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C.S. Sethi, F. Schlichtenbrede, G.P. Lewis, S.K. Fisher, P.J. Luthert, D.G. Charteris, R.R. Ali; Subretinal CNTF Gene Delivery in a Feline Model: Cell Transfection and Morphological Sequelae . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5217.
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Purpose:Ciliary Neurotrophic Factor (CNTF) gene expression can ameliorate photoreceptor loss in retinal degeneration models. However, recent evidence suggests that this may adversely affect ERG amplitudes in wild–type animals. We have assessed subretinal CNTF gene delivery in feline retina, using a recombinant adeno–associated virus vector (rAAV) with CMV promoter and fluorescent tag (GFP). Methods: Subretinal cannulae delivered constructs to the subretinal space of control (n=2: rAAV.CMV.GFP) and test (n=4: rAAV.CMV.CNTF.GFP) animals, which were monitored clinically and by fluorescence fundoscopy. After 8 weeks, tissue was processed for confocal microscopy, with a variety of probes. Results: Transfection was achieved in rods, some cones and occasional Müller cells. All treatment blebs flattened, but test animals transfected with the CNTF gene subsequently developed tractional retinal detachments with epiretinal membrane formation. Neurite extension was observed from rods, bipolar cells and horizontal cells, with accumulation of neurofilament in ganglion cells and a marked microglial response. Control retinas remained flat with normal histology. Conclusions: Our results demonstrate the feasibility of an rAAV vector–mediated approach for the treatment of retinal disease by gene delivery, in a well–characterised animal model. There are, however, concerns in using a CNTF–based strategy given our observation of its effect on retinal cell biology.
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