Polymeric biomaterial-based microparticle vaccine for amelioration of Type 1 diab

用于改善 1 型糖尿病的基于聚合物生物材料的微粒疫苗

• 批准号: 8592629
• 负责人: Jamal S Lewis
• 金额: $ 22.62万
• 依托单位: ONEVAX, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592629
• 关键词: Address; Animal Model; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; B-Lymphocytes; Biocompatible Materials; Biodistribution; Biological; Biological Availability; Biological Factors; Biomedical Engineering; Blood; Cells; Cholecalciferol; Clinic; Collaborations; Data; Dendritic Cells; Development; Diabetes Mellitus; Digestive System Disorders; Drug Formulations; Encapsulated; Failure; Figs - dietary; Florida; Funding; Goals; Health; Heart Diseases; Homing; Human; Immune; Immune system; Immunity; In Vitro; Inbred NOD Mice; Incidence; Injectable; Injection of therapeutic agent; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Kidney Failure; Left; Life; Lymph; Maintenance; Mediating; Medicine; Methods; Mission; Modification; Nature; Pancreas; Particle Size; Particulate; Patients; Phagocytes; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Pre-Clinical Model; Prevention; Public Health; Qualifying; Regulation; Regulatory T-Lymphocyte; Resolution; Self Tolerance; Shipping; Ships; Site; Structure of beta Cell of islet; Surface; System; T-Lymphocyte; Technology; Therapeutic; Time; Toxic effect; Translating; Treatment Cost; United States National Institutes of Health; Universities; Vaccination; Vaccines; Work; base; cell type; college; conditioning; controlled release; design; glucose metabolism; in vivo; mouse model; novel; novel therapeutics; particle; pre-clinical; preclinical safety; preclinical study; prevent; public health relevance; research clinical testing; response; socioeconomics; targeted delivery

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is thought to result from a breakdown of self-tolerance that is characterized by T cell-mediated destruction of the insulin-producing ¿-cells in the pancreas. Ultimately, glucose metabolism is interrupted, resulting in the development of life-threatening complications such as heart disease and renal failure. A number of factors are known to promote advantageous immune cell responses in experimental systems for T1D. However, systemic delivery of these agents often results in significant harmful off-target effects. We have pioneered a novel, biomaterial-based, particle vaccine system for in vivo delivery of pro- tolerance factors and insulin antigen, targeted to a key immune cell type, dendritic cells (DCs). Dendritic cells are professional antigen presenting cells (APCs), directly involved in T cell and B cell immunity, including the maintenance of tolerance to self-antigens. Moreover, exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro- tolerance DC phenotype as well as ameliorate T1D. Vaccination with DC-targeting microparticles (MPs) holds promise to correct T1D autoimmune responses, critically, without the costly ex vivo manipulations required of DC-based cellular therapy. Our long term goal is to develop an easily injectable, particle vaccine capable of prevention and reversal of T1D in humans. This approach greatly enhances the potential for widespread use. The objective of this Phase I proposal is to complete preclinical studies that demonstrate the feasibility of our most promising particle vaccine formulation for use in humans. More specifically, we want to assess biodistribution, bioavailability, toxicity and potentially harmful ff-target effects of the particle vaccine in preclinical models of T1D. Our preliminary data strongly suggests that this biomaterial-based, particle vaccine system holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Biomedical Engineering Department, College of Medicine and Diabetes Center of Excellence at the University of Florida boost our capability to complete the desired goals.

描述（由申请人提供）：1型糖尿病（T1D）被认为是由自身耐受性的破坏引起的，其特征在于T细胞介导的胰腺中产生胰岛素的细胞的破坏。最终，葡萄糖代谢中断，导致危及生命的并发症，如心脏病和肾衰竭的发展。已知许多因素在T1D的实验系统中促进有利的免疫细胞应答。然而，这些药剂的全身递送通常导致显著有害的脱靶。 方面的影响.我们开创了一种新型的基于生物材料的颗粒疫苗系统，用于体内递送促耐受因子和胰岛素抗原，靶向关键的免疫细胞类型，树突状细胞（DC）。树突状细胞（Dendritic cells，DC）是一种专职的抗原呈递细胞（antigen presenting cells，APC），直接参与T细胞和B细胞免疫，包括维持对自身抗原的耐受。此外，已显示用某些免疫调节剂对DC进行外源性调节可诱导促耐受DC表型以及改善T1D。用DC靶向微粒（MP）进行疫苗接种有望纠正T1D自身免疫反应，关键是，无需基于DC的细胞疗法所需的昂贵的离体操作。我们的长期目标是开发一种易于注射的颗粒疫苗，能够预防和逆转人类T1D。这种方法大大提高了广泛使用的潜力。该I期提案的目的是完成临床前研究，以证明我们最有前途的颗粒疫苗制剂用于人类的可行性。更具体地说，我们希望评估颗粒疫苗在T1D临床前模型中的生物分布、生物利用度、毒性和潜在有害的脱靶效应。我们的初步数据强烈表明，这种基于生物材料的颗粒疫苗系统有望纠正T1D的自身免疫反应。此外，我们与佛罗里达大学生物医学工程系、医学院和糖尿病卓越中心的战略合作提高了我们完成预期目标的能力。