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/NEJMoa2309915

摘要内容如下：

背景

由于CEP290的致病性变异，CEP290相关的遗传性视网膜变性导致严重的早发性视力丧失。Edit-101是一种成簇的规则间隔短回文重复序列（CRISPR）-CRISPR相关蛋白9（Cas9）基因编辑复合物，设计用于治疗由CEP290的内含子26中的特定损伤变体（IVS26变体）引起的遗传性视网膜变性。

方法

我们进行了一项1-2期、开放标签、单次递增剂量研究，在该研究中，由纯合子或复合杂合子IVS26变异体引起的CEP290相关遗传性视网膜变性的3岁或3岁以上患者接受了视网膜下注射EDIT-101。主要结果是安全性，包括不良事件和剂量限制性毒性作用。关键的次要疗效结果是最佳矫正视力相对于基线的变化、使用全视野刺激测试（FST）检测到的视网膜敏感度、ORA视觉导航挑战移动测试的评分以及美国国家眼科研究所视觉功能问卷-25（成人）或儿童视觉功能问卷（儿童）的视觉相关生活质量评分。

结果

12名年龄在17至63岁（中位数为37岁）的成人以低剂量（2名参与者）、中等剂量（5名参与者）或高剂量（5名参与者）注射了EDIT-101，2名9岁和14岁的儿童以中等剂量注射了EDIT-101。基线时，研究眼的最佳矫正视力中位数为最小分辨角的2.4 log10（范围为3.9至0.6）。未记录到与治疗或程序相关的严重不良事件，也未记录到剂量限制性毒性作用。通过使用FST评估，6名参与者的视锥调节视力较基线有显著改善，其中5名参与者至少有一项其他关键次要结果得到改善。9名参与者（64%）在最佳矫正视力、FST测量的红光敏感度或移动性测试得分方面较基线有显著改善。六名参与者的视力相关生活质量评分较基线有显著改善。

结论

在这项小型1-2期研究中，EDIT-101治疗后的安全性和光感受器功能的改善支持进一步研究体内CRISPR-Cas9基因编辑，以治疗由CEP290的IVS26变体和其他遗传原因引起的遗传性视网膜变性。（由Editas Medicine和其他机构资助；Brilliance ClinicalTrials.gov编号，NCT03872479。）

英文原文如下：

Abstracts

BACKGROUND  CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).

METHODS  We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children).

RESULTS  EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.

CONCLUSIONS  The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.).

-----------分割线---------

点击链接：https://www.mediecogroup.com/community/user/vip/categories/ ，成为医咖会员，获取12项专属权益。