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Knut Stieger, Daniela Klein, Alexandra Mendes-Madeira, Fabienne Rolling, Silke Haverkamp, Birgit Lorenz; Changes in S and L/M cone opsin expression in the RPE65 dog model following AAV mediated gene addition therapy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2720.
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© ARVO (1962-2015); The Authors (2016-present)
The Swedish Briard dog containing a null mutation in the RPE65 gene represents a naturally occurring animal model for early onset severe retinal dystrophy (EOSRD) in humans. Adeno-associated virus (AAV) mediated gene therapy in these dogs resulted in tremendous treatment benefits in terms of restoration of function in both, rods and cones. However, treatment benefit in humans is less pronounced. The aim of this study was to examine changes in cone opsin expression in RPE65 -/- dogs following gene therapy in order to further elucidate the treatment effect.
Retinae from 9 affected dogs (n=18) were used in this study, four of them treated unilaterally, at the age of 7-12 months, with an AAV vector carrying the human RPE65 gene. Dogs were sacrificed at various ages, between 2 and 4.5 years. Antibodies against S-opsin and L/M-opsin were used to study opsin delocalisation on cryosections and to quantify cone density on flatmount preparations.
Following gene therapy, opsin delocalisation was reduced in both L/M and S cones. The total number of opsin stained S cones increased by up to 40% in treated areas, compared to non-treated areas in the same eye. L/M cone opsin staining did not increase following gene therapy.
The remarkable increase in S cone staining and reduced delocalisation of S cone opsin indicates a strong treatment effect on this photoreceptor subtype. In contrast, L/M cones seem to benefit less efficiently from gene therapy, given only the reduction of opsin delocalization. These results may have consequences for the analysis of gene therapy results in humans, where central visual acuity is L/M cone dependent.
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