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

目的：评价眼用腺相关病毒RS 1载体的安全性和耐受性 （AAV 8-scRS/IRBPhRS）基因转移到受X连锁青少年遗传病影响的参与者的视网膜 视网膜劈裂（XLRS）。 研究人群：受XLRS影响的男性受试者将接受眼部基因转移。 最多可招募24名参与者。 设计：这是一项I/IIa期、前瞻性、剂量递增、单中心研究。每只一只眼睛 参与者将通过玻璃体内注射接受AAV-RS 1基因载体应用。 将与DSMC监督一起密切监测参与者。参与者将被 随访18个月，之后将继续随访长达15年， 入组，或根据FDA要求，进行进一步的安全性分析。 结果测量：主要结果是眼部AAV-RS 1载体的安全性， 根据视网膜功能、眼部结构和不良事件发生率的评估， 实验室测试次要结局包括视功能、视网膜电图（ERG） 反应，视野测量，光学相干断层扫描（OCT）视网膜成像， 以及抗AAV和抗RS 1抗体的形成。 统计学：本项I/IIa期剂量递增研究中未使用正式的样本量计算。 该试验在多个剂量水平入组了12名受试者。 前9名参与者的初步数据于2018年发表（Cukras et al 2018）。 在2020财政年度，参与者12在方案修改的背景下接受1 e11剂量的载体注射后接受了随访，包括改变靶向深层玻璃体的递送方法（视网膜旁）注射，纳入新的预防性局部免疫抑制策略（使用Ozurdex），并开始眼内液取样（前房穿刺术）以尝试检测分泌的视网膜劈裂素。 继续对试验中的其他11名参与者进行年度随访评价，并继续招募研究。

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 2020, participant 12 was followed after receiving a vector injection at a 1e11 dose in the setting of modifications to the protocol, including alteration of the delivery method to target deep vitreous (para-retinal) injection, incorporation of a new prophylactic local immunosuppressive strategy (use of Ozurdex), and initiation of intraocular fluid sampling (anterior chamber paracentesis) to attempt detection of secreted retinoschisin. Annual follow up evaluation was continued for the other 11 participants in the trial, and enrollment in the study continues.