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

• 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
• 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

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）是美国年轻人非创伤性残疾的主要原因。 States.在MS中，免疫系统攻击中枢神经系统髓鞘中的自身抗原 (CNS)导致神经系统退化，目前还没有治愈的方法。一种治疗MS的方法 因为我们急需全面的免疫抑制。对此，一种主要策略是诱导抗原特异性 免疫耐受性，其可以防止针对髓鞘的免疫应答，而不具有全身性免疫耐受性。 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 递送编码MS自身抗原髓鞘少突胶质细胞糖蛋白的mRNA的纳米颗粒 (MOG)抗原呈递细胞（APC）作为基于耐受性纳米颗粒（NP）的疫苗。通过 工程化NP以选择性靶向肝脏，其中APC表达低水平的激活信号， 周围的细胞分泌高浓度的免疫抑制信号，我们将能够提出的 MOG抗原在致耐受性背景下对T细胞的作用。作为第二层安全防护，防止不慎免疫 为了刺激靶向MOG抗原，我们将共同递送免疫抑制剂。这是为了引导 MOG特异性调节性T细胞（TCRs）的扩增，这将提供抗原特异性保护性， 免疫抑制与此同时，在缺乏激活共刺激分子的情况下，转染的 APC还可以引起MOG特异性Th1、Th17和CD8+ T细胞的无反应性或死亡，从而防止这种免疫应答。 导致疾病的细胞。该提议将进一步优化NP制剂以使APC转染最大化， 最小化非预期的免疫激活，并进一步选择性地改善NP的体内递送。这个NP 技术代表了预防或治疗MS的创新疫苗平台，具有安全性 与其他相关技术相比，如使用病毒载体进行基因转移， 交付.