Novel mechanism-based targeted approach to rheumatoid arthritis

描述（由申请人提供）：风湿性关节炎（RA）是一种慢性全身性炎症性疾病，可导致关节慢性炎症。RA影响大约150万美国人，每年给社会造成超过400亿美元的损失。尽管在治疗方面取得了进展，但RA无法治愈。目前RA的治疗方法包括非甾体抗炎药、皮质类固醇和改善疾病的抗风湿药物（DMARD）。它们都有多种缺点，包括高水平的严重副作用和疗效不足。甲氨蝶呤（MTX）是一种叶酸拮抗剂，阻断叶酸的活性，是最广泛使用的非生物DMARD。然而，其显著的毒性通常与服用的剂量有关，这极大地限制了其临床应用，并且是停止MTX治疗的最常见原因。生物DMARD包括肿瘤坏死因子（TNF）阻断剂，如修美乐。TNF阻断剂可能会导致严重的副作用，如感染和恶性肿瘤。这凸显了对新疗法的需求。近年来发现，髓系细胞表达的触发受体（TREM-1）是一种炎症放大因子，参与了RA的发病过程。RA患者滑膜中TREM-1表达增加。在动物中，阻断TREM-1可减轻炎症，并对胶原诱导的关节炎（CIA）发挥显著的治疗作用，而不影响抗感染的能力。目前针对TREM-1的方法建议阻断配体与TREM-1的结合。TREM-1配体的真实性质尚不清楚，这大大增加了这些方法在临床开发中失败的风险。拟议项目的长期目标是开发一种新的，配体独立的方法来靶向TREM-1治疗RA。I期研究的主要目标是证明在RA的动物模型系统中，用基于新机制的抑制肽特异性灭活TREM-1抑制全身炎症并改善关节炎。I期的具体目标是：1）产生和表征TREM-1抑制肽的可注射制剂，和2）在小鼠模型系统中测试TREM-1抑制肽。这些肽将使用SignaBlok专有的TREM-1信号模型进行设计。这些无毒肽采用配体非依赖性作用机制，预计副作用较轻。为了增加肽溶解度、生物利用度和靶向炎症部位，我们将利用SignaBlk的专有纳米系统进行巨噬细胞特异性递送。我们将使用RA的CIA小鼠模型来测试游离和颗粒形式的肽抑制促炎细胞因子的产生和改善关节炎的能力。预计拟议的研究将确定新型抗风湿先导化合物，为开发新的RA靶向低毒疗法奠定基础，从而改善RA治疗并减少长期残疾。如果成功，I期将在II期进行毒理学、吸收/处置/代谢/排泄（ADME）、药理学和化学/生产/对照（CMC）研究，向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请，并随后进行人体评价。重要的是，所提出的巨噬细胞特异性纳米颗粒是一种通用的多功能递送平台。因此，I期的成功完成将为可能适用于RA的抗风湿联合疗法和诊断的靶向递送的假设提供概念证明。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that causes chronic inflammation of the joints. RA affects about 1.5 million Americans and costs society more than $40 billion each year. Despite advances in therapy, RA has no cure. Current treatments of RA include non-steroidal anti- inflammatory drugs, corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs). They all have multiple shortcomings including a high level of serious side effects and insufficient efficacy. Methotrexate (MTX), a folate antagonist that blocks folic acid activity, is the most widely used non-biologic DMARD. However, its significant toxicity which is usually related to the dose taken drastically limits its clinical use and is the most common cause of discontinuing MTX therapy. Biologic DMARDs include tumor necrosis factor (TNF) blockers such as Humira. TNF blockers may cause serious side effects such as infections and malignancies. This highlights the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, is involved in RA. TREM-1 expression is increased in the synovium of RA patients. In animals, blockade of TREM-1 attenuates inflammation and exerts significant therapeutic effects on collagen-induced arthritis (CIA) without affecting the ability to fight infections. Current approaches to TREM-1 suggest to block binding of ligand to TREM-1. The true nature of the TREM-1 ligand is not yet known, highly increasing the risk of failure of these approaches in clinical development. The long-term objective of the proposed project is to develop a novel, ligand-independent approach to a TREM-1-targeted treatment of RA. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel mechanism-based inhibitory peptides suppresses systemic inflammation and ameliorates arthritis in animal model system of RA. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test TREM-1 inhibitory peptides in a mouse model system. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These non-toxic peptides employ ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to sites of inflammation, we will utilize SignaBlk's proprietary nanosystem for macrophage- specific delivery. We will use the CIA mouse model of RA to test the ability of the peptides in free and particulate forms to inhibit production of pro-inflammatory cytokines and to ameliorate arthritis. It is anticipated that the proposed research will identify novel anti-rheumatic lead compounds that will set the stage for the development of new targeted low-toxic therapies of RA, thereby improving RA treatment and decreasing long-term disability. If successful, the Phase I will be followed in the Phase II by toxicology, absorption/disposition/metabolism/excretion (ADME), pharmacology and chemistry/ manufacturing/ control (CMC) studies, filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. Importantly, the proposed macrophage- specific nanoparticles is a versatile multifunctional delivery platform. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable for targeted delivery of anti- rheumatic combination therapies and diagnostics for RA.