使用奈昔古兰（Ziclumeran）进行CRISPR-Cas9基因编辑治疗转甲状腺素蛋白淀粉样变心肌病

CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.

作者信息

Fontana Marianna, Solomon Scott D, Kachadourian Jessica, Walsh Liron, Rocha Ricardo, Lebwohl David, Smith Derek, Täubel Jörg, Gane Edward J, Pilebro Björn, Adams David, Razvi Yousuf, Olbertz Joy, Haagensen Alexandra, Zhu Peijuan, Xu Yuanxin, Leung Adia, Sonderfan Alison, Gutstein David E, Gillmore Julian D

机构信息

From the National Amyloidosis Centre, University College London, Royal Free Hospital (M.F., Y.R., J.D.G.), and Richmond Pharmacology (J.T.) - both in London; Brigham and Women's Hospital, Boston (S.D.S.), and Intellia Therapeutics, Cambridge (J.K., L.W., R.R., D.L., D.S., J.O., A.H., P.Z., Y.X., A.L., A.S.) - both in Massachusetts; the University of Auckland, Auckland, New Zealand (E.J.G.); Umea University, Umea, Sweden (B.P.); Centre Hospitalo-Universitaire de Bicêtre, Assistance Publique-Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France (D.A.); and Regeneron Pharmaceuticals, Tarrytown, NY (D.E.G.).

出版信息

N Engl J Med. 2024 Dec 12;391(23):2231-2241. doi: 10.1056/NEJMoa2412309. Epub 2024 Nov 16.

DOI:10.1056/NEJMoa2412309

PMID:39555828

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 ().

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.).

摘要

背景

转甲状腺素蛋白淀粉样变心肌病（ATTR-CM）是一种进行性疾病，通常会致命。Nexiguran ziclumeran（nex-z）是一种基于CRISPR-Cas9（成簇规律间隔短回文重复序列及其相关的Cas9内切酶）靶向转甲状腺素蛋白（TTR）编码基因的研究性疗法。

方法

在这项1期开放标签试验中，我们对ATTR-CM患者单次静脉输注nex-z。主要目标包括评估nex-z对安全性和药效学的影响，包括血清TTR水平。次要终点包括N末端B型利钠肽原（NT-proBNP）水平、高敏心肌肌钙蛋白T水平、6分钟步行距离和纽约心脏协会（NYHA）心功能分级的变化。

结果

共有36例患者接受了nex-z治疗并完成了至少12个月的随访。在这些患者中，50%为NYHA III级，31%患有变异型ATTR-CM。血清TTR水平较基线的平均变化百分比在28天时为-89%（95%置信区间[CI]，-92至-87），在12个月时为-90%（95%CI，-93至-87）。34例患者报告了不良事件。5例有短暂的输液相关反应，2例有短暂的肝酶升高，被评估为与治疗相关。14例患者报告了严重不良事件，其中大多数与ATTR-CM一致。NT-proBNP水平从基线到第12个月的几何平均变化因子为1.02（95%CI，0.88至1.17），高敏心肌肌钙蛋白T水平为0.95（95%CI，0.89至1.01）。从基线到第12个月，6分钟步行距离的中位数变化为5米（四分位间距，-33至49）。共有92%的患者NYHA心功能分级有所改善或无变化。