A Non-Viral Genetic Vaccine for Prevention and Treatment of Multiple Sclerosis

项目总结 多发性硬化症(MS)是美国年轻人非创伤性残疾的主要原因 各州。在多发性硬化症中，免疫系统攻击中枢神经系统髓鞘中的自身抗原 (CNS)，导致神经退行性变，目前还没有治愈方法。一种治疗多发性硬化症的方法 原因全面的免疫抑制是迫切需要的。其中一个主要的策略是诱导抗原特异性 免疫耐受，可防止针对髓鞘的免疫反应，而不具有系统性 抑制效应。为了实现这一点，我们建议使用合成的、可生物降解的聚合物 携带编码MS自身抗原髓鞘少突胶质细胞糖蛋白基因的纳米粒 (MOG)到抗原提呈细胞(APC)作为耐受性纳米颗粒(NP)为基础的疫苗。通过 改造NPs以选择性地靶向肝脏，在那里APC表达低水平的激活信号和 周围细胞分泌高浓度的免疫抑制信号，我们将能够呈现 在耐受性的背景下，MOG抗原到T细胞。作为防止不慎免疫的第二层安全措施 针对MOG抗原的刺激，我们将联合传递一种免疫抑制剂。这是为了引领 对MOG特异性调节性T细胞(Tregs)的扩增，这将提供抗原特异性保护 免疫抑制。同时，在没有激活共刺激分子的情况下，转基因细胞 APC还可以导致MOG特异性Th1、Th17和CD8+T细胞的无能或死亡，从而防止这种 细胞不会致病。该建议将进一步优化NP配方以最大限度地提高APC的转染率， 最大限度地减少意外的免疫激活，进一步提高NPs的体内选择性递送。这个NP 科技代表了一个预防或治疗多发性硬化症的创新疫苗平台，具有安全的优势 与其他相关技术相比，例如使用基因的病毒载体，更容易制造 送货。

PROJECT SUMMARY Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults in the United States. In MS, the immune system attacks autoantigens in the myelin sheath of the central nervous system (CNS), leading to neurological degeneration, and there is currently no cure. A treatment for MS that does not cause general immunosuppression is urgently needed. One leading strategy for this is to induce antigen-specific immune tolerance, which can prevent immune responses against the myelin sheath without having a systemic suppressive effect. In order to accomplish this, we propose to use synthetic, biodegradable polymeric nanoparticles to deliver mRNA encoding the MS autoantigen myelin oligodendrocyte glycoprotein (MOG) to antigen-presenting cells (APCs) as a tolerogenic nanoparticle (NP)-based vaccine. By engineering the NPs to selectively target the liver, where APCs express low levels of activating signals and surrounding cells secrete high concentrations of immunosuppressive signals, we will enable presentation of the MOG antigen to T cells in a tolerogenic context. As a second layer of safety to prevent inadvertent immune stimulation targeting the MOG antigen, we will co-deliver an immunosuppressive agent. This is designed to lead to expansion of MOG-specific regulatory T cells (Tregs), which will provide antigen-specific protective immunosuppression. At the same time, in the absence of activating co-stimulatory molecules, the transfected APCs can also cause anergy or death of MOG-specific Th1, Th17, and CD8+ T cells, thereby preventing such cells from causing disease. This proposal will further optimize the NP formulations to maximize APC transfection, minimize unintended immune activation, and further improve in vivo delivery of NPs selectively. This NP technology represents an innovative vaccine platform for preventing or treating MS, with advantages of safety and ease of manufacture compared to other related technologies, such as the use of viral vectors for gene delivery.