Developing a Nrf2 activator for the treatment of COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是世界范围内死亡和发病的主要原因。仅在美国，这种疾病就困扰着约1300万人，是第三大死亡原因。吸烟是慢性阻塞性肺疾病的主要危险因素，会引发持续性和渐进性的炎症免疫反应。呼吸道感染和污染物会加剧COPD症状，通常会导致肺组织损伤。目前，还没有批准的药物可以减缓或阻止COPD的进展。咳嗽和呼吸急促等症状通常使用支气管扩张剂治疗。尽管炎症在COPD的发病机制中起着关键作用，但抗炎皮质类固醇药物的治疗效果有限。皮质类固醇治疗只缓解了大约20%的COPD患者的症状，而不能提高存活率或减缓疾病进展。抑制炎症和改善皮质类固醇反应的新疗法将为COPD患者带来实质性好处。COPD患者皮质类固醇疗效降低与吸烟引起的肺细胞氧化应激增加有关。众所周知，核转录因子Nrf2在氧化或炎症应激时激活细胞保护程序。约翰霍普金斯大学的Shyam Biswal博士最近的研究表明，COPD患者肺细胞中Nrf2的激活可以恢复这些细胞对皮质类固醇抗炎活性的敏感性。这表明 NRF2激活剂有可能提供一种新的治疗方法来改善COPD患者的皮质类固醇反应。比斯瓦尔博士的实验室与美国国家癌症研究所合作，发现了一系列新的Nrf2激活剂，其中最有希望的是Veda-1209。Cureveda正在开发Veda-1209作为治疗COPD和其他适应症的候选药物。目前的第一阶段STTR项目的目标是进行关键研究，以确定VEDA-1209‘S作为一种新型慢性阻塞性肺疾病治疗药物的潜力，将用于改善患者的皮质类固醇敏感性。具体地说，拟议的项目将确定Veda-1209治疗对COPD小鼠模型皮质类固醇反应性的影响，并将测试Veda-1209恢复COPD患者肺泡巨噬细胞皮质类固醇反应性的能力。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. In the US alone, the disease afflicts ~13 million people and is the third-leading cause of death. Cigarette smoking is the primary risk factor for COPD, initiating a persistent and progressive inflammatory immune response. Respiratory infections and pollutants can exacerbate COPD symptoms, often leading to pulmonary tissue injury. Currently, there are no approved medicines that can slow or stop the progression of COPD. Symptoms such as coughing and shortness of breath are typically treated using bronchodilators. Despite the key role of inflammation in the pathogenesis of COPD, treatment with anti-inflammatory corticosteroid drugs provides limited therapeutic benefit. Corticosteroid treatment reduces symptoms in only about 20% of COPD patients without improving survival or slowing disease progression. New treatments that inhibit inflammation and improve corticosteroid responses would offer substantial benefit to COPD patients. The reduced efficacy of corticosteroids in COPD patients has been linked to the increased oxidative stress on lung cells caused by cigarette smoking. It is known that the nuclear transcription factor, Nrf2, activates a program of cellular protection in response to oxidative or inflammatory stress. Recent research by Dr. Shyam Biswal at Johns Hopkins University has shown that activation of Nrf2 in lung cells from COPD patients restores the sensitivity of these cells to the anti-inflammatory activity of corticosteroids. This suggests that Nrf2 activators have the potential to provide a new therapeutic approach to improve corticosteroid responsiveness in COPD patients. Dr. Biswal's laboratory, in collaboration with the National Cancer Institute, has discovered a series of new Nrf2 activators, the most promising of which is VEDA-1209. Cureveda is developing VEDA-1209 as a drug candidate for the treatment of COPD and other indications. The goal of the current Phase I STTR project is to conduct key studies to determine VEDA-1209's potential as a novel COPD treatment that would be used to improve patients' corticosteroid sensitivity. Specifically, the proposed project will determine the effect of VEDA-1209 treatment on corticosteroid responsiveness in a mouse model of COPD and will test VEDA-1209 for its ability to restore corticosteroid responsiveness in alveolar macrophages from COPD patients.