Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia.
Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
Ophthalmology. 2021 May;128(5):649-660. doi: 10.1016/j.ophtha.2020.12.012. Epub 2021 Jan 12.
To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).
RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.
Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.
Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 10 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.
The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.
Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.
At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
评估单次玻璃体内注射 rAAV2/2-ND4 在患有莱伯遗传性视神经病变（LHON）导致视力丧失的患者中的疗效。
RESCUE 是一项多中心、随机、双盲、假对照、3 期临床试验。
纳入了携带 m.11778G>A 线粒体 DNA 突变且在 1 只或 2 只眼中发病后≤6 个月出现视力丧失的患者。
每位患者的右眼被随机（1:1）分配接受 rAAV2/2-ND4 治疗（90μl 中 9×10 病毒基因组的单次注射）或假注射。左眼接受未分配给右眼的治疗。
主要终点为治疗 48 周时 rAAV2/2-ND4 治疗眼与假治疗眼之间从基线变化的最佳矫正视力（BCVA）差异。其他观察指标包括对比敏感度、Humphrey 视野计、视网膜解剖学指标和生活质量。随访时间延长至 96 周。
疗效分析纳入了 38 例患者。平均年龄为 36.8 岁，82%为男性。rAAV2/2-ND4 治疗眼和假治疗眼的治疗时视力丧失的平均持续时间分别为 3.6 个月和 3.9 个月。rAAV2/2-ND4 治疗眼和假治疗眼的基线最小角分辨率（logMAR）BCVA（标准差）的平均对数分别为 1.31（0.52）和 1.26（0.62），范围为-0.20 至 2.51。治疗 48 周时，rAAV2/2-ND4 治疗眼与假治疗眼之间从基线变化的 BCVA 差异为-0.01 logMAR（P=0.89）；未达到主要终点的-0.3 logMAR（15 个字母）差异。两组的平均 BCVA 在最初几周内均恶化，在 24 周时达到最差水平，随后在 48 周时进入平台期，然后 rAAV2/2-ND4 治疗眼和假治疗眼分别从平台期水平改善+10 和+9 个早期糖尿病视网膜病变研究字母等价。
在单侧注射 rAAV2/2-ND4 后 96 周，携带 m.11778G>A 突变且在视力丧失后 6 个月内接受治疗的 LHON 患者在注射眼和未注射眼中获得了可比的视力结果。
