Tolerogenic dual microparticle system for treatment of multiple sclerosis

项目总结/摘要 多发性硬化症（MS）是一种使人衰弱的免疫介导的神经系统疾病，通常影响年轻人， 成年人，在女性中更常见。在这种疾病中，免疫细胞靶向并破坏中枢神经系统中的髓鞘。 神经系统（CNS）引起脱髓鞘并因此引起神经学改变。没有已知的治疗MS的方法 目前的许多治疗方法都不是特异性的，并且抑制了整个免疫系统的功能。 人们对开发新的、更特异的和更有效的MS疗法非常感兴趣。 开发了一种新的疗法，在治疗实验性自身免疫性 脑脊髓炎（EAE），MS的小鼠模型，在半治疗设置。所述治疗基于 递送包封在FDA批准的聚（乳酸-共-乳酸）中的特异性髓鞘抗原和致耐受性因子， 用于通过可吞噬MP进行受控细胞内递送的PLGA微粒（MP）， 以及用于通过不可吞噬的MP控制递送至表面受体，因此构成了双重的 MP系统（dMP）。治疗是特异性的，依赖于特定的髓鞘抗原，因为MP负载 并不能阻止疾病的发生。此外，EAE阻断依赖于包封 治疗药物中可溶性因子和空颗粒无效。我们 假设dMP治疗阻断EAE的治疗成功是一个结果 耐受诱导。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 缓解/复发模型，并进一步优化治疗方案。本研究中提出的研究 应用是最重要的，鉴于其特异性和事实，MS的治疗选择 它们是有限的，其中许多缺乏必要的特异性。

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.