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James W B Bainbridge, ; Long-term effect of gene therapy on Leber congenital amaurosis caused by defects in RPE65. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2061.
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© ARVO (1962-2015); The Authors (2016-present)
Gene defects affecting retinal pigment epithelium-specific 65 kD protein (RPE65) cause severe sight impairment in childhood and progressive retinal degeneration. We sought to determine the long-term safety and efficacy of AAV-mediated RPE65 gene therapy in human subjects, and to investigate the relationship between vector dose, visual function and electroretinography in RPE65-deficient dogs.
We performed a phase I/II open-label dose-escalation trial of gene therapy using a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 cDNA at doses of 1x1011 or 1x1012 vector genomes. We report the 3-year outcomes in all 12 subjects. In a parallel study we administered the same vector to RPE65-deficient dogs at a range of titres to determine the effect on visually-guided behaviour and electroretinography.
Improvements in retinal sensitivity were evident in 6 human subjects and lasted for up to 3 years. We observed no associated change in ERG. Retinal sensitivity improved to a maximum at 6-12 months and subsequently declined. There was variable reduction in central retinal thickness and, in 3 subjects administered the higher dose, transient intraocular inflammation indicating the maximum safe vector dose. In dogs, administration of the same vector at lower doses resulted in improved visual behavior, but only higher doses resulted in improved ERG.
rAAV2/2-mediated RPE65 gene therapy can improve sight, but the benefit observed to date is modest and not sustained in the long-term. The results indicate that the demand for RPE65 is not fully met. Early intervention using more efficient gene augmentation may provide greater and more sustained benefit with protection against progressive degeneration.
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