Why the study?
Arterial hypertension is the leading preventable cause of life-threatening comorbidities affecting over 1.3 billion adults, motivating synthetic biology approaches to dynamically monitor and control renin-angiotensin system-driven hypertension.
Does subcutaneous implantation of microencapsulated ARCH-transgenic human cells restore and maintain normal blood pressure in mice with experimental angiotensin-dependent hypertension?
Does subcutaneous implantation of microencapsulated ARCH-transgenic human cells restore and maintain normal blood pressure in mice with experimental angiotensin-dependent hypertension?
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This preclinical proof-of-concept study demonstrates that a synthetic, closed-loop human gene circuit (ARCH) in microencapsulated cells can autonomously sense elevated Ang-II and secrete stabilized ACE2 to rapidly normalize blood pressure in hypertensive mice without causing hypotension.
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 (AT₁R) to monitor the blood level of the hypertension biomarker Ang-II. We then rewire the AT₁R 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.
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Unal et al. (2026) studied Experimental angiotensin-dependent hypertension and RAS dysregulation (n=16). ARCH (autonomous regulator of chronic hypertension) microencapsulated transgenic human HEK-293T cells secreting stACE2 vs. Untreated hypertensive mice, wild-type mice, or single intraperitoneal injection of valsartan (25 mg/kg) was evaluated on Systolic blood pressure restoration and maintenance (<120 mmHg) (p=<0.0001).
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