Novel mechanism-based targeted approach to rheumatoid arthritis

描述（由申请人提供）：类风湿关节炎（RA）是一种引起关节慢性炎症的慢性全身性炎症疾病。类风湿性关节炎影响了大约150万美国人，每年给社会造成的损失超过400亿美元。尽管治疗取得了进步，但类风湿关节炎仍无法治愈。目前治疗类风湿性关节炎的药物包括非甾体类抗炎药、皮质类固醇和疾病调节抗风湿药（DMARDs）。它们都有多种缺点，包括高水平的严重副作用和功效不足。甲氨蝶呤（MTX）是一种阻断叶酸活性的叶酸拮抗剂，是应用最广泛的非生物性DMARD。然而，其通常与服用剂量有关的显著毒性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）阻滞剂，如Humira。TNF阻滞剂可能引起严重的副作用，如感染和恶性肿瘤。这凸显了对新疗法的需求。最近发现，髓细胞上表达的触发受体（TREM-1）是一种炎症放大器，参与了RA的发生。TREM-1在RA患者滑膜中表达升高。在动物实验中，阻断TREM-1可减轻炎症，并在不影响抗感染能力的情况下对胶原诱导关节炎（CIA）发挥显著的治疗作用。目前研究TREM-1的方法建议阻断配体与TREM-1的结合。TREM-1配体的真正性质尚不清楚，这大大增加了这些方法在临床开发中失败的风险。该项目的长期目标是开发一种新的、不依赖配体的方法，以trem -1为靶点治疗RA。I期研究的主要目标是证明TREM-1的特异性失活与基于新机制的抑制肽抑制RA动物模型系统的全身炎症和改善关节炎。第一阶段的具体目标是：1)生成和表征TREM-1抑制肽的可注射配方，以及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。这些无毒肽采用与配体无关的作用机制，预计副作用较小。为了提高肽的溶解度、生物利用度和对炎症部位的靶向性，我们将利用SignaBlk专有的纳米系统进行巨噬细胞特异性递送。我们将使用CIA小鼠RA模型来测试自由和颗粒形式的肽抑制促炎细胞因子产生和改善关节炎的能力。预计该研究将确定新的抗风湿病先导化合物，为开发新的靶向低毒性RA疗法奠定基础，从而改善RA治疗并减少长期残疾。如果成功，第一阶段将在第二阶段进行毒理学、吸收/处置/代谢/排泄（ADME）、药理学和化学/制造/控制（CMC）研究，向美国食品和药物管理局（FDA）提交新药研究（IND）申请，随后进行人体评估。重要的是，所提出的巨噬细胞特异性纳米颗粒是一种多功能的递送平台。因此，第一阶段的成功完成将为该假设的概念提供证明，该假设可能适用于抗风湿病联合治疗的靶向递送和RA的诊断。

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.