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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要系统性红斑狼疮 (SLE) 是一种多系统自身免疫性疾病，其特征是耐受性丧失多种内源性抗原，目前无法治愈。目前 SLE 患者的治疗选择包括多种非特异性免疫抑制剂或抗炎药，具有显着的相关副作用的影响，而且常常是不够的。因此，对于开发这种疾病的治疗方法存在巨大的未满足的需求。在 SLE 中，组织损伤通常是由免疫调节信号蛋白的异常表达介导的。在特别是，含有磷酸酶 2 (SHP-2) 的 Src 同源区 2 结构域已被证明可以增强疾病活性 T 细胞增殖并促进下游细胞因子的产生，每一个都与生俱来到该疾病的病理生理学。这种磷酸酶在促进 SLE 中的重要性已被证实通过其抑制进一步证明了这一点，其中全身治疗使许多症状正常化疾病伴随着寿命的延长。然而，SHP-2 在全身表达，因此全身治疗产生脱靶效应的可能性很大。脾脏是最大的次级淋巴组织器官和免疫反应的主动调节者，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之间的相互作用。虽然脾不被认为是系统性红斑狼疮的靶器官，它是自身抗体生成和积累的活性位点致病细胞，包括 DNTC，它们被运输到全身以引发观察到的多器官损害。因此，我们假设治疗药物定位于脾脏，特别是调节剂 SHP-2可能足以实现全身治疗效果。为了实现这一目标，我们建议利用设计衰老红细胞模拟纳米杂化物以特异性地递送小分子抑制剂或针对脾脏环境的基于寡核苷酸的疗法。如果成功，生成的材料可能会增强发现治疗 SLE 的新治疗方案，能够提高特异性和减少副作用。