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Research on clinical trial outcomes for XLRS have proposed prolonged trial periods in order to assess disease stabilization. 

Researchers at the Institute for Vision Research, University of Iowa, USA, and Ophthalmology and Visual Sciences, Duke-NUS Graduate Medical School, Singapore, have reported a publication in Frontiers in Medicine (Front. Med. 10:1204095, 2023), outlining long-term structural and functional outcomes to better inform current therapeutic approaches to support and improve clinical trial design.  X-linked retinoschisis (XLRS) is an uncommon inherited retinal degeneration (IRD), with a prevalence estimated between 1 to 200 cases per 100,000.   The slow progression of vision loss in the disorder is challenging, not least of all the duration required to measure key outcome measurements.  Researchers in this study have commented that trials “should prompt a re-thinking of how an interventional XLRS treatment trial should be designed”, potentially a more prolonged trial period to observe stabilization of the pathology.

X-linked retinoschisis (XLRS) is a monogenic X-linked disease that leads to schisis (or splitting) of the neural retina leading to reduced visual acuity in approximately 12,000 males in the US.  XLRS disease is caused by mutations in the RS1 gene coded by the retinoschisin protein secreted principally in the outer retina. The disorder affects visual acuity from an early age, typically with visual limitations in their daily function, including difficulty with reading, and obtaining a driver’s license.  According to the literature, XLRS manifests haplo-sufficiency as female carriers have no evidence of the disease and demonstrate preservation of visual function and retinal structure across their lifespan.  As a consequence, using gene transfer as a therapeutic intervention may be capable to partially restore XLRS gene therapy.  In the current retrospective patient chart study, the results showed a cohort of fifty-two patients with XLRS from 33 families a median age at symptom onset of 5 years (range 0–49) and with a median follow-up of 5.7 years (range 0.1–56.8). Macular retinoschisis occurred in 103 of 104 eyes (99.0%), while peripheral retinoschisis occurred in 48 of 104 eyes (46.2%), most often in the inferotemporal quadrant (40.4%). Initial and final VA were similar (logMAR 0.498 vs. 0.521; p = 0.203). Fifty of 54 eyes (92.6%) developed detectable outer retinal loss by age 20, and 29 of 66 eyes (43.9%) had focal or diffuse outer retinal atrophy (ORA) by age 40. ORA but not central subfield thickness (CST) was associated with reduced VA. Inter-eye correlation was modest for VA (r-squared = 0.03; p = 0.08) and CST (r-squared = 0.15; p = 0.001). Carbonic anhydrase inhibitors (CAIs) improved CST (p = 0.026), but not VA (p = 0.380). Eight of 104 eyes (7.7%) had XLRS-related retinal detachment (RD), which was associated with poorer outcomes compared to eyes without RD (median final VA 0.875 vs. 0.487; p <0.0001). Finally, RS1 null genotypes had greater odds of at least moderate visual impairment at final follow-up (OR 7.81; 95% CI 2.17, 28.10; p = 0.002) which was independent of age at onset, initial CST, initial ORA, or previous RD.

Despite the availability of RS1 gene therapy clinical trial data to date, the primary endpoints were not met, “perhaps due to short time points (e.g., 9 months) of study as well as clinically significant intraocular inflammation that contributed to study discontinuation”. However, a revised clinical trial design may provide more relevant results. Following their analysis on the data, the researchers concluded that, “using contemporary structural and functional outcome measures, we suggest that a more prolonged trial period (likely greater than 5 years) will be necessary to observe stabilization of the disease unless patients are enrolled during their visual acuity decline phase, in which case a briefer trial may be possible.”