Insights into the Effects of Subretinal Voretigene Neparvovec-rzyl in RPE65-Associated Leber Congenital Amaurosis: A One-Year Report

Theme: Retina*
What: Retina
Part of: Retina III: A Passionate Potpourri for Pinching Out Pathology / Rétine III: Pot-pourri passionné pour éliminer les pathologies
When: 6/2/2024, 11:15 AM - 12:45 PM
Where: Room | Salle 713 AB

Abstract

Purpose

Leber Congenital Amaurosis (LCA) is a heterogeneous group of blinding retinal disorders commonly inherited in an autosomal recessive manner. Biallelic mutations in the RPE65 gene cause ~8% of LCA, and patients demonstrate significant vision impairment from infancy. RPE65 encodes an isomerase key to Vitamin A recycling. The first gene augmentation therapy (Voretigene Neparvovec, Luxturna) developed for RPE65-related LCA was approved by Health Canada in 2020. Provincial reimbursement was obtained in 2023. We were privileged to treat the first 3 Canadian patients whose treatment was reimbursed through private insurance. This study evaluates the safety and effectiveness of  Voretigene Neparvovec until one year after treatment.

Study Design 

Retrospective study of the three patients (6 eyes) with RPE65-related LCA who underwent subretinal administration of Voretigene Neparvovec. 

Methods

Following ethics committee approval at The Hospital for Sick Children, data were collected from electronic medical records. This included pre- and post-operative best corrected visual acuity (BCVA), optical coherence tomography [elliposoid zone area (Eza) and width (Ezw), nuclear layer area (ONLa), and central macular thickness (CMT)], full-field stimulus threshold (FST), Goldman visual field (GVF) and a list of postoperative complications. We conducted a simple patient satisfaction index following surgery (0: unsatisfactory, 1: satisfactory, 2: very satisfactory).

Results  

Caucasian males aged 25 years (case 1) and 13 years (cases 2 and 3, twins) participated in the study. Case 1 was compound heterozygous for two splice-site variants: c.11+5G>A and c.495+1dupG, while the twins had biallelic pathogenic missense variants [(p.Leu341Ser)/(p.Gly187Glu)]. There were no surgical complications. The BCVA did not change after surgery except for the left eye of case 2, which showed an improvement of 15 letters [baseline: 50 ETDRS letters (20/100), one year: 65 ETDRS (20/50)]. Manual OCT segmentation could be done only in the twins. At one year, all eyes had smaller EZa (mean reduction: - 4.38 mm²), EZw (mean reduction: - 1167.5 um) and ONLa (mean reduction: - 2.66 mm²). Except for the left eye of case 1, all eyes showed a decrease in CMT (mean reduction -29.6 um). All patients had significantly improved FST following therapy (Mean Baseline for white stimulus: -21.33 db; 1-year: -34.50 db). Patients had mild GVF loss to V4e (case 1) or III4e (the twins); however, the left eye of case 2 showed improved paracentral visual field (III4e). All patients were very satisfied to have undergone gene therapy.

Conclusion

Voretigene Neparvovec was found to be safe and significantly improved FST and night vision in all three patients despite a structural loss on macular OCT.

 

Presenter(s)

Presenting Author: Alaa Tayyib

Additional Author(s):

Peter Kertes, Department of Ophthalmology and Vision Sciences, University of Toronto, The Hospital of Sick Children, Sunnybrook Hospital

Rajeev Muni, Department of Ophthalmology and Vision Sciences, University of Toronto, The Hospital of Sick Children, St. Michael's Hospital

Anupreet Tumber, The Hospital for Sick Children

Alex Schramm, The Hospital for Sick Children

Heather MacDonald, The Hospital for Sick Children

Regan Klatt, The Hospital for Sick Children

Ajoy Vincent, Department of Ophthalmology and Vision Sciences, University of Toronto, The Hospital of Sick Children

Elise Heon, Department of Ophthalmology and Vision Sciences, University of Toronto, The Hospital of Sick Children

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