Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy
Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy
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DOI：
10.1126/scitranslmed.aaz7423
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发表时间：
2020-12-09
影响因子：
17.1
通讯作者：
Sahel, Jose-Alain
中科院分区：
文献类型：
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作者：
Yu-Wai-Man, Patrick;Newman, Nancy J.;Sahel, Jose-Alain
REVERSE是一项随机、双盲、假对照、多中心、3期临床试验，旨在评估单次玻璃体内注射rAAV2/2-ND4对Leber遗传性视神经病变（LHON）视力丧失患者的疗效。共有37名携带m.11778G>A （MT-ND4）突变且视力丧失持续时间在6至12个月之间的受试者接受治疗。每个受试者的右眼按1:1的比例随机分配给rAAV2/2-ND4 （GS010）治疗或假注射。左眼接受了没有分配给右眼的治疗。出乎意料的是，在96周的随访期间，两只眼睛的视力持续改善。在第96周，raav2 /2- nd4治疗的眼睛的最佳矫正视力（BCVA）平均改善为-0.308 LogMAR （+15 ETDRS字母）。在假治疗眼中观察到-0.259 LogMAR （+13 ETDRS字母）的平均改善。因此，未达到主要终点，即两个治疗组从基线到第48周BCVA变化的差异（P = 0.894）。96周时，25名受试者（68%）至少一只眼睛的BCVA从基线恢复到临床相关水平，29名受试者（78%）双眼视力改善。一项非人灵长类动物研究进行了调查这种双边改善。病毒载体DNA从注射眼转移到对侧未注射眼的前段、视网膜和视神经的证据支持单侧注射后双侧视觉功能意外改善的合理机制解释。
REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.