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

项目摘要/摘要 肺动脉高压(PAH)是一种进展迅速的肺血管疾病，导致右 心力衰竭和过早死亡。PAH的显著特征是肺动脉压升高， 血管重塑和右室肥厚。目前尚无治疗PAH和 在美国，每年约有1000例新诊断的PAH病例，中位生存期为6年。 迫切需要新的治疗方法。低氧诱导因子(HIF)是氧敏感的重要介质 和适应性途径，有力的证据支持缺氧诱导因子-2α通路在肺动脉高压中的激活。帕金森病患者 有升高的缺氧诱导因子-2α水平，通路激活得到临床前模型的很好支持。相反， 通过药物抑制或条件性基因敲除降低通路活性在多发性骨髓瘤中具有保护作用 动物模型。HIF-2α的作用被对高海拔人群的全基因组研究进一步支持 低肺动脉压，携带HIF-2α变异体，活性降低。我们假设基因- Editing代表了一种新的治疗方法，可以抑制作为肺动脉高压基础的HIF-2α途径的激活 病因学。Hunterian的专利技术可以将CRISPR组件打包成单一的AAV病毒。 在这个阶段，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.