Novel Immunological Modifier to Treat Arthritic Disease

描述（由申请人提供）：风湿性关节炎（RA）是一种慢性、全身性、炎症性自身免疫性疾病，靶向滑膜（骨关节内衬组织），并与感染、骨质疏松症和心血管疾病风险增加相关。RA引起疼痛和肿胀，导致不可逆的关节损伤，严重的功能障碍和过早死亡。全世界大约1%的人口受到影响，平均发病年龄在30至50岁之间（2002年，大约280万美国人）。RA造成了巨大的个人、社会和经济成本。尽管有可用的治疗方法，但没有治愈RA的方法。一些患者的病情仍然控制不佳或不完全。此外，目前使用的治疗剂表现出可变的响应率，与严重的副作用有关，需要皮下给药，并且在某些情况下非常昂贵。因此，仍然非常需要开发一种安全、有效的RA治疗方法。我们正在开发COG 133，这是一种来自载脂蛋白E（apoE）的肽，它在各种基于细胞的炎症和整个动物模型中显示出有效的抗炎活性。COG 133显著降低了小鼠血液和脑中脂多糖（LPS）诱导的TNF-α和IL-6水平（Lynch等人，2003）。此外，COG 133有效减少LPS刺激的人全血中TNF-α的释放。小鼠模型实验性过敏性脑脊髓炎模型（EAE）的数据表明，用COG 133治疗显著延迟症状的发作和严重程度。这些数据共同表明，COG 133在许多基于细胞的炎症模型和整个动物模型中有效抑制细胞因子和自由基的释放。在这个I期提案中，我们将进行基于整体动物和细胞的测试，以证明COG 133可以有效减轻炎症的原理，这是RA的标志。具体目标1：在小鼠类风湿性关节炎的胶原蛋白诱导的模型中测量COG 133与盐水和地塞米松对照相比的抗炎活性。具体目标二：在释放IL-6、一氧化氮、基质金属蛋白酶（MMP）和MMP的组织抑制剂的刺激的人滑膜细胞成纤维细胞中，测量与盐水和地塞米松对照相比，COG 133的抗炎活性。这些研究的结果将确定COG 133是否是类风湿性关节炎的候选疗法。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines bone joints, and is associated with increased risk of infection, osteoporosis, and cardiovascular disease. RA causes pain and swelling, leading to irreversible joint damage, severe functional impairment, and premature death. Approximately 1 % of population is affected worldwide with an average of onset between 30 to 50 years of age (in 2002, approximately 2.8 million Americans). RA causes significant personal, social, and economic costs. Despite the therapeutics available, there is no cure for RA. Some patients still have poorly or incompletely controlled disease. Furthermore, the therapeutics currently in use exhibit variable response rates, have been associated with serious side-effects, require subcutaneous administration, and in some cases are extremely expensive. Thus, there is still a great need for the development of a safe, effective treatment for RA. We are developing COG133, a peptide derived from apolipoprotein-E (apoE), which displays potent anti-inflammatory activity in a variety of cell-based and whole animal models of inflammation. COG133 significantly decreased lipopolysaccharide (LPS)-induced TNF-alpha and IL-6 levels in the blood and the brain of mice (Lynch et al. 2003). In addition, COG133 was effective in reducing TNF-alpha release in whole human blood stimulated with LPS. Data with a murine model experimental allergic encephalomyelitis model (EAE) indicated that treatment with COG133 significantly delayed the onset and the severity of symptoms. These data collectively indicate that COG 133 effectively suppresses release of cytokines and free radicals in a number of cell-based and whole animal models of inflammation. In this Phase I proposal, we will perform whole animal and cell-based tests to prove the principle that COG133 can effectively reduce the inflammation, which is the hallmark of RA. Specific Aim 1: Measure the anti- inflammatory activity of COG133 compared to saline and dexamethasone controls in a collagen induced model of rheumatoid arthritis in mice. Specific Aim 2: Measure the anti-inflammatory activity of COG133 compared to saline and dexamethasone controls in stimulated human synovial cell fibroblasts that release IL-6, nitric oxide, matrix metalloproteases (MMPs) and tissue inhibitors of MMPs. Results from these studies will determine if COG133 is a candidate therapy for rheumatoid arthritis.