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

RS1 眼部基因转移治疗 X 连锁视网膜劈裂症的 I/IIa 期研究

• 批准号: 10266923
• 负责人: Henry Wiley
• 金额: $ 5.85万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266923
• 关键词: Adolescent; Adverse event; Affect; Antibodies; Aqueous Humor; Blindness; Data; Detection; Dose; Electroretinography; Enrollment; Evaluation; Eye; Gene Transfer; Genes; Genetic; Injections; Laboratories; Link; Macular degeneration; Measurement; Methods; Modification; Monitor; Optical Coherence Tomography; Outcome Measure; Paracentesis; Participant; Phase; Phase I/II Clinical Trial; Protocols documentation; Publishing; Retina; Retinal Diseases; Safety; Sample Size; Sampling; Scheme; Structure; Testing; Transgenes; Vision; Visual Fields; X-Linked Retinoschisis; XLRS1 protein; anterior chamber; base; design; first-in-human; follow-up; intravitreal injection; male; primary outcome; prophylactic; prospective; response; retinal imaging; secondary outcome; statistics; study population; vector; young man

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.

目的：评估眼部AAV-RS1矢量的安全性和耐受性 （AAV8-SCRS/IRBPHR）基因转移到受X连锁少年影响的参与者的视网膜转移 视网膜（XLRS）。 研究人群：受XLR影响的男性参与者将接受眼基因转移。 最多可能会招募24名参与者。 设计：这是I/IIA期，前瞻性，剂量升级，单中心研究。一只眼睛 参与者将通过玻璃体内注射获得AAV-RS1基因载体的应用。 参与者将与DSMC监督一起密切监视。参与者会 紧随其后的18个月之后，他们将继续跟踪长达15年 入学或根据FDA要求进行进一步的安全分析。 结果指标：主要结果是确定的眼部AAV-RS1矢量的安全性 评估视网膜功能，眼结构和不良事件的发生 实验室测试。次要结果包括视觉功能的变化，电子图（ERG） 响应，视野测量值，具有光学相干断层扫描（OCT）的视网膜成像， 以及抗AAV和抗RS1抗体的形成。 统计：在此I/IIA剂量降低研究中未使用形式的样本量计算。 该试验已在多个剂量水平上招募了12名参与者。 前9名参与者的初步数据于2018年发布（Cukras等，2018年）。 在2020财政年度，在对协议进行修改的情况下以1E11剂量注射矢量后，参与者12紧随其后，包括对靶向深层玻璃体（para视网膜）注入的交付方法的改变，纳入了一种新的预防性预防性的局部局部免疫策略（使用Ozurdex的启动（使用静脉内），（使用静脉内的）（使用了静脉内的逐渐消除）（静脉内的逐渐消除）（分泌的视网膜感染。 对该试验的其他11名参与者继续进行年度随访评估，研究继续进行。