A synthetic angiotensin II/ACE2-based hormone shunt controlling experimental hypertension

Abstract

Abstract Arterial hypertension is the leading preventable cause of various life-threatening medical conditions and comorbidities that affect over 1.3 billion adults, causing over 7.5 million annual deaths worldwide. Capitalizing on a synthetic biology-inspired engineering approach, we design a fully human, antihypertensive gene circuit called ARCH (autonomous regulator of chronic hypertension), which precisely monitors and efficiently controls angiotensin-dependent, renin-angiotensin system (RAS)-driven hypertension, in which angiotensin II (Ang-II) is persistently elevated, in a reversible, self-sufficient, and closed-loop manner. We utilize the ectopically expressed native type-1 angiotensin receptor (AT 1 R) to monitor the blood level of the hypertension biomarker Ang-II. We then rewire the AT 1 R activation during hypertension to a synthetic promoter to coordinate the expression of clinically licensed, secretion-engineered, soluble therapeutic angiotensin-converting enzyme 2 (stACE2), which degrades Ang-II and restores normotension. Implantation of microencapsulated ARCH-transgenic human cells into male hypertensive mice restores and maintains normal blood pressure.