好的表征新的纳米生物技术，并验证它在 体外模型（目的1）。然后，我们将评估纳米生物技术在体内的小鼠模型， T1D（目标2）。最后，我们将在体外和体内用人免疫细胞评估这些纳米颗粒， 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 旨在提供一种安全有效的免疫细胞工程方法来治疗T1D。