The British journal of ophthalmology · 2026
Safety and vision outcomes of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa: a non-randomised controlled trial.
СтатьяКлиническое исследование II фазыКлиническое исследование I фазыНазвание и аннотация: Перевод пока не подготовлен
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Reichel Felix F, Fischer M Dominik, Stingl Katarina, Kuehlewein Laura, Seitz Immanuel, Peters Tobias, Ziegler Melanie, Wilhelm Barbara, Kohl Susanne, Weisschuh Nicole, Martus Peter, Seeliger Mathias, Muehlfriedel Regine, Paquet-Durand Francois, Tsang Stephen H, Bartz-Schmidt Karl Ulrich, Ueffing Marius, Zrenner Eberhart, Biel Martin, Wissinger Bernd, Michalakis Stylianos, RD-Cure Consortium
Аннотация
PURPOSE: PDE6A-associated retinitis pigmentosa (RP) is a rare inherited retinal disease leading to severe vision loss and blindness, with no available treatment. This study assessed the safety and vision outcomes of a gene therapy using an adeno-associated virus (AAV) vector encoding PDE6A (AAV8.hPDE6A).
METHODS: In an open-label, non-randomised controlled phase I/IIa trial, nine patients with biallelic PDE6A variants received a single subretinal injection of AAV8.hPDE6A. Doses were either 1.0×10¹⁰ (n=6) or 5.0×10¹⁰ (n=3) total vector genomes. Safety was the primary endpoint, assessed via clinical examinations, laboratory analyses and optical coherence tomography imaging. Secondary outcomes included changes in visual function, such as best corrected visual acuity (BCVA), contrast sensitivity, colour perception, dark adaptation thresholds, visual fields, patient-reported outcomes and chromatic pupil campimetry over 1 year.
RESULTS: The mean patient age was 40.1 years, with baseline BCVA ranging from 40 to 82 letters (0.9-0.1 logMAR). No systemic adverse events occurred, and most ocular events resolved without treatment. Persistent adverse events included small peripheral atrophic areas (n=2), disturbed colour discrimination (n=3), cataract (n=1), slight central retinal thinning (n=5) and moderate visual acuity loss (n=2, 1 in each dose group). BCVA, full-field stimulus thresholds and other visual function measures showed statistically non-significant changes, with a trend towards worsening of retinal sensitivity in the treated eyes.
CONCLUSION: Subretinal gene therapy with AAV8.hPDE6A did not improve visual function over 1 year and posed risks, including central retinal thinning and visual acuity decline. This is in contrast to the safety and efficacy profile established in preclinical models.
METHODS: In an open-label, non-randomised controlled phase I/IIa trial, nine patients with biallelic PDE6A variants received a single subretinal injection of AAV8.hPDE6A. Doses were either 1.0×10¹⁰ (n=6) or 5.0×10¹⁰ (n=3) total vector genomes. Safety was the primary endpoint, assessed via clinical examinations, laboratory analyses and optical coherence tomography imaging. Secondary outcomes included changes in visual function, such as best corrected visual acuity (BCVA), contrast sensitivity, colour perception, dark adaptation thresholds, visual fields, patient-reported outcomes and chromatic pupil campimetry over 1 year.
RESULTS: The mean patient age was 40.1 years, with baseline BCVA ranging from 40 to 82 letters (0.9-0.1 logMAR). No systemic adverse events occurred, and most ocular events resolved without treatment. Persistent adverse events included small peripheral atrophic areas (n=2), disturbed colour discrimination (n=3), cataract (n=1), slight central retinal thinning (n=5) and moderate visual acuity loss (n=2, 1 in each dose group). BCVA, full-field stimulus thresholds and other visual function measures showed statistically non-significant changes, with a trend towards worsening of retinal sensitivity in the treated eyes.
CONCLUSION: Subretinal gene therapy with AAV8.hPDE6A did not improve visual function over 1 year and posed risks, including central retinal thinning and visual acuity decline. This is in contrast to the safety and efficacy profile established in preclinical models.