CRISPR Gene-Editing Therapy Shows Promise in Treating Cardiac Amyloidosis

A novel CRISPR-Cas9 gene-editing therapy, nexiguran ziclumeran查看药品详情 (nex-z), has shown promising results in reducing transthyretin (搜索)搜索该靶点 (TTR) levels and halting disease progression in patients with cardiac amyloidosis (搜索)搜索该疾病 (ATTR-CM). The phase 1 open-label trial, involving 36 patients, demonstrated significant reductions in TTR levels following a single intravenous infusion of the therapy. These findings, presented at the American Heart Association Scientific Sessions, suggest a potential new approach to treating this debilitating condition.

The study, led by Marianna Fontana, MD, PhD, from University College London, involved patients with transthyretin (搜索)搜索该靶点 amyloidosis with cardiomyopathy (69% with wild-type) and NYHA class I to III heart failure. The median age of participants was 78 years, with 97% being men and 22% Black. The primary outcome measured was the change in serum transthyretin levels.

Significant Reduction in Transthyretin Levels

The results indicated a substantial decrease in TTR levels, with a mean percent change from baseline of -89% (95% CI, -92 to -87) at 28 days post-treatment. This reduction was sustained at 1 year, with a mean change of -90% (95% CI, -93 to -87). These findings suggest that the one-time treatment effectively inactivates the TTR gene, potentially reducing disease progression.

Clinical Improvements and Disease Stabilization

In addition to the reduction in TTR levels, the study also assessed clinical markers of disease progression. Approximately 8% of patients experienced worsening NYHA class over 1 year, while the majority either improved or remained stable. The geometric mean factor change from baseline to 1 year in N-terminal pro-B type natriuretic peptide (NT-pro BNP) was 1.02 (95% CI, 0.88-1.17), and in high-sensitivity cardiac troponin T, it was 0.95 (95% CI, 0.89-1.01).

Furthermore, the six-minute walk distance improved by 5 meters from baseline to 1 year (interquartile range, -33 to 49). Overall, nearly 80% of patients showed stabilization or improvement in disease progression, considering markers such as NT-pro BNP, troponin, and six-minute walk distance. Specifically, 83% of patients with NYHA class I or II at baseline and 47% of patients with NYHA class III at baseline had no worsening in any of these markers at 1 year.

Safety and Tolerability

Adverse events were reported in 34 patients, with serious adverse events occurring in 14 patients. However, most of these serious adverse events were consistent with those typically observed in ATTR-CM. Transient infusion-related reactions were reported in five patients, and transient liver-enzyme elevations, deemed treatment-related by the researchers, occurred in two patients.

Expert Commentary

Sarah Cuddy, MBBCh BAO, MD, FACC, FASNC, a cardiologist at Brigham and Women's Hospital Amyloidosis Program and assistant professor of medicine at Harvard Medical School, noted the significance of these findings, stating that gene knockdown is safe and effective, opening the door for a permanent treatment with gene editing. Mary Norine Walsh, MD, MACC, Medical Director of Heart Failure and Cardiovascular Research at St. Vincent Heart Center, also commented on the potential of this therapy to change the future of ATTR-CM, depending on its availability and cost.

Ongoing Phase 3 Trial

The effects of nex-z on clinical outcomes are currently being evaluated in MAGNITUDE, an ongoing phase 3 randomized, placebo-controlled trial in patients with ATTR cardiomyopathy (搜索)搜索该疾病. This trial will provide further insights into the efficacy and safety of this novel gene-editing therapy.