Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results

Purpose: To evaluate the safety and efficacy of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin (RS1), in individuals with retinal disease caused by mutations in the RS1 gene. Design: Open-label, phase I or II dose-escalation clinical trial. Subjects: Twenty-two adults and 5 children with X-linked retinoschisis (XLRS), aged 10 to 79 years, were enrolled. Methods: The participants received an intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, at 1 of 3 dose levels, in the poorer-seeing eye and were followed up for a minimum of 1 year after treatment. Main Outcome Measures: The primary safety measures were local (ocular) or systemic (nonocular) adverse events (AEs) during the 12-month period after study agent administration. Efficacy was assessed based on measures of best-corrected visual acuity (BCVA), schisis cavity volume, static perimetry visual field testing, and electroretinography (ERG). Results: The IVT administration of rAAV2tYF-CB-hRS1 was generally safe at each of the dose levels. There were no AEs resulting in early termination, and no dose-limiting toxicities were reported. The most common ocular AEs observed were related to ocular inflammation (blurred vision, visual impairment, and the presence of vitreous cells, keratic precipitates, vitreous floaters, anterior chamber cells, and vitreous haze). Ocular inflammation was generally either mild or moderate in severity and responsive to standard immunosuppressive therapy, except in 3 participants (all in the highest-dose group) who developed chronic uveitis, which required prolonged therapy. Two patients experienced retinal detachments. There was no overall improvement in BCVA, visual fields, or ERG in the study eye compared with that in the fellow eye for any dose group. Variable changes in the cystic cavity volume over time were similar in the study and fellow eyes. Conclusions: Gene augmentation therapy with rAAV2tYF-CB-hRS1 for XLRS was generally safe and well tolerated but failed to demonstrate a measurable treatment effect. The clinical trial is ongoing through 5 years of follow-up to assess its long-term safety.