Low Dose Oral Carbon Monoxide Therapeutic for Virus-Induced Lung Injury

项目摘要 迫切需要开发新的方法来治疗患有肺损伤的患者 2019冠状病毒病（COVID-19）的严重影响证明了这一点，COVID-19是一种全球大流行病， 据估计，在撰写本文时，美国约有5000万人受到影响， 发病率、大量的医院和重症监护利用率以及死亡率。在多项临床前研究中，我们和 其他人已经确定了低剂量外源性一氧化碳（CO）在急性肺损伤中的治疗潜力， 包括在病毒诱导的肺损伤中，通过减少炎症和促进病毒清除。 到目前为止，吸入CO气体（iCO）和CO结合载体分子（CORM）已成为选择的模式 在大多数动物和所有临床研究中，已证明CO的安全性和耐受性 在23项成功的I期和II期临床研究中，包括患有肺部疾病（如ARDS）的患者 和COPD。然而，预期iCO和CORMS不是药学上可接受的和可行的。 COVID患者的治疗选择，因为对于iCO， 压缩CO气瓶的存在和不精确的剂量，特别是在COVID-19患者中， 有限和可变的呼吸功能，以及对于CORM，有问题的释放动力学和毒理学 与载体分子有关。本项目的目的是研究HBI-002， 剂量CO药物产品，其使得能够在与急性肺部感染相关的病毒感染中使用低剂量CO。 例如COVID-19。 HBI-002是一种含有CO的口服液体药物产品。HBI-002的IND已经到位，并进行了1期临床试验 计划在2022年进行的健康志愿者研究。开发的下一步是证明HBI-002是有效的 在病毒性急性肺损伤的临床相关动物模型中，如用其他形式的CO所示， 更好地了解潜在的作用机制。基于大量的急性肺损伤中CO的文献， 损伤以及我们和其他人在病毒诱导的肺损伤中的发现，我们的中心假设将在本研究中进行验证。 项目是：HBI-002调节免疫反应以调节炎症并改善病毒清除 在病毒诱导的肺损伤的实验模型中，足以保证2期临床试验。

PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from pulmonary injury from viral infections, as demonstrated by the severe impact of COVID-19, which is a global pandemic that, at the time of writing, is estimated have impacted approximately 50 million people in the United States, leading to morbidity, substantial hospital and intensive care utilization, and mortality. In multiple preclinical studies, we and others have defined the therapeutic potential of low dose exogenous carbon monoxide (CO) in acute lung injury, including in virus-induced pulmonary injury, by reducing inflammation and promoting viral clearance. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies, and the safety and tolerability of CO has been demonstrated in 23 successful Phase 1 and 2 clinical studies, including in patients with pulmonary conditions such as ARDS and COPD. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options in COVID patients due to, for iCO, the risk of accidental inhalation exposure from the presence of compressed CO gas cylinders and imprecise dosing, especially in COVID-19 patients that have limited and variable respiratory function, and, for CORMs, problematic release kinetics and toxicological concerns with carrier molecules. The objective of the proposed project is to investigate HBI-002, a novel oral low dose CO drug product that enables the use of low dose CO in viral infections associated with acute pulmonary injury, such as COVID-19. HBI-002 is an oral liquid drug product containing CO. An IND is in place for HBI-002, with a Phase 1 clinical trial in healthy volunteers planned in 2022. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of viral acute lung injury as has been shown with other forms of CO and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in acute lung injury and our and others findings in virus-induced lung injury, our central hypothesis that will be tested in this project is: HBI-002 modulates the immune response to regulate inflammation and improve viral clearance in experimental models of virally induced lung injury sufficiently to warrant a Phase 2 clinical trial.