BACKGROUND Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1. METHODS 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 1010 vg/eye (low dose), 3·0 × 1010 vg/eye (middle dose), and 1·0 × 1011 vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported. FINDINGS Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye. INTERPRETATION ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose. FUNDING Atsena Therapeutics.

中文翻译：

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ATSN-101 对 GUCY2D 双等位基因突变引起的 Leber 先天性黑蒙患者的安全性和有效性：一项 1/2 期、多中心、开放标签、单侧剂量递增研究。


背景 Leber 先天性黑蒙 1 (LCA1) 由 GUCY2D 突变引起，是一种罕见的遗传性视网膜疾病，通常会导致儿童早期失明。本研究的目的是评估 ATSN-101 剂量递增的安全性和初步疗效，ATSN-101 是一种针对 LCA1 的视网膜下 AAV5 基因疗法。方法 本 1/2 期研究纳入了 15 名经基因证实具有 GUCY2D 双等位基因突变的患者。所有患者均接受单侧视网膜下注射 ATSN-101。在剂量递增阶段，三个成人队列（每组 n=3）接受三种递增剂量治疗：1·0 × 1010 vg/眼（低剂量）、3·0 × 1010 vg/眼（中剂量）和1·0 × 1011 vg/眼（高剂量）。在剂量扩展阶段，一组成人组（n=3）和一组儿科组（n=3）接受高剂量治疗。主要终点是治疗引起的不良事件（TEAE）的发生率，次要终点包括全视野刺激测试（FST）和最佳矫正视力（BCVA）。还进行了多亮度迁移率测试（MLMT）。报告了 12 个月主要研究期间的数据。结果 2019 年 9 月 12 日至 2022 年 5 月 5 日期间入组患者。总共观察到 68 例 TEAE，其中 56 例与外科手术相关。没有严重的 TEAE 与研究药物相关。眼部炎症轻微，可通过类固醇治疗逆转。对于接受高剂量的患者，治疗眼睛的暗适应 FST 平均变化为 20·3 分贝（dB；95% CI 6·6 至 34·0），而暗适应 FST 平均变化为 1·1 dB（-3·7 至 5· 9) 第 12 个月时未经治疗的眼睛（白色刺激）；在第 28 天首次观察到改善，并持续超过 12 个月 (p=0·012)。还观察到 BCVA 略有改善 (p=0·10)。 接受高剂量并进行 MLMT 的 6 名患者中有 3 名在接受治疗的眼睛中获得了最高分数。解释 ATSN-101 治疗 12 个月后耐受性良好，未出现与药物相关的严重不良事件。接受高剂量的患者的视网膜敏感性在临床上持续显着改善。资助 Atsena Therapeutics。