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

用于预防和治疗多发性硬化症的非病毒基因疫苗

基本信息

批准号：
10228440
负责人：
Jordan Green
金额：
$ 20.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-17 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228440
关键词：
Antigen Presentation Antigen-Presenting Cells Antigens Artificial nanoparticles Autoantigens Autoimmune Autoimmune Diseases Biocompatible Materials Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cessation of life Coculture Techniques Dendritic Cells Disease Engineering Ensure Environment Esters Experimental Autoimmune Encephalomyelitis Formulation Gene Delivery Genes Genetic Engineering GpG-oligonucleotide Health Human Immune Immune Tolerance Immune response Immune system Immunization Immunocompromised Host Immunologic Receptors Immunosuppression Immunosuppressive Agents In Vitro Incidence Inflammation Injections Intravenous Lead Liver Mediating Messenger RNA Methods Modeling Multiple Sclerosis Mus Muscle Myelin Sheath Nerve Nerve Degeneration Neuraxis Nucleic Acids Oligonucleotides Organ Patients Prevention Property Regulatory T-Lymphocyte Reporter Genes Risk Safety Scheme Severity of illness Signal Transduction Specificity T-Lymphocyte Technology Time Tissues Toxic effect Transfection Transgenic Mice United States Vaccines Viral Vector Virus Vision Work anergy autoreactivity base biodegradable polymer biophysical properties cell type chemical property conventional therapy cytokine design disability genetic vaccine immune activation immunoengineering immunogenicity immunoregulation improved in vivo innovation intravenous administration lymphoid organ mRNA delivery macrophage monocyte motor impairment mouse model multiple sclerosis treatment nanoparticle nanoparticle delivery next generation non-viral gene delivery oligodendrocyte-myelin glycoprotein particle prevent recruit response side effect targeted delivery vector young adult

项目摘要

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.

项目概要多发性硬化症 (MS) 是美国年轻人非创伤性残疾的主要原因国家。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（中枢神经系统），导致神经退行性变，目前尚无治愈方法。一种多发性硬化症的治疗方法导致迫切需要一般免疫抑制。对此的一项主要策略是诱导抗原特异性免疫耐受，可以防止针对髓鞘的免疫反应，而不会产生全身性反应抑制作用。为了实现这一目标，我们建议使用合成的、可生物降解的聚合物纳米粒子传递编码 MS 自身抗原髓磷脂少突胶质细胞糖蛋白的 mRNA (MOG) 到抗原呈递细胞 (APC) 作为基于耐受性纳米颗粒 (NP) 的疫苗。经过设计纳米颗粒选择性地靶向肝脏，其中 APC 表达低水平的激活信号，周围细胞分泌高浓度的免疫抑制信号，我们将能够呈现耐受环境下 T 细胞的 MOG 抗原。作为第二层安全，防止意外免疫针对 MOG 抗原的刺激，我们将共同递送免疫抑制剂。此举旨在引导 MOG 特异性调节 T 细胞 (Treg) 的扩增，这将提供抗原特异性保护免疫抑制。同时，在缺乏激活共刺激分子的情况下，转染的 APC 还可导致 MOG 特异性 Th1、Th17 和 CD8+ T 细胞无反应或死亡，从而防止此类细胞避免引起疾病。该提案将进一步优化 NP 配方，以最大化 APC 转染，最大限度地减少意外的免疫激活，并进一步改善纳米粒子的体内选择性递送。这个NP 技术代表了预防或治疗多发性硬化症的创新疫苗平台，具有安全性优势与其他相关技术（例如使用基因病毒载体）相比，易于制造送货。