Splenic Modulation of SHP-2 Activity as a Therapeutic Option for Systemic Lupus Erythematosus

脾脏调节 SHP-2 活性作为系统性红斑狼疮的治疗选择

• 批准号: 10668102
• 负责人: JASON R. McCARTHY
• 金额: $ 23.5万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668102
• 关键词: Active Sites; Anti-Inflammatory Agents; Antibodies; Antigen-Presenting Cells; Antigens; Antisense Oligonucleotides; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Biological Assay; Biological Response Modifiers; Biomimetics; Blood Platelets; Case Study; Cell membrane; Cells; Circulation; Clonal Expansion; Complement; Crescentic Glomerulonephritis; Dendritic Cells; Disease; Disease remission; Dose; Drug Delivery Systems; Engineering; Erythrocytes; Excision; Exhibits; Functional disorder; Generations; Goals; HDAC4 gene; Heart; Hematology; Histologic; Histone Deacetylase Inhibitor; Human; IL17 gene; Immune; Immune Tolerance; Immune response; Immunosuppressive Agents; In Vitro; Incidence; Infarction; Inflammatory; Innate Immune Response; Lipids; Longevity; Lupus; Lymphocyte; Macrophage; Measures; Mediating; Molecular; Mus; Myocardial Infarction; Nature; Necrosis; Nephritis; Oligonucleotides; Organ; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylserines; Phosphoric Monoester Hydrolases; Physiological; Platelet Count measurement; Play; Population; Process; Production; Protein Tyrosine Phosphatase; RNA Interference; Role; Safety; Severities; Signaling Protein; Source; Specificity; Spleen; Splenectomy; Splenic Tissue; Splenomegaly; Structure; Symptoms; System; Systemic Lupus Erythematosus; Systemic Therapy; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Effect; Thrombocytopenia; Treatment Efficacy; adaptive immune response; cell type; cohort; conventional therapy; curative treatments; cytokine; design; drug release profile; experimental study; follow-up; immunoregulation; improved; indexing; inhibitor; loss of function; lupus prone mice; mimetics; monocyte; mouse model; multiorgan damage; nanomaterials; nanoparticle; novel; novel therapeutics; organ injury; protein phosphatase inhibitor-2; secondary lymphoid organ; senescence; side effect; skin lesion; small molecule; small molecule inhibitor; src Homology Region 2 Domain; standard of care; targeted treatment; tissue injury; trafficking; uptake; zeta potential

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by a loss of tolerance to multiple endogenous antigens, for which there is no cure. Current therapeutic options for SLE patients involve a variety of non-specific immunosuppressive or anti-inflammatory agents that have significant associated side effects and are often inadequate. There is thus a great unmet need to develop curative therapies for this disease. In SLE, tissue injury is often mediated by aberrant expression of immunoregulatory signaling proteins. In particular, Src homology region 2 domain-containing phosphatase-2 (SHP-2) has been shown to enhance disease-active T cell proliferation and promote downstream cytokine production, each of which are innately tied to the pathophysiology of the disease. The importance of this phosphatase in the promotion of SLE has been further demonstrated by its inhibition, wherein systemic treatment normalized many of the symptoms of the disease concomitant with an extension of lifespan. Yet, SHP-2 is expressed throughout the body, thus the potential for off-target effects from systemic therapies is great. The spleen is the largest secondary lymphoid organ and an active regulator of the immune response, with a structure designed to increase the likelihood of rare interactions between cells, in particular cognate lymphocytes and antigen-presenting cells. While the spleen is not considered a target organ in SLE, it is an active site for autoantibody generation and the accumulation of pathogenic cells, including DNTCs, which are trafficked throughout the body to elicit the observed multi-organ damage. We thus hypothesize that the localization of therapeutics to the spleen, in particular modulators of SHP-2, may be sufficient to enable a systemic therapeutic effect. To accomplish this, we propose to utilize engineered senescent red blood cell mimetic nanohybrids to specifically deliver small molecule inhibitors or oligonucleotide-based therapeutics to the splenic milieu. If successful, the generated materials may potentiate the discovery of novel therapeutic options for the treatment of SLE with the capacity for increased specificity and decreased side effects.

项目摘要 全身性红斑狼疮（SLE）是一种多系统自身免疫性疾病，其特征是耐受性丧失 对于多种内源性抗原，无法治愈。 SLE患者的当前治疗选择涉及 各种具有显着相关侧的非特异性免疫抑制或抗炎药 效果，通常不足。因此，为这种疾病开发治愈疗法有很大的未满足。 在SLE中，组织损伤通常是由免疫调节信号蛋白异常表达介导的。在 特别是，SRC同源区2含域的磷酸酶-2（SHP-2）已显示可增强 疾病活跃的T细胞增殖并促进下游细胞因子的产生 疾病的病理生理学。该磷酸酶在促进SLE中的重要性已经 进一步证明了其抑制作用，其中系统治疗使许多症状归一化 疾病伴随着寿命的延长。然而，SHP-2在整个身体中表达，因此 从系统性疗法中产生脱靶作用的潜力很大。脾脏是最大的次要淋巴样 器官和免疫反应的主动调节剂，其结构旨在增加 细胞之间的罕见相互作用，特别是同源淋巴细胞和抗原呈递细胞。而脾脏 不被认为是SLE中的目标器官，它是自身抗体产生的活跃部位，并且积累 病原细胞，包括DNTC，这些细胞在整个人体中被运输以引起观察到的多器官 损害。因此，我们假设将治疗剂定位于脾脏，特别是 SHP-2可能足以实现系统性的治疗作用。为此，我们建议使用 设计的衰老红细胞模拟纳米杂化剂特异性分子抑制剂或 基于寡核苷酸的治疗疗法。如果成功，生成的材料可能会增强 发现新颖的治疗选择用于治疗SLE，并具有提高特异性和的能力 副作用减少。