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F.C. Schlichtenbrede, M. Tschernutter, J.W. B. Bainbridge, P. Buch, A. Georgiadis, A.J. Smith, R.R. Ali; Gene therapy leads to long term improvement of retinal function in the heterozygous retinal degeneration slow mouse (rds+/–) . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3706.
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Purpose: Gene replacement therapy is a powerful, novel treatment approach for inherited retinal degeneration. To date we have shown restoration of retinal morphology and function after AAV–mediated gene delivery in the rds mouse, a model for rapid retinal degeneration due to a homozygous null mutation in the gene encoding the photoreceptor–specific structural protein, peripherin. However, the functional benefit was limited to a 12–week period and no slowing of the rate of photoreceptor cell loss was observed. We have now treated heterozygous rds mice. These animals exhibit relatively mild retinal abnormalities and a delayed retinal degeneration over 18 months. Whilst it is comparatively more difficult to show treatment benefits in this model, it is important to demonstrate treatment efficacy by gene therapy in this model, since the degeneration in heterozygous animals more closely resembles human disease. Methods: The right eyes of 16 heterozygous rds mice were treated on p10 with double subretinal injections of AAV.rho.rds, expressing peripherin. To transfect the entire retina, injections were repeated on p15 in the remaining quadrants. Retinal function was assessed by electroretinography (ERG) at regular intervals over a period of twelve months. The untreated left eyes served as internal controls. Additionally eyes were prepared for histology at various time points (semithin sections and scanning EM) to analyse morphological treatment effects. Results: A significant improvement of retinal function was demonstrated by ERG, both in terms of b–wave amplitude and wave pattern in the treated right eyes. This was first seen 2 months after injection and persisted up to 12 months after treatment. Histological analysis using scanning EM demonstrated marked improvement of outer segment morphology in the treated retina. However, no slowing effect on the rate of photoreceptor cell loss was observed evaluating semithin sections. Conclusions: These results demonstrate for the first time that treatment of relatively mild retinal degenerations by gene therapy can result in long–term preservation of retinal function.
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