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

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.