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Jasmina Cehajic Kapetanovic, Annette E Allen, Nina Milosavljevic, Timothy M Brown, Paul N Bishop, Robert J Lucas; Enhancing visual responses in retinal degeneration with human melanopsin. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1218.
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© ARVO (1962-2015); The Authors (2016-present)
Optogenetic therapies show promise for the treatment of degenerative retinal conditions, in particular advanced retinal dystrophies. Melanopsin is a native retinal photopigment normally expressed in a subset of (intrinsically photosensitive) retinal ganglion cells (ipRGCs). Here, we set out to determine the extent of restored visual responses in vivo and to characterise the sensitivity and kinetic properties of augmented (versus native) melanopsin responses in rd1 mice, a model of advanced retinal degeneration.
We delivered human melanopsin via intravitreal AAV gene therapy to inner retinal neurons in combination with glycosidic enzymes to improve retinal penetration. Visual function was assessed with pupillometry and the downstream effects of more complex visual processing were examined by in-vivo electrophysiology recordings from the lateral geniculate nucleus (LGN).
We expressed human melanopsin ectopically in both RGCs and inner nuclear layer (INL) cells of rd1 mice. Functionally, melanopsin treated mice showed enhanced pupil light reflex. In addition, light responses driven by ectopic melanopsin were superior in terms of sensitivity, amplitude and latency of response compared to native melanopsin responses. Moreover, restored responses could be elicited under moderate light intensities, typical of indoor lighting levels and were present under light adapted conditions.
Melanopsin expressed in degenerating retina, has potential to enhance light sensitivity. It operates at a range of irradiances under physiological light conditions, ~2-3 orders of magnitude lower than necessary for current microbial-based optogenetic and photopharmacological strategies. However, the kinetics of the melanopsin response were relatively slow.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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