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Ivan Tochitsky, Aleksandra Polosukhina, Andrew Noblet, Dirk Trauner, Richard Kramer; Restoration of light sensitivity to blind mice with red-shifted chemical photoswitches. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1400.
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Degenerative blinding diseases such as retinitis pigmentosa and age-related macular degeneration affect millions of patients around the world. These disorders cause the progressive loss of rod and cone photoreceptors in the retina, while sparing the remaining amacrine, bipolar and retinal ganglion cells. Visual function can be restored to a blind retina through gene delivery of light-sensitive ion channels to the remaining retinal neurons. However, gene therapy can also produce an unfavorable immune response or cause cancer. It would thus be highly desirable to develop more conventional pharmaceutical means of restoring light sensitivity to a blind retina. Our goal is to develop and test such pharmacological therapies.
We have created several small molecule chemical “photoswitches” that can be used to control the activity of neurons by reversibly blocking native ion channels in response to light. In order to evaluate the ability of these photoswitches to restore light sensitivity to blind mice, we have tested them in an rd1 mouse model of retinitis pigmentosa. Our in vitro assays were carried out using a multi-electrode array (MEA). We also tested the restoration of visually guided behavior in vivo in several assays.
We have previously demonstrated that the photoswitch AAQ restores light responses to blind retinas in vitro and also restores the pupillary light reflex and light-aversive behaviors in blind mice. Now, we present the restoration of light sensitivity to blind mice in vitro and in vivo with two improved photoswitch molecules, DENAQ and BENAQ. Unlike AAQ, DENAQ and BENAQ do not require the use of ultraviolet light and can be used to photosensitize the retina to visible (blue-green) light. These red-shifted molecules photosensitize the retinas of blind rd1 mice in vitro. The photoswitches persist up to several weeks in vivo and are well tolerated in the eye. DENAQ and BENAQ are selective for degenerated rather than healthy retinal tissue. Intravitreal injection of DENAQ also restores light sensitivity to rd1 mice in vivo in an exploratory locomotory behavioral assay.
Red-shifted chemical photoswitches such as DENAQ and BENAQ, and our pharmacological approach in general, hold great promise for restoring visual function in end-stage degenerative blinding diseases.
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