SyNTase Gene Editor Corrects Antitrypsin Deficiency In Vivo

AATD most often arises from the SERPINA1 Z allele, which substitutes glutamate for lysine at position 342 (E342K) in the alpha-1 antitrypsin (AAT) protein. Patients with two copies of this variant (ZZ) accumulate misfolded Z-AAT in the liver and lack sufficient functional inhibitor in the blood, predisposing to fibrosis, cirrhosis and emphysema. Weekly intravenous augmentation raises AAT levels but does not correct the genotype or address hepatic polymer accumulation.

CTX460 packages the SyNTase editor in lipid nanoparticles that target hepatocytes. Once inside the liver, SyNTase rewrites the pathogenic base to restore the wild-type M sequence at the DNA level, enabling production of correctly folded AAT.

At the European Society of Gene and Cell Therapy Annual Congress, CRISPR Therapeutics reported studies in two models: NSG-PiZ mice harbouring human SERPINA1 Z alleles, and a humanised PiZ rat in which the rat gene is replaced with the human E342K variant.

A single dose produced dose-dependent DNA correction in both species, with near-saturating hepatocyte editing at doses as low as 0.1 milligrams per kilogram. In PiZ mice, a clinically relevant 0.5 milligrams per kilogram achieved greater than 90 per cent mRNA correction.

In the rat model, total serum AAT increased more than five-fold from pre-dose values, and the M-AAT:Z-AAT ratio in serum exceeded 99 per cent, indicating near-exclusive production of the corrected protein. Protein rescue scaled linearly with editing efficiency, and edited alleles were maintained through the study windows (up to seven weeks in rats and nine weeks in mice).

»The goal of therapy should be to normalise alpha-1 antitrypsin levels,« said Naimish Patel, Chief Medical Officer at CRISPR Therapeutics, noting that SyNTase aims to correct the mutation »with precision and efficiency.«

CTX460 is the first investigational candidate from SyNTase. While the company has not yet disclosed the platform’s enzymatic architecture, the data support precise single-nucleotide correction in vivo. Compared with gene addition, allele repair offers the prospect of restoring native regulation while reducing production of misfolded Z-AAT, a key driver of liver injury.

The planned mid-2026 clinical study will need to address durability over years, genome-wide off-target effects and translation of the protein gains seen in rodents to human physiology.

The research was conducted by CRISPR Therapeutics and presented at the European Society of Gene and Cell Therapy 2025 Annual Congress on 10 October 2025.