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<p>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<sub>1</sub>R) to monitor the blood level of the hypertension biomarker Ang-II. We then rewire the AT<sub>1</sub>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月11日

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  • Gokberk Unal,
  • Maysam Mansouri,
  • Yu-Qing Xie,
  • Christian Mueller,
  • Ghislaine Charpin-El Hamri,
  • Martin Fussenegger

摘要

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.