本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2309149

摘要内容如下：

背景

遗传性血管性水肿是一种罕见的遗传性疾病，会导致严重和不可预测的肿胀发作。NTLA-2002是一种基于成簇规则间隔短回文重复序列（CRISPR）-CRISPR相关蛋白9的体内基因编辑疗法。NTLA-2002靶向编码激肽释放酶B1（KLKB1）的基因，目标是在单次给药后终身控制血管性水肿发作。

方法

在NTLA-2002治疗成人遗传性血管性水肿的联合1-2期试验的1期剂量递增部分中，我们以25 mg、50 mg或75 mg的单剂量给予NTLA-2002。主要终点是NTLA-2002疗法的安全性和副作用。次要和探索性终点包括药代动力学、药效学和根据研究者证实的血管性水肿发作确定的临床疗效。

结果

3名患者接受了25 mg的NTLA-2002，4名患者接受了50 mg，3名患者接受了75 mg。在所有剂量水平下，最常见的不良事件是输液相关反应和疲劳。服用NTLA-2002后，未观察到剂量限制性毒性作用、严重不良事件、3级或更高级别的不良事件或临床上重要的实验室检查结果。在基线和最近一次评估之间观察到血浆激肽释放酶总蛋白水平的剂量依赖性降低，25 mg组的平均百分比变化为-67%，50 mg组为-84%，75 mg组为-95%。从基线到第1周至第16周（主要观察期），25 mg组每月血管性水肿发作次数的平均百分比变化为-91%，50 mg组为-97%，75 mg组为-80%。在所有患者中，从基线到最近一次评估，每月血管性水肿发作次数的平均百分比变化为-95%。

结论

在这项小型研究中，单剂量NTLA-2002导致血浆总激肽释放酶水平显著、剂量依赖性和持久降低，并且未观察到严重不良事件。在探索性分析中，在所有剂量水平下均观察到每月血管性水肿发作次数减少。（由Intellia Therapeutics资助；ClinicalTrials.gov编号，NCT05120830。）

英文原文如下：

Abstracts

BACKGROUND  Hereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose.

METHODS  In this phase 1 dose-escalation portion of a combined phase 1-2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks.

RESULTS  Three patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of -67% in the 25-mg group, -84% in the 50-mg group, and -95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was -91% in the 25-mg group, -97% in the 50-mg group, and -80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was -95%.

CONCLUSIONS  In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.).

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