荷兰阿姆斯特丹大学医学中心Danny M. Cohn团队研究了基于CRISPR的遗传性血管性水肿治疗的效果。这一研究成果于2024年10月24日发表在《新英格兰医学杂志》上。

遗传性血管性水肿是一种罕见的遗传性疾病，其特征是严重且不可预测的肿胀发作。NTLA-2002是一种体内基因编辑疗法，其基于簇状规则间隔短回文重复序列（CRISPR）-CRISPR相关蛋白9。NTLA-2002靶向编码激肽释放酶B1（KLKB1）的基因。单剂量NTLA-2002可以终身控制血管性水肿发作。

在1-2期临床试验的第2期部分，研究组以2:2:1的比例随机分配患有遗传性血管性水肿的成年人接受单剂量25mg或50mg的NTLA-2002或安慰剂。主要终点是从第1周到第16周每月血管水肿发作的次数（每月发作率）。次要终点包括安全性、药代动力学和药效学（即血浆激肽释放酶总蛋白水平与基线相比的变化）；探索性终点包括患者报告的结果。

在接受随机分组的27名患者中，10名接受了25mg NTLA-2002，11名接受了50mg，6名接受了安慰剂。从第1周到第16周，25 mg NTLA-2002组的估计平均月发病率为0.70（95%置信区间[CI]，0.25至1.98），50 mg组为0.65（95%CI，0.24至1.76），安慰剂组为2.82（95%CI，0.80至9.89）；25 mg和50 mg NTLA-2002组的估计平均发作率与安慰剂相比分别降低75%和77%。

在接受NTLA-2002治疗的患者中，接受25 mg治疗的10名患者中有4名（40%）和接受50 mg治疗的11名患者中有8名（73%）在第1周至第16周期间没有发作，也没有额外治疗。接受NTLA-2002治疗的患者中最常见的不良事件是头痛、疲劳和鼻咽炎。从基线到第16周，25 mg和50 mg的血浆激肽释放酶总蛋白水平的平均百分比变化分别为-55%和-86%；与安慰剂相比，水平保持不变。

研究结果表明，NTLA-2002以25mg或50mg的单剂量给药可减少血管性水肿的发作，并导致遗传性血管性水肿患者血浆激肽释放酶总水平的显著和持续降低。这些结果支持在更大的3期试验中继续进行调查。

附：英文原文

Title: CRISPR-Based Therapy for Hereditary Angioedema

Author: Danny M. Cohn, Padmalal Gurugama, Markus Magerl, Constance H. Katelaris, David Launay, Laurence Bouillet, Remy S. Petersen, Karen Lindsay, Emel Aygren-Pürsün, David Maag, James S. Butler, Mrinal Y. Shah, Adele Golden, Yuanxin Xu, Ahmed M. Abdelhady, David Lebwohl, Hilary J. Longhurst

Issue&Volume: 2024-10-24

Abstract:

BACKGROUND

Hereditary angioedema is a rare genetic disease characterized by severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy that is based on clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1). A single dose of NTLA-2002 may provide lifelong control of angioedema attacks.

METHODS

In this phase 2 portion of a phase 1–2 trial, we randomly assigned adults with hereditary angioedema in a 2:2:1 ratio to receive NTLA-2002 in a single dose of 25 mg or 50 mg or placebo. The primary end point was the number of angioedema attacks per month (the monthly attack rate) from week 1 through week 16. Secondary end points included safety, pharmacokinetics, and pharmacodynamics (i.e., the change from baseline in total plasma kallikrein protein level); exploratory end points included patient-reported outcomes.

RESULTS

Of the 27 patients who underwent randomization, 10 received 25 mg of NTLA-2002, 11 received 50 mg, and 6 received placebo. From week 1 through week 16, the estimated mean monthly attack rate was 0.70 (95% confidence interval [CI], 0.25 to 1.98) with 25 mg of NTLA-2002, 0.65 (95% CI, 0.24 to 1.76) with 50 mg, and 2.82 (95% CI, 0.80 to 9.89) with placebo; the difference in the estimated mean attack rate with NTLA-2002 as compared with placebo was 75% with 25 mg and 77% with 50 mg. Among patients who received NTLA-2002, 4 of the 10 patients who received 25 mg (40%) and 8 of the 11 who received 50 mg (73%) were attack-free with no additional treatment during the period from week 1 through week 16. The most common adverse events among patients who received NTLA-2002 were headache, fatigue, and nasopharyngitis. The mean percent change in total plasma kallikrein protein levels from baseline to week 16 was 55% with 25 mg and 86% with 50 mg; levels remained unchanged with placebo.

CONCLUSIONS

NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema. These results support continued investigation in a larger phase 3 trial.

DOI: NJ202410240000001

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2405734