用于恢复视觉功能某些方面的光遗传学治疗
完整摘要 · 中文译文
背景：视网膜色素变性是一种遗传性退行性视网膜疾病，可导致不可逆性失明。光遗传学治疗在疾病晚期已显示出恢复视觉功能的潜力。方法：在这项开放标签研究中，我们评估了10名因晚期视网膜色素变性而失明的参与者中，神经节细胞定向光遗传学治疗的安全性。每位参与者在视力较差眼中接受一次玻璃体内注射，注射物为编码红移通道视紫红质ChrimsonR的腺相关病毒（AAV）载体。主要结局为安全性。次要结局包括通过全视野刺激阈值（FST）检测所测得的光敏感度变化，该检测在未治疗眼被遮盖并使用旨在激活ChrimsonR的光刺激护目镜的情况下进行。FST临床有意义改善的定义（基于文献证据，且并非在方案中预先规定）为至少降低0.6个对数单位（即光敏感度增加约4倍）。 结果：10名受试者中有9名共发生34例眼部不良事件，包括23例轻度事件和10例中度事件。发生1例严重事件：玻璃体内注射后立即出现视网膜中央动脉短暂闭塞，滴入阿普可乐定后数分钟内缓解。10名受试者中有7名光敏感性增加，增加范围为2.0倍至62.3倍；6名受试者的光敏感性增加具有临床意义。 结论：在这项小型研究的范围内，玻璃体内注射靶向视网膜神经节细胞的表达ChrimsonR的AAV载体联合使用光刺激护目镜是安全的。需要进一步研究以评估安全性和有效性。（由GenSight Biologics资助；PIONEER ClinicalTrials.gov编号，NCT03326336。）
完整摘要 · 英文原文
BACKGROUND: Retinitis pigmentosa is an inherited degenerative retinal disease that can lead to irreversible blindness. Optogenetic therapy has shown potential for restoring visual function at late stages of the disease. METHODS: In this open-label study, we evaluated the safety of ganglion cell-directed optogenetic therapy in 10 participants with blindness due to advanced retinitis pigmentosa. Each participant received a single intravitreal injection of an adeno-associated viral (AAV) vector encoding the red-shifted channelrhodopsin ChrimsonR in the worse-seeing eye. The primary outcome was safety. Secondary outcomes included changes in light sensitivity as measured by full-field stimulus threshold (FST) testing conducted with the untreated eye patched and with the use of light-stimulating goggles designed to activate ChrimsonR. The definition of a clinically meaningful improvement in the FST (based on evidence from the literature and not prespecified in the protocol) was a decrease of at least 0.6 log units (i.e., an increase in light sensitivity by a factor of approximately 4). RESULTS: A total of 34 ocular adverse events occurred among 9 of the 10 participants, including 23 mild events and 10 moderate events. One severe event occurred: transient occlusion of the central retinal artery that occurred immediately after intravitreal injection and resolved within minutes after instillation of iopidine. Light sensitivity increased in 7 of the 10 participants, with increases ranging from a factor of 2.0 to a factor of 62.3; 6 participants had a clinically meaningful increase in light sensitivity. CONCLUSIONS: Within the limits of this small study, intravitreal administration of a ChrimsonR-expressing AAV vector targeting retinal ganglion cells combined with use of light-stimulating goggles was safe. Additional research is needed to further assess safety and efficacy. (Funded by GenSight Biologics; PIONEER ClinicalTrials.gov number, NCT03326336.).