2-HOBA for Treatment of Pulmonary Hypertension

项目摘要 尽管肺动脉高压（PH）中普遍存在的代谢问题已经被认为是一个多世纪以来的问题， 十年来，关于这一问题性质的大量新的细节提供了干预的机会。一 结合细胞和动物的实验工作以及人类的早期试验，表明这些 代谢问题是PH的部分原因，线粒体赖氨酸的失活 脱乙酰酶SIRT 3是调节代谢缺陷的中心节点。这是一个恶性循环， 触发事件或突变增加活性氧（ROS），产生活性脂质， 加合物和CSIRT 3，引起代谢变化，导致进一步增加的ROS。在这里，我们打破 这个循环使用2-HOBA，一种可以有效吸收体内反应性脂质的小分子， 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体毒性 安全性试验，并显示了巨大的希望，在治疗核心分子缺陷的PH值。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，但也表明潜在的 对负荷应激下的心脏功能有实质性的积极影响。在第二期工程中，我们将建立 剩余的数据需要通过以下目标进行商业化：1）我们将测试安全性 在一项小型开放标签机制性先导试验中，2-HOBA在PH患者中的分子效率 2）我们将证明2-HOBA在改善右心室功能方面的疗效; 心室在一个良好建立的绵羊模型的压力下;和3）我们将测试的有效性，2-HOBA单独 以及在小鼠模型和大型动物中的标准护理的背景下。2-HOBA是一种全新的 解决分子问题的方法，一些现有的临床试验和病例报告试图 决心，但迄今为止，成功有限。2-HOBA的特定作用机制应允许其 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.