PDE6A-associated Retinitis Pigmentosa Gene Therapy May Cause Loss of Vision in Some Patients


STZ eyetrial’s treatment rAAV8.hPDE6A was otherwise deemed well-tolerated.

STZ eyetrial’s rAAV8.hPDE6A, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat PDE6A-associated retinitis pigmentosa, which is being evaluated in a phase 1/2a clinical trial (NCT04611503), was generally well-tolerated but may have the potential to cause loss of vision. The findings were presented in a poster at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, 2023, in New Orleans, Louisiana.

The pretreatment baseline best corrected visual acuity (BCVA) letter score of the 9 patients who received treatment in the trial ranged from 40 (20/160) to 82 (20/25). Following treatment, 7 of the 9 patients experienced a postoperative decline in BCVA, with a mean change of -1.67 letters (95% CI, -5.77-2.44; P = 0.38; 2-sided t test paired samples). Although the decline was mild and temporary in 5 of these patients, resolving at 3 months posttreatment, in the other 2 patients the visual acuity loss was moderate to severe with foveal thinning and was not resolved at 12 months posttreatment.

“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,” investigator Felix Friedrich Lambert Reichel, MD, University Hospital Tübingen, and colleagues wrote. “However, gene therapy targeting PDE6A-related retinitis pigmentosa has the potential to cause loss of vision. Further research is needed to find predictive factors for patients at risk of vision loss and to assess the risk/benefit ratio of such an approach.”

Reichel and colleagues noted that most adverse events (AEs) determined to be related or probably related to rAAV8.hPDE6A resolved during the trial. Among these AEs were retinal detachment, ocular hypotension, nausea, mild leukocytosis, vasculitis, diplopia, and hyperreflective intraretinal foci.

The age of the 9 treated patients, who were enrolled between September 2019 and August 2021, ranged from 20 to 60 years (mean, 40.1, SD, 13.1). The group included 4 men and 5 women. Six of the 9 patients received a dose of 1x1011 total vector genomes of rAAV8.hPDE6A while 3 of the patients received a dose of 5x1011 total vector genomes. Reichel and colleagues pointed out that of the 2 patients with moderate to severe BCVA losses, 1 had received the lower dose and 1 had received the higher dose. All patients were treated at the Center for Ophthalmology Tübingen.

The open-label, nonrandomized clinical trial remains active but is not currently recruiting additional patients. The trial was open to patients with a clinical diagnosis of retinitis pigmentosa with a confirmed mutation in the PDE6A gene who were at least 18 years of age. Patients were required to have a visual acuity of at least 20/400 in order to participate. Patients with additional ocular conditions that could interfere with study results; HIV infection; recent ocular surgery; recent intravitreal or subretinal implantation of a medical device; disease-causing mutations in another known retinitis pigmentosa gene; disorders of the internal retina; damage of the optic nerve; vascular retinal occlusion; or any other retinopathy due to other diseases were excluded from participation in the study. Additional exclusion criteria related to patient health status, health history, and treatment history. The trial has an estimated primary completion date of July 2023 and an estimated completion date of July 2027.

Click here for more coverage of ARVO 2023.

1. Reichel FFL, Michalakis S, Fischer DM, et al. Safety and vision outcomes of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa. Presented at: Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting. April 23-27, 2023; New Orleans, LA. Abstract #782 - C0383
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