权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

肺动脉高压的早期干预基因编辑疗法

基本信息

批准号：
10603715
负责人：
Vinod Jaskula-Ranga
金额：
$ 35万
依托单位：
HUNTERIAN MEDICINE LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603715
关键词：
Agreement Alleles Altitude Animal Model Benchmarking Biological Assay Cell Line Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Dependovirus Diagnosis Disease Early Intervention Endothelial Cells Endothelium Etiology Exposure to Gene Delivery Genes Human Human Genome Human Rights Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway In Vitro International Intervention Lead Legal patent Licensing Lung Lung diseases Mediator Medicine Modeling Morbidity - disease rate Mus Outcome Oxygen Pathologic Pathway interactions Patients Pharmaceutical Preparations Phase Physiologic intraventricular pressure Population Pre-Clinical Model Proteins Pulmonary Hypertension Pulmonary arterial remodeling Research Personnel Right Ventricular Hypertrophy Rights Rodent Model Role Site System Technology Tertiary Protein Structure Testing Therapeutic Toxicology Transcript Transfection Tropism Validation Variant Vascular remodeling Virus clinically relevant commercialization conditional knockout curative treatments delivery vehicle genetic payload genome-wide analysis in vitro Assay in vivo in vivo Model innovation mortality novel therapeutic intervention novel therapeutics pharmacologic premature promoter prophylactic public health relevance pulmonary arterial hypertension pulmonary arterial pressure pulmonary artery endothelial cell pulmonary vascular disorder repaired response right ventricular failure small molecule inhibitor therapeutic development therapeutic genome editing timeline

项目摘要

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.

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。