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.).

中文翻译：

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使用 Nexiguran Ziclumeran 进行 CRISPR-Cas9 基因编辑治疗 ATTR 心肌病。


背景 转甲状腺素蛋白淀粉样变性伴心肌病 （ATTR-CM） 是一种进行性、通常致命的疾病。Nexiguran ziclumeran （nex-z） 是一种基于 CRISPR-Cas9 （成簇的规则间隔短回文重复序列和相关的 Cas9 核酸内切酶） 的研究性疗法，靶向编码转甲状腺素蛋白 （TTR） 的基因。方法 在这项 1 期开放标签试验中，我们对 ATTR-CM 患者进行了单次静脉输注 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 型利钠肽前体 （NT-proBNP） 水平的变化、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。结果 共有 36 例患者接受了 nex-z 并完成了至少 12 个月的随访。在这些患者中，50% 为 NYHA III 级，31% 为变异型 ATTR-CM。血清 TTR 水平相对于基线的平均百分比变化在 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 例有短暂的输注相关反应，2 例有短暂的肝酶升高，被评估为治疗相关。14 例患者报告了严重不良事件，其中大多数与 ATTR-CM 一致。从基线到第 12 个月的几何平均因子变化为 NT-proBNP 水平 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）。6 分钟步行距离从基线到第 12 个月的中位变化为 5 m（四分位距，-33 至 49）。 共有 92% 的患者的 NYHA 分级有改善或没有变化。结论 在这项涉及 ATTR-CM 患者的 1 期研究中，单剂量 nex-z 治疗与短暂性输注相关反应和血清 TTR 水平的持续、快速和持久降低相关。（由 Intellia Therapeutics 和 Regeneron Pharmaceuticals 资助;ClinicalTrials.gov 号，NCT04601051 号）。