用 Nexiguran Ziclumeran 进行 CRISPR-Cas9 基因编辑,治疗 ATTR 心肌病。

IF 96.2 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
New England Journal of Medicine Pub Date : 2024-12-12 Epub Date: 2024-11-16 DOI:10.1056/NEJMoa2412309
Marianna Fontana, Scott D Solomon, Jessica Kachadourian, Liron Walsh, Ricardo Rocha, David Lebwohl, Derek Smith, Jörg Täubel, Edward J Gane, Björn Pilebro, David Adams, Yousuf Razvi, Joy Olbertz, Alexandra Haagensen, Peijuan Zhu, Yuanxin Xu, Adia Leung, Alison Sonderfan, David E Gutstein, Julian D Gillmore
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引用次数: 0

摘要

背景:转甲状腺素淀粉样变性伴有心肌病(ATTR-CM)是一种进展性疾病,通常是致命的。Nexiguran ziclumeran(nex-z)是一种基于CRISPR-Cas9(簇状规则间隔短回文重复序列及相关的Cas9内切酶)的靶向转甲状腺素(TTR)基因的研究性疗法:在这项 1 期开放标签试验中,我们为 ATTR-CM 患者单次静脉输注 nex-z。首要目标包括评估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末端前B型钠尿肽(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)分级的变化:共有 36 名患者接受了 nex-z 治疗,并完成了至少 12 个月的随访。在这些患者中,50%属于NYHA III级,31%患有变异型ATTR-CM。28天时血清TTR水平与基线相比的平均变化百分比为-89%(95%置信区间[CI],-92至-87),12个月时为-90%(95%置信区间[CI],-93至-87)。34名患者出现了不良反应。其中五例为一过性输液相关反应,两例为一过性肝酶升高,经评估与治疗相关。14名患者报告了严重不良事件,其中大部分与ATTR-CM一致。从基线到第 12 个月,NT-proBNP 水平的几何平均因子变化为 1.02(95% CI,0.88 至 1.17),高敏心肌肌钙蛋白 T 水平的几何平均因子变化为 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变化为 5 米(四分位间范围为-33 到 49)。92%的患者的NYHA分级有所改善或没有变化:在这项涉及ATTR-CM患者的1期研究中,单剂量nex-z治疗与短暂的输液相关反应有关,而血清TTR水平的下降一致、迅速且持久。(由 Intellia Therapeutics 和 Regeneron Pharmaceuticals 资助;ClinicalTrials.gov 编号:NCT04601051)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.

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.).

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来源期刊
New England Journal of Medicine
New England Journal of Medicine 医学-医学:内科
CiteScore
145.40
自引率
0.60%
发文量
1839
审稿时长
1 months
期刊介绍: The New England Journal of Medicine (NEJM) stands as the foremost medical journal and website worldwide. With an impressive history spanning over two centuries, NEJM boasts a consistent publication of superb, peer-reviewed research and engaging clinical content. Our primary objective revolves around delivering high-caliber information and findings at the juncture of biomedical science and clinical practice. We strive to present this knowledge in formats that are not only comprehensible but also hold practical value, effectively influencing healthcare practices and ultimately enhancing patient outcomes.
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