Myeloperoxidase, imaging biomarker and treatment target for multiple sclerosis

描述（由申请人提供）：多发性硬化症（MS）是影响年轻人的最常见的非创伤性神经系统疾病。然而，由于MS的症状和常规MR成像结果都是非特异性的，并不总是相互对应，因此疾病活动的及时诊断和治疗随访存在重大挑战。此外，目前的MS疗法仅部分有效，患者通常具有突破性疾病活动。髓过氧化物酶（MPO）是一种高度氧化的酶，由活性巨噬细胞/小胶质细胞和某些单核细胞在炎症中大量分泌，并在活动性炎症MS病变中发现。我们最近在体外和体内实验中表明，MR成像剂双-5 HT-DTPA-Gd（MPO-Gd）对MPO活性具有高度特异性和敏感性。我们已经发现MPO-Gd是无毒的，具有高Gd稳定性，并且即使在高剂量下也被动物很好地耐受。我们发现，MPO-Gd成像可以检测和确认临床前疾病，并且在小鼠实验性自身免疫性脑脊髓炎（EAE）模型中，与常规MR对比成像相比，可以识别40%以上和40%以下的病变。我们和其他人还发现，髓过氧化物酶活性与MS和MS动物模型中的小胶质细胞/巨噬细胞浸润和脱髓鞘区域高度相关。在EAE诱导的小鼠中给予MPO特异性抑制剂的初步研究减少了炎症细胞募集并改善了症状。因此，我们推测MPO不仅是追踪MS疾病活动的理想生物标志物，而且可能在脱髓鞘的发病机制中起重要作用。由于目前用于MS的免疫调节疗法主要靶向淋巴细胞，通过修饰巨噬细胞/小胶质细胞功能的终产物（即，MPO活性），可能代表了治疗MS的新领域。此外，这种策略可以与靶向淋巴细胞的疗法组合，以潜在地实现协同有益效果，从而允许使用较低剂量的每种疗法来降低药物毒性。因此，使用EAE小鼠模型，该提议旨在1）通过在疾病恶化和缓解时跟踪和调节MPO活性，将成像、生物化学和组织病理学变化与炎症和抗炎标志物以及免疫细胞群变化相关联，将MPO确立为炎性脱髓鞘的生物标志物，以及2）将MPO-Gd成像确立为用于跟踪治疗效果的上级方法，并设计新的协同治疗方案来治疗淋巴细胞和巨噬细胞/小胶质细胞炎症。我们预计该提案的结果将验证MPO作为成像生物标志物和治疗靶点，改变目前专注于淋巴细胞并使用非特异性常规成像验证的药物开发策略，并为未来将MPO-Gd成像和MPO治疗转化为人类MS奠定基础。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the most common non-traumatic neurological disorder affecting young adults. Yet because both symptoms and conventional MR imaging findings of MS are nonspecific and do not always correspond to each other, prompt diagnosis of disease activity and treatment follow-up present significant challenges. Furthermore, current therapies for MS are only partially effective and patients often have breakthrough disease activity. Myeloperoxidase (MPO) is a highly oxidizing enzyme abundantly secreted by active macrophages/microglial cells and certain monocytes in inflammation, and is found in active inflammatory MS lesions. We have recently shown that the MR imaging agent, bis-5HT-DTPA-Gd (MPO-Gd) is highly specific and sensitive to MPO activity in in vitro and in vivo experiments. We have found that MPO-Gd to be nontoxic, possesses high Gd stability, and is well tolerated by animals even at high doses. We found that MPO-Gd imaging can detect and confirm preclinical disease, and can identify 40% more and 40% smaller lesions compared to conventional MR contrast imaging in the mouse experimental autoimmune encephalomyelitis (EAE) model. We and others have also found that myeloperoxidase activity is highly associated with areas of microglia/macrophage infiltration and demyelination both in MS and animal models of MS. Preliminary studies administering an MPO-specific inhibitor in mice induced with EAE reduced inflammatory cell recruitment and ameliorated symptoms. Therefore, we hypothesize that MPO is not only an ideal biomarker to track MS disease activity, but may also play an important role in the pathogenesis of demyelination. As current immunomodulatory therapies for MS target predominately lymphocytes, targeting macrophage/microglial inflammation by modifying the end product of macrophage/microglia function (i.e., MPO activity), may represent a new area for treating MS. In addition, this strategy may be combined with therapies targeting lymphocytes to potentially achieve synergistic beneficial effects, thus allowing lower doses of each therapy to be used to decrease drug toxicity. Therefore, using the EAE mouse model, this proposal aims to 1) establish MPO as a biomarker for inflammatory demyelination by tracking and modulating MPO activity as the disease exacerbates and remits, correlating imaging, biochemical, and histopathological changes to inflammatory and anti-inflammatory markers and immune cell populations shifts, and 2) establish MPO-Gd imaging as a superior method for tracking treatment effects, and design novel synergistic therapeutic regimen to treat both lymphocytic and macrophage/microglial inflammation. We expect the results of this proposal will validate MPO as an imaging biomarker and treatment target, change drug development strategies that are currently focused on lymphocytes and validated using nonspecific conventional imaging, and set the stage for future translation of MPO-Gd imaging and MPO treatment to human MS.