Tolerogenic dual microparticle system for treatment of multiple sclerosis

用于治疗多发性硬化症的致耐受性双微粒系统

• 批准号: 9918870
• 负责人: Dorina Avram
• 金额: $ 52.1万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918870
• 关键词: Affect; Antigens; Asses; Autoimmune Process; Autoimmunity; Bone Marrow; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell Surface Receptors; Cells; Cholecalciferol; Complex; Data; Demyelinations; Dendritic Cells; Development; Disease; Disease remission; Dose; Encapsulated; Experimental Autoimmune Encephalomyelitis; FDA approved; Formulation; Frequencies; Generations; Glycolates; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune System Diseases; Immune system; Immunization; Immunosuppression; In Vitro; Inbred NOD Mice; Infection; Infiltration; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Mediating; Microglia; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Myelogenous; Neuraxis; Neurologic; Neurons; Opportunistic Infections; Pathogenicity; Patients; Peptides; Peripheral; Phagocytes; Pharmaceutical Preparations; Phase; Phenotype; Population; Prevention; Proteins; Proteolipids; Regimen; Regulatory T-Lymphocyte; Relapse; Risk; Role; SJL Mouse; Specificity; Surface; System; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Thymus Gland; Translating; Treatment Protocols; Woman; base; controlled release; cytokine; effective therapy; improved; interest; macrophage; mouse model; multiple sclerosis treatment; nervous system disorder; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; particle; peptide B; receptor; recruit; release factor; subcutaneous; success; tumor; young adult

Project Summary/Abstract Multiple sclerosis (MS) is a debilitating, immune-mediated neurological disease that typically affects young adults, with higher frequency in women. In this disease immune cells target and destroy myelin in the central nervous system (CNS) causing demyelination and thus neurological alterations. There is no known cure for MS and many of the current treatments are not specific and suppress the function of the entire immune system. There is a great interest in development of novel, more specific and more effective therapies for MS. We developed a new therapy, which shows high efficiency in the treatment of Experimental Autoimmune Encephalomyelitis (EAE), the mouse model for MS, in a semitherapeutic setup. The treatment is based on delivery of specific myelin antigens and tolerogenic factors encapsulated in the FDA-approved poly(lactic-co- glycolic acid) (PLGA) microparticles (MPs) for controlled intracellular delivery through phagocytosable MPs, as well as for controlled delivery to surface receptors through non-phagocytosable MPs, thus constituting a dual MP system (dMP). The treatment is specific, being dependent on the specific myelin antigens, as MPs loaded with an irrelevant peptide did not block the disease. In addition, EAE blocking was dependent on encapsulation of the treating drugs, as soluble factors and empty particles were not effective in the treatment. We hypothesize that the therapeutic success translated in blocking of EAE by the dMP treatment is a consequence of tolerance induction. We thus propose to establish the mechanisms by which the dMP treatment blocks EAE. Additionally, we propose to test the dMP treatment in advanced stages of EAE, as well as in a remission/relapsing model and further optimize the regimen of treatment. The proposed studies in this application are of the highest significance, given its specificity and the fact that the therapeutic options for MS are limited and many of them lack the needed specificity.

项目摘要/摘要 多发性硬化症(MS)是一种衰弱的、免疫介导的神经系统疾病，通常影响年轻人 成人型，女性发病率较高。在这种疾病中，免疫细胞靶向并破坏中央的髓鞘 神经系统(CNS)导致脱髓鞘，从而导致神经系统改变。目前还没有治疗多发性硬化症的已知方法 而且目前的许多治疗方法都没有特效性，会抑制整个免疫系统的功能。 人们对开发更新颖、更具体、更有效的治疗方法非常感兴趣 开发了一种新的治疗方法，在实验性自身免疫性疾病的治疗中显示出高效 脑脊髓炎(EAE)，MS的小鼠模型，处于半治疗状态。治疗的基础是 FDA批准的聚(乳酸-共聚物)中包裹的特定髓鞘抗原和耐受因子的递送 羟基乙酸)(PLGA)微粒(MPS)通过可吞噬的MPS控制细胞内递送，AS 以及通过非吞噬的MPS受控递送到表面受体，从而构成双重 MP系统(DMP)。这种治疗是特定的，依赖于特定的髓鞘抗原，因为MPS被加载 不相关的多肽并不能阻止这种疾病。此外，EAE阻止依赖于封装 治疗药物中，作为可溶性因子和空粒的治疗效果不佳。我们 假设治疗的成功转化为DMP治疗阻断EAE是一种结果 耐受性诱导。因此，我们建议建立DMP治疗阻断EAE的机制。 此外，我们建议在EAE的晚期阶段以及在 缓解/复发模式，进一步优化治疗方案。在这方面的拟议研究 考虑到其特异性和MS的治疗选择，应用具有最高的意义 它们都是有限的，其中许多缺乏所需的特异性。