An early-intervention gene-editing therapeutic for Pulmonary Arterial Hypertension

项目总结/摘要 肺动脉高压（PAH）是一种快速进展的肺血管疾病， 心力衰竭和过早死亡。PAH的标志性特征是肺动脉压升高， 血管重塑和右心室肥大PAH尚无治愈性治疗方法， 在美国每年诊断出大约1,000例PAH新病例，中位生存期为6年。 迫切需要新的治疗方法。缺氧诱导因子（Hypoxia-inducible factors，HIF）是氧感受的重要介质 和适应性通路，强有力的证据支持PAH中HIF-2α通路的激活。PAH患者 具有升高的HIF-2α水平，并且临床前模型充分支持通路激活。相反地， 通过药理学抑制或条件性基因敲除降低的途径活性在多个 动物模型HIF-2α的作用得到了高海拔人群全基因组研究的进一步支持， 肺动脉压低，携带活性降低的HIF-2α变体。我们假设基因- 编辑代表了一种新的治疗方法，可以抑制PAH基础的HIF-2α通路激活 病因学Hunterian的专有技术能够将CRISPR组件包装到单个AAV病毒中。 在第一阶段，我们开发了一种针对HIF-2α激活的基因编辑方法。

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a rapidly progressing pulmonary vascular disease that leads to right heart failure and premature death. The hallmark features of PAH are increased pulmonary arterial pressure, vascular remodeling, and right ventricle hypertrophy. There are no curative treatments for PAH and approximately 1,000 new cases of PAH are diagnosed in the U.S. each year with a median survival of 6 years. Novel therapies are urgently needed. Hypoxia-inducible factors (HIF) are critical mediators of the oxygen sensing and adaptive pathways, and strong evidence supports HIF-2α pathway activation in PAH. Patients with PAH have elevated HIF-2α levels, and pathway activation is well supported by preclinical models. Conversely, reduced pathway activity through either pharmacologic inhibition or conditional knockouts is protective in multiple animal models. A role for HIF-2α is further supported by genome-wide studies of high-altitude populations with low pulmonary arterial pressure that carry HIF-2α variants with reduced activity. We hypothesize that gene- editing represents a novel therapeutic approach to suppress HIF-2α pathway activation that underlies PAH etiology. Hunterian's proprietary technology enables packaging of CRISPR components into a single AAV virus. In this Phase I, we develop a gene-editing approach to target HIF-2α activation.