CRISPR Therapeutics has initiated a first-in-human Phase I/II trial of CTX340, an in vivo CRISPR-Cas9 gene-editing therapy delivered by lipid nanoparticle to hepatocytes, targeting the AGT gene to durably suppress hepatic AGT production and downstream angiotensin II-mediated vasoconstriction. CTX340 is the only one of four investigational hypertension gene therapies worldwide to enter clinical development.

The multicentre, dose-escalation study across the US and Australia (n=69) uses an open-label single-ascending-dose Phase I segment to establish the recommended Phase II dose via dose-limiting toxicity monitoring, followed by a placebo-controlled Phase II segment assessing pharmacodynamic effect measured by percentage change in circulating AGT from baseline.

Preclinical data in spontaneously hypertensive rats showed 60% hepatocyte editing efficiency at 2 mg/kg, approximately 90% reduction in AGT protein, and sustained mean arterial pressure lowering through day 251 post-dose, supporting the one-time treatment, lifelong control thesis.

The programme leverages CRISPR Therapeutics' LNP-gRNA platform proven in ex vivo haemoglobinopathies and repositions it for durable in vivo editing of a secreted hepatic protein, a modality class now racing alongside siRNA and antisense approaches from Alnylam and others in cardiovascular risk reduction.