A Phase I/IIa Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

目的：评价眼部AAV-RS1载体的安全性和耐受性 (AAV8-SCRS/IRBPhRS)基因转移到X连锁青少年受试者的视网膜 视网膜劈裂(XLRS)。 研究人群：受XLRS影响的男性参与者将接受眼部基因转移。 报名人数最多可达24人。 设计：这是一项I/IIa期、前瞻性、剂量递增、单中心研究。每个人都有一只眼睛 参与者将通过玻璃体内注射的方式获得AAV-RS1基因载体应用。 参与者将与DSMC的监督一起受到密切监控。参与者将是 随访18个月，之后将继续随访长达15年 登记，或根据FDA的要求，进行进一步的安全分析。 观察指标：主要结果是已确定的眼部AAV-RS1载体的安全性 通过评估视网膜功能、眼结构和不良事件的发生 实验室检测。次要结果包括视功能、视网膜电信号(ERG)的改变 响应、视野测量、光学相干断层扫描(OCT)的视网膜成像、 并形成抗AAV和抗RS1抗体。 统计数据：在这项I/IIa阶段剂量递增研究中没有使用正式的样本量计算。 这项试验招募了12名参与者，涉及多个剂量水平。2018年公布了前9名参与者的初步数据(Cukras等人，2018年)。在2021财年，参与者继续跟进。

Objective: To evaluate the safety and tolerability of ocular AAV-RS1 vector (AAV8-scRS/IRBPhRS) gene transfer to the retina of participants affected with X-linked juvenile retinoschisis (XLRS). Study Population: Male participants affected with XLRS will receive ocular gene transfer. A maximum of up to 24 participants may be enrolled. Design: This is a Phase I/IIa, prospective, dose escalation, single-center study. One eye of each participant will receive the AAV-RS1 gene vector application by intravitreal injection. Participants will be closely monitored in conjunction with DSMC oversight. Participants will be followed for 18 months after which they will continue to be followed for up to 15 years after enrollment, or per FDA requirements, for further safety analysis. Outcome Measures: The primary outcome is the safety of ocular AAV-RS1 vector as determined from assessment of retinal function, ocular structure and occurrence of adverse events and laboratory tests. Secondary outcomes include changes in visual function, electroretinogram (ERG) responses, visual field measurements, retinal imaging with optical coherence tomography (OCT), and the formation of anti-AAV and anti-RS1 antibodies. Statistics: No formal sample size calculations are used in this Phase I/IIa dose-escalation study. The trial has enrolled 12 participants across multiple dosing levels. Preliminary data for the first 9 participants were published in 2018 (Cukras et al 2018). In fiscal year 2021, participant follow up continued.