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Jasmina Cehajic Kapetanovic, Paul N Bishop, Robert J Lucas; Enhancement of light sensitivity in retinal degeneration in mice by use of novel optogenetic approaches. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3307.
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Inherited retinal degenerations (including retinitis pigmentosa) that lead to irreversible blindness due to progressive loss of rods and cones in the outer retina affect one in 2500 people worldwide. Despite this high prevalence, there is no cure. The therapeutic approaches that are being explored in clinical trials have some limitations in terms of efficacy (gene augmentation) or resolution (artificial retinal implants). In this study we investigated the effect of ectopic expression of two light sensitive proteins, human melanopsin and human rhodopsin, on visual function in a mouse model (rd1) of advanced retinal degeneration using enhanced gene therapy. We hypothesised that this combined gene therapy and optogenetic approach might render surviving inner retinal cells photosensitive and enhance visual function.
The melanopsin or rhodopsin expressing adeno-associated virus serotype 2 (AAV2) vector was injected intravitreally into the eyes of adult rd1 mice with a combination of glycosidic enzymes, which we have previously shown to improve retinal transduction efficiency. Visual function was assessed with pupillometry at 6 weeks post treatment. The downstream effects of more complex visual processing were examined by in-vivo electrophysiology recordings from the lateral geniculate nucleus (LGN).
We found expression of ectopic human melanopsin and rhodopsin in a variety of surviving retinal cells in treated eyes, including ganglion and bipolar cells. The pupillary light reflex showed an enhancement in visual sensitivity, by two orders of magnitude, in eyes treated with melanopsin. We found that rhodopsin treatment led to a similar shift in light sensitivity. We are now in the process of evaluating the benefits of this enhanced sensitivity in terms of changes in visual responses in mouse LGN.
Melanopsin and rhodopsin, expressed in degenerating retina, have potential to enhance light sensitivity. Both receptors operated within physiological light conditions, unlike some optogenetic approaches which require stimulation with high light intensities that are potentially toxic to the retina.
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