Developing a Nrf2 activator for the treatment of COPD

点击翻译按钮获取中文摘要

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.