2-HOBA for Treatment of Pulmonary Hypertension

项目总结 尽管肺动脉高压(PH)中普遍存在的代谢问题早在一年多前就已为人所知 十年来，关于这一问题性质的大量新细节为干预提供了机会。一个 结合在细胞和动物上的实验工作以及在人类上的早期试验，表明这些 代谢问题是PH的部分原因，线粒体赖氨酸失活 脱乙酰酶SIRT3是调节代谢缺陷的中心节点。存在一种恶性循环，在这种循环中， 触发事件或突变会增加活性氧物种(ROS)，从而产生活性脂质，从而 加合和失活SIRT3，引起代谢变化，导致ROS进一步增加。在这里，我们休息一下 这个循环使用了2-HOBA，这是一种小分子，可以在体内有效地吸收活性脂肪和我们的 初步研究表明，2-HOBA是一种安全的化合物，在IND中具有动物毒性和人类毒性 安全性试验，在治疗PH核心分子缺陷方面显示出巨大的前景。我们的初步数据和 I期研究表明，不仅对降低肺血管阻力有明显的积极影响 I组和II组PH，以及疾病的细胞因子和分子生物标志物，但也表明 在负荷压力下对心脏功能有实质性的积极影响。在这项第二期计划中，我们会设立 通过以下目标进行商业化所需的剩余数据：1)我们将测试安全性 在一项小型开放标记机械性先导试验中，2-HOBA在PH患者中的分子效率 两周的HOBA暴露；2)我们将展示2HOBA在改善右脑功能方面的疗效 3)我们将单独测试2-Hoba的有效性 在小鼠模型和大型动物的标准护理的背景下。2-Hoba是一个全新的 解决分子问题的方法，现有的几项临床试验和病例报告都试图解决这一问题 决心，但到目前为止，成效有限。2-HOBA的具体作用机制应该允许它 在其他干预措施失败的地方取得成功。

PROJECT SUMMARY Although the ubiquity of metabolic problems in pulmonary hypertension (PH) has been known for more than a decade, a wealth of new details on the nature of this problem presents the opportunity for intervention. A combination of experimental work in cells and animals and early trials in humans, suggests that these metabolic problems are part of the causation for PH, and that inactivation of the mitochondrial lysine deacetylase SIRT3 is a central node in regulating the metabolic defects. A vicious cycle exists in which a triggering event or mutation increases reactive oxygen species (ROS), which produces reactive lipids, which adduct and inactivate SIRT3, causing metabolic changes that result in further increased ROS. Here, we break this cycle using 2-HOBA, a small molecule which can effectively soak up reactive lipids in vivo and our preliminary studies show that 2-HOBA is a safe compound and in IND enabling animal toxicity and human safety trials and shows great promise in treating the core molecular defects in PH. Our preliminary data and Phase I studies demonstrate not only clear positive impact on reducing pulmonary vascular resistances in Group I and II PH, and both cytokine and molecular biomarkers of disease, but also indicated the potential for a substantial positive effect on heart function under load stress. In this Phase II project, we will establish the remaining data needed to proceed to commercialization through the following aims: 1) we will test the safety and molecular efficiency of 2-HOBA in PH patients in a small open label mechanistic pilot trial with of two weeks of 2-HOBA exposure; 2) we will demonstrate efficacy of 2HOBA in improving function of the right ventricle under stress in a well-established sheep model; and 3) we will test effectiveness of 2-HOBA alone and in the context of standard-of-care in mouse models and large animals. 2-HOBA is an entirely new approach to solving a molecular problem that several existing clinical trials and case reports have tried to resolve, but so far with limited success. The specific mechanism of action of 2-HOBA should allow it to succeed where other interventions have failed.