Novel Gene Therapy for XLRS: Initial Findings from a Clinical Trial Showing Visual Improvement

Abstract

Purpose : Mutations in the RS1 gene result in dysfunctional or absent retinoschisin, leading to the separation of retinal and vision loss (X-linked retinoschisis, XLRS), with no effective treatment available. In this open-label, investigator-initiated study, a novel adeno-associated viral-based gene augmentation therapy (ZM-01) has been tested in two XLRS patients.

Methods : We enrolled two pediatric XLRS male patients. Each received a single intravitreal injection of 2.07x10¹¹ vg/eye of ZM-01. The primary endpoint was the safety of ZM-01, measured as the adverse events (AEs) of serious adverse events (SAEs) incidence. Assessments including best-corrected visual acuity (BCVA), fundus photography, optical coherence tomography (OCT), and self-developed quality of life questionnaire were performed during a 12-month follow-up (Clinical Trial Registry: NCT06066008). We compared our results with the previous XLRS trails.

Results : Both subjects exhibited low vision shortly after birth and had confirmed RS1 mutation. Both of them maintained good general health and stable vital signs and no dose-limiting toxicity, drug-related AEs, or SAEs were observed within the first week post-treatment and 12 months following up. Sustained improvement in visual acuity was observed in 12 months: the logMAR BCVA of the study eye of Subject 1 increased from 0.82 to 0.60, while the study eye of Subject 2 improved from 0.92 to 0.50. Interestingly, BCVA improvements in the non-treated eye were also observed (Fig. 1A). Our trial marks the first effective XLRS gene therapy, showing over 10 letters of BCVA improvement (Fig. 1B), which is better than the previous cases. Fundus images revealed a reduction in peripheral retinal elevation compared to pre-treatment status (Fig. 1C). Enhancements in daily visual functions and overall life quality were reported by subjects and corroborated by family.

Conclusions : Two subjects gained improvements both in visual acuity and life quality after the ZM-01 injection, maintaining safety. This is the first effective promising approach and provides a strong foundation for future practice for XLRS patients.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Fig 1. (A) shows the BCVA of two subjects in 12 months after ZM-01 injection. (B) shows the change in BCVA (compared with baseline) of three groups (ZM-01, NEI, and AGTC). The gray area represents unmeasurable visual acuity changes. (C) shows the fundus before and after the injection of two subjects.