Spatiotemporal tuning of myelin antigens and rapamycin for enhanced antigen-specific immune tolerance in multiple sclerosis.

髓磷脂抗原和雷帕霉素的时空调节可增强多发性硬化症的抗原特异性免疫耐受。

• 批准号: 10325547
• 负责人: Joseph J Catino
• 金额: $ 29.51万
• 依托单位: STATERA THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325547
• 关键词: Address; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; B-Lymphocytes; Cells; Characteristics; Clinical; Cyclosporine; Development; Disease; Disease Management; Disease model; Dose; Education; Encapsulated; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Expression Profile; Goals; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunization; Immunomodulators; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammatory Response; Injectable; Interferon-beta; Lead; Ligands; Literature; MS4A1 gene; Magic; Mediating; Modality; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Basic Proteins; Myelin Proteolipid Protein; Myelin Sheath; Neuraxis; Oligodendroglia; Outcome; Pathogenicity; Peptides; Pharmaceutical Preparations; Placebos; Proteins; Recurrence; Regulatory T-Lymphocyte; Relapse; Research Personnel; Self-Direction; Sirolimus; Specificity; Spinal Cord; Steroids; Symptoms; Technology; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Time; Treatment Efficacy; Treatment Protocols; Work; antigen-specific T cells; autoreactive T cell; base; clinical effect; clinical efficacy; clinically significant; combinatorial; design; disability; immune function; improved; innovation; lead candidate; mTOR inhibition; multiple sclerosis patient; multiple sclerosis treatment; nanocarrier; nanoparticle; nerve damage; novel; particle; preclinical efficacy; programs; side effect; spatiotemporal; standard of care; subcutaneous; treatment strategy; zeta potential

Project Summary Multiple sclerosis (MS) is an autoimmune disorder thought to be caused by the self-attack on myelin sheath by autoreactive T cells. Despite improvements in technologies to temporarily suppress the immune system to mitigate the recurrence of MS attacks, there is no current solution that addresses the underlying autoimmune response in MS. For instance, existing injectable therapies such as beta-interferons are only temporary, lasting only about six months. While ocrelizumab is the first CD20 therapeutic antibody to show an effect in progressive MS, its clinical effects are rather modest, only showing a 6% reduction compared to placebo in both 12 and 24 week disability progression. Development of approaches that direct re-education of the immune system to be tolerogenic to self-antigens in MS is therefore an unmet need. In order to generate selective specific immune tolerance to myelin autoantigens, combinatorial delivery of antigen and immunosuppressive drugs (e.g. rapamycin) to antigen presenting cells is a powerful approach. However, dual delivery of antigen and rapamycin raises spatial and temporal considerations, as localization (space) and sequence (time) of antigen/rapamycin can dictate the magnitude of cis-priming of antigen presenting cells. To prime antigen presenting cells more efficiently by maneuvering the favorable spatiotemporal modality of rapamycin and antigen, we previously formulated a novel nanocarrier platform, Spatiotemporally Tuned Particle (STP), that delivers rapamycin and antigen specifically to antigen presenting cells in a preferred sequence. Our ability to tune the spatiotemporal delivery of antigen and rapamycin resulted in significant improvement of immune tolerance in mice, expanding Tregs and improving clinical symptoms in experimental autoimmune encephalomyelitis (EAE). In this program, we will utilize our promising platform to generate myelin autoantigen specific tolerance in EAE induced by multiple antigens found in the myelin sheath of spinal cord homogenate, which is representative of MS in humans. In aim 1, we fabricate and characterize STP candidates encapsulating myelin peptides and rapamycin. In aim 2, we validate the therapeutic efficacy of STP candidates in spinal cord homogenate EAE and investigate antigen- specificity and immune cell infiltration. Overall, our proposed approaches will ultimately allow researchers to leverage our platform for targeted and sequential delivery of multiple therapeutic agents to unlock their full potentials in MS and other autoimmune diseases.

项目概要 多发性硬化症（MS）是一种自身免疫性疾病，被认为是由自我攻击引起的 髓鞘由自身反应性 T 细胞形成。尽管技术的进步暂时 抑制免疫系统以减轻多发性硬化症攻击的复发，目前没有解决方案 解决多发性硬化症中潜在的自身免疫反应。例如，现有的注射剂 β-干扰素等疗法只是暂时的，只能持续大约六个月。尽管 ocrelizumab 是第一个在进展性多发性硬化症中显示出疗效的 CD20 治疗抗体，其 临床效果相当有限，与安慰剂相比，12 项研究仅减少了 6% 和 24 周残疾进展。制定指导再教育的方法 因此，免疫系统对多发性硬化症自身抗原具有耐受性是一个未得到满足的需求。在 为了产生对髓磷脂自身抗原的选择性特异性免疫耐受，组合 将抗原和免疫抑制药物（例如雷帕霉素）递送至抗原呈递细胞是 一个强有力的方法。然而，抗原和雷帕霉素的双重递送提高了空间和 时间考虑因素，因为抗原/雷帕霉素的定位（空间）和序列（时间）可以 决定抗原呈递细胞顺式引发的程度。引发抗原呈递 通过操纵雷帕霉素和的有利时空模式更有效地细胞 抗原，我们之前制定了一个新颖的纳米载体平台，时空调谐 颗粒 (STP)，将雷帕霉素和抗原特异性递送至抗原呈递细胞 优选顺序。我们调节抗原和雷帕霉素时空递送的能力 显着改善小鼠的免疫耐受性，扩大 Tregs 和 改善实验性自身免疫性脑脊髓炎（EAE）的临床症状。在这个 计划，我们将利用我们有前途的平台来生成髓鞘质自身抗原特异性 脊髓髓鞘中多种抗原诱导的 EAE 耐受性 匀浆，它是人类 MS 的代表。在目标 1 中，我们制造并表征 封装髓磷脂肽和雷帕霉素的 STP 候选物。在目标 2 中，我们验证 STP 候选药物对脊髓匀浆 EAE 的治疗效果并研究抗原 特异性和免疫细胞浸润。总的来说，我们提出的方法最终将允许 研究人员利用我们的平台进行多种治疗的靶向和顺序递送 药物以释放其在多发性硬化症和其他自身免疫性疾病方面的全部潜力。