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

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.