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.

项目摘要多发性硬化症（MS）是联合成年人非创伤性残疾的主要原因国家。在MS中，免疫系统攻击中枢神经系统髓鞘中的自动抗原（CNS），导致神经变性，目前无法治愈。 MS的治疗迫切需要一般的免疫抑制。这样做的一种主要策略是诱导特定于抗原免疫耐受性，可以防止不具有全身性的髓鞘对髓鞘的免疫反应抑制作用。为了实现这一目标，我们建议使用合成，可生物降解的聚合物纳米颗粒以传递编码MS自动抗原髓磷脂少突胶质细胞糖蛋白的mRNA （MOG）作为基于耐酸的纳米颗粒（NP）的疫苗作为抗原呈递细胞（APC）。经过设计NP以选择性地靶向肝脏，在该肝脏中，APC表示较低的激活信号和周围细胞分泌高浓度的免疫抑制信号，我们将启用在耐受性的情况下，对T细胞的MOG抗原。作为预防无意免疫的第二层安全刺激针对MOG抗原的刺激，我们将与免疫抑制剂共同使用。这是为了领导扩展MOG特异性调节T细胞（TREG），该细胞将提供抗原特异性保护性免疫抑制。同时，在没有激活共刺激分子的情况下，转染了 APC还可能导致MOG特异性TH1，TH17和CD8+ T细胞的反应或死亡，从而防止这种情况细胞引起疾病。该建议将进一步优化NP公式，以最大化APC转染，最大程度地减少意外免疫激活，并选择性地进一步改善NP的体内递送。这个NP 技术代表了一个创新的疫苗平台，用于防止或治疗MS，并具有安全性与其他相关技术相比，易于制造，例如使用病毒载体作为基因送货。