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Sergei Nikonov, Roman Nikonov, Natalia Dolgova, Richard H Kramer, Russell Van Gelder, Gustavo D Aguirre, William A Beltran; Azobenzene-based BENAQ photoswitch confers light-sensitivity to degenerating and WT canine retinas.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4285.
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© ARVO (1962-2015); The Authors (2016-present)
Following results demonstrating BENAQ effectiveness at conferring light sensitivity to mouse (Tochitsky et al. Sci. Reports, 2017) and dog retinas with end stage retinal degeneration, the aim of the current study was to examine whether BENAQ is also effective in canine retinas at earlier stages of disease when there is a reduced yet persistent number of photoreceptors.
Retinal ganglion cell (RGC) firing rates were recorded ex-vivo using a multi electrode array technique from 3 mutant rcd1/PDE6B dogs (14-17 weeks of age), 3 mutant xlpra2/RPGR dogs (29-31 wks), and 3 WT dogs (18-24 wks) before, during, and after application of 20 μM of BENAQ (in Ames) and during perfusion with synaptic blockers following BENAQ application. Retinas were stimulated with calibrated flashes of 455 nm light.
All BENAQ-treated retinas including those of WT dogs demonstrated robust light responses during and after BENAQ application. BENAQ profoundly changed the kinetics and amplitudes of the pre-existing light-responses in all WT and mutant retinas, increasing intensity thresholds by up to 10x and simultaneously increasing maximum response amplitudes at the bright intensities (> 1016 photons cm-2 s-1). BENAQ-driven responses included a fast ON- and a slower suppression components. The fast disappearance of the ON-response at the flash offset while suppression was still present resulted in what appeared as a negative OFF-response. None of the recorded retinas demonstrated “suppression” responses prior to the BENAQ application. Synaptic blockers reduced but did not eliminate ON- and suppression responses, suggesting that BENAQ-driven responses have a component due to the direct action of BENAQ on RGCs and a component due to the synaptically transmitted inputs from the BENAQ-targeted cells upstream of RGCs.
BENAQ confers light-sensitivity to degenerating retinas of two naturally-occurring canine forms of inherited retinal degeneration before a complete loss of photoreceptor cells, as well as in normal/non-degenerated canine retinas. BENAQ-driven responses have lower sensitivity and larger maximum amplitude compared to the pre-existing cone-driven responses. BENAQ has multiple cellular targets in the retina including RGCs and upstream neurons. BENAQ should only be considered as a therapeutic strategy in patients with end stage retinal degeneration.
This is a 2020 ARVO Annual Meeting abstract.
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