Author’s Name(s): Kirk Stephenson, Deepika Parameswarappa, Mark Seamone, Flavio Rizende, Cynthia Qian, Rajeev Muni, Peter Kertes, Ian MacDonald, Ajoy Vincent, Elise Heon

Author’s Disclosure Block: Kirk Stephenson: Foundation Fighting Blindness Career Development / Clinical Research Fellowship Award, Grant/research support; Deepika Parameswarappa: none; Mark Seamone: none; Flavio Rizende: none; Cynthia Qian: none; Rajeev Muni: none; Peter Kertes: none; Ian MacDonald: none; Ajoy Vincent: none; Elise Heon: none

Abstract Body
Purpose:Biallelic variants in the RPE65 gene cause Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy. LuxturnaTM is a Health Canada (HC)-approved subretinal gene therapy which improves retinal sensitivity in RPE65-LCA. Though functional criteria (best-corrected visual acuity, BCVA ≤20/60 and/or visual field, VF <20o) were used for inclusion in both the clinical trial and for HC post-trial access, there are no accepted lower limits for BCVA or VF. Herein, we report the outcomes of patients with RPE65-LCA and baseline vision meeting World Health Organization ‘blindness’ criteria (BCVA <20/400 or visual field <10o) who were treated with LuxturnaTM. Study Design: Retrospective cohort study. Methods: A multicentre retrospective analysis was performed on RPE65-LCA patients treated with LuxturnaTM who met the inclusion criteria for treatment but also had BCVA <20/400 or GVF <10o. Patients were followed for a mean of 6 months. Data analysed included age, sex, BCVA, optical coherence tomography (OCT), development of retinal atrophy, Goldmann visual fields (GVF), full-field stimulus testing (FST) and a subjective visual function survey. Genuine change was considered for: GVF as >30% of baseline, BCVA >0.3 LogMAR (15 letters) and FST >5dB. Results: Nine patients met the inclusion criteria (BCVA mean 1.89 LogMAR, range 1.4 – 2.7, mean 28.7-years-old, range 17 – 59). Improvement in FST was greater and persistent in the younger group (n=6, 17 – 24 years) while the older group (n=3, 40 – 52 years) remained at baseline (50%) or deteriorated (50%). FST improved in patients with better baseline FST (-8.8dB vs -0.56dB, p=0.01), and better GVF V4e (p<0.001) and III4e (p=0.011) area. BCVA improved in the younger group (p=0.011) though they had thinner central retinal thickness (176.4 vs 193.2μm, p=0.038). GVF V4e loss occurred in the older group (p=0.001) with worse baseline V4e area (1728.4 ±2451.5 vs 8158.6 ±2749.7o square, p<0.001). Eight of nine patients were happy with visual outcomes and improved dim-light navigation occurred in the younger group (p<0.001). Conclusions: Ultra-low vision or WHO blindness is not a contraindication to LuxturnaTM treatment in RPE65-LCA. The best outcomes were in patients ≤24-years-old with greater baseline FST and GVF V4e area with identifiable outer retinal architecture on OCT. Caution should be exercised when considering treatment for patients ≥40-years-old, even if structural minimums are met, as functional deterioration may be more likely.