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Kuldeep Kaur, Laura Laprell, Joseph Nemargut, Dirk Trauner, Russell Van Gelder; Comparison of second and third generation photoswitches in restoration of vision in blind mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5039.
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© ARVO (1962-2015); The Authors (2016-present)
Small molecular photoswitches bind to endogenous ion channels in neurons and change their activity in response to light. In this study, we used small molecular photoswitches, phenyl-ethyl aniline azobenzene quaternary ammonium (PhENAQ), a second generation photoswitch and red-DAD, a third generation compound to restore light sensitivity in the retina from the adult blind mice.
Multielectrode Array Electrophysiology: The light responses from adult Opn4-/-;rd/rd blind mice retinal explants were recorded on multi-electrode array following brief application of PhENAQ and red-DAD. We analyzed the light-triggered firing of ganglion cells in response to different wavelengths and intensities of light.<br /> Intravitreal Injections: PhENAQ and red-DAD were tested in vivo by injecting these compounds intravitreally into Opn4-/-;rd/rd mice. The dark-light shuttle box test was performed on Opn4-/-;rd/rd mice pre-injection and post-injection. Mice injected with PhENAQ and red-DAD were compared to the wild-type mice.
PhENAQ and red-DAD both bestowed light sensitivity onto blind mice retinal explants, which responded to broad-spectrum white or blue light. Typically, the light increased ganglion cell firing with rapid cessation in the dark. PhENAQ and red-DAD selectively photosensitized RGCs from retina with degenerated photoreceptors but not from wild-type retinas. The photoswitch red-DAD is soluble in FDA approved excipients and diffuses very quickly in the vitreous of macaque in comparison to PhENAQ. Red-DAD showed higher potency compared to PhENAQ. In vivo experiments indicate that a single injection of red-DAD is sufficient to restore some light-dependent behavior in the blind mice.
Application of PhENAQ and red-DAD on degenerated retina confers light sensitivity in vitro and in vivo. In the absence of the classical photoreceptors the photoswitch compounds might have therapeutic applications to treat retinitis pigmentosa or macular degeneration by conferring photosensitivity on retinal ganglion cells.
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