CRISPR-Cas9 TTR Gene Editing Achieves 90% Transthyretin Reduction in ATTR Cardiomyopathy
In this phase 1 trial, a single intravenous dose of nexiguran ziclumeran, a CRISPR-Cas9 therapy targeting the transthyretin gene, produced rapid and durable 90% reductions in serum TTR levels sustained at 12 months in 36 patients with ATTR cardiomyopathy. NT-proBNP and high-sensitivity troponin T levels remained stable, NYHA class improved or was maintained in 92% of patients, and adverse events were manageable, marking a milestone for in vivo gene editing in cardiac disease.
The original study
CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.
- Authors
- Fontana M, Solomon SD, Kachadourian J, Walsh L, Rocha R, Lebwohl D, et al.
- Journal
- The New England journal of medicine
- Type
- Clinical Trial, Phase I, Journal Article
- PMID
- 39555828
Original abstract
BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR). METHODS: In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class. RESULTS: A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was -89% (95% confidence interval [CI], -92 to -87) at 28 days and -90% (95% CI, -93 to -87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, -33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class. CONCLUSIONS: In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).