Safety and Vision Outcomes of subretinal gene supplementation therapy in PDE6A-associated Retinitis pigmentosa

Abstract

Purpose : PDE6A-associated Retinitis pigmentosa is a rare form of an inherited retinal degeneration leading to nyctalopia, visual field defects, profound vision loss and blindness. Currently, no treatment is available. The purpose of the study was to assess safety and vision outcomes of a supplemental gene therapy with an adeno-associated virus (AAV) encoding PDE6A (rAAV8.hPDE6A) in patients.

Methods : This is an open-label, exploratory nonrandomized controlled trial. Nine patients with a clinical diagnosis of PDE6A-associated Retinitis pigmentosa and confirmed biallelic disease-linked variants in PDE6A were enrolled between September 25, 2019, and August 11, 2021. Patients received a single unilateral subretinal injection of 1x10^11 (6) or 5x10^11 (3) total vector genomes of rAAV8.hPDE6A. Safety as the primary end point was assessed by clinical examination vital signs and blood tests. As secondary outcomes the change in visual function from baseline was assessed. Analysis included spatial and temporal resolution and chromatic luminance and contrast sensitivity throughout a period of 12 months after treatment.

Results : Nine patients (5 female, 55%) with a mean age of 40.1 years (SD 13.1; range 20-60 years) were included in the study. Baseline best corrected visual acuity letter score ranged from 40 (20/160) to 82 (20/25). Most adverse events with certain or probable causal relationship to the treatment resolved during the study period (retinal detachment, ocular hypotension, nausea, mild leukocytosis, vasculitis, diplopia and hyperreflective intraretinal foci). A postoperative decline in BCVA occurred in 7/9 patients. In 5 patients this decline was mild, temporary and resolved at month 3. Two patients, one of each dose group, experienced a moderate to severe visual acuity loss with foveal thinning that was not resolved by month 12. The mean change in visual acuity was -1.67 letters (95% CI, -5.77-2.44; p=0.38, 2-sided t test paired samples).

Conclusions : Subretinal gene therapy with rAAV8.hPDE6A was well tolerated by the majority of patients with no unresolved serious adverse event related to the gene therapy 12 months after treatment. However, gene therapy targeting PDE6A related Retinitis Pigmentosa has the potential to cause loss of vision. Further research is needed to to find predictive factors for patients at risk of vision loss and to assess the risk/benefit ratio of such an approach.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.