CRISPR Therapeutics has initiated first-in-human testing of CTX340, an in vivo gene-editing therapy designed to permanently disrupt the hepatic angiotensinogen (AGT) gene and potentially deliver long-lasting blood-pressure control after a single treatment. The Phase I/II study (NCT07758634) targets patients with uncontrolled hypertension who remain inadequately controlled despite four or more antihypertensive medications, a population with few remaining pharmacological options and substantial cardiovascular risk.
The 69-patient Phase I/II study begins with open-label single-dose escalation before moving into a placebo-controlled Phase II cohort. Participants must have uncontrolled hypertension despite at least four antihypertensive drugs, including a diuretic. The study will primarily assess safety and circulating AGT suppression, with 24-hour ambulatory blood pressure among the key efficacy measures.
CTX340 packages CRISPR-Cas9 machinery in lipid nanoparticles that deliver the editor to hepatocytes, where it is designed to permanently disrupt AGT. Angiotensinogen is the sole precursor of angiotensin peptides in the RAAS, making hepatic AGT suppression a validated strategy for lowering blood pressure. In preclinical hypertensive rats, CRISPR reported more than 70% liver editing and a 53 mm Hg reduction in mean arterial pressure versus vehicle, sustained for roughly 8.5 months.
The clearest validation of AGT as a therapeutic target comes from zilebesiran, the GalNAc-siRNA developed by Alnylam and Roche. Zilebesiran suppresses hepatic AGT mRNA rather than altering DNA and has advanced into the Phase III ZENITH cardiovascular outcomes trial after producing sustained blood-pressure reductions across the KARDIA program. CTX340 pushes the same biological strategy further by aiming for permanent gene disruption after a single treatment. That permanence could offer exceptional durability, but it also reduces reversibility if excessive RAAS suppression or other safety problems emerge.
The same LNP-CRISPR liver-editing platform underpins CRISPR Therapeutics' more advanced cardiovascular program, CTX310, which targets ANGPTL3 and has reported Phase I data showing that at the highest dose it produced mean reductions of 73% in ANGPTL3, 55% in triglycerides and 49% in LDL. That precedent provides some platform-level reassurance but does not directly address liver safety or immunogenicity at the doses required for hypertension, a chronic condition affecting a much broader and generally healthier population than the dyslipidemia patients enrolled in CTX310 studies.