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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    808—Neurologic Disorders

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    808.12: Restoration of visual function to blind mice with chemical photoswitches

    Location: Halls B-H

    1Mol. and Cell Biol., 2Vision Sci., 3Integrative Biol., UC Berkeley, Berkeley, CA; 4Ophthalmology, Univ. of Washington, Seattle, WA; 5Chem., Univ. of Munich, Munich, Germany

    Abstract Body: Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rod and cone photoreceptors, leaving the remainder of the visual system unable to respond to light. A number of approaches, including retinal implants and stem cell transplants, have been proposed to treat these disorders, but these treatments are invasive, irreversible or both. We have now developed an alternative pharmacological therapy for restoring visual function in RP patients. Our strategy involves the use of light sensitive small molecule "photoswitch" compounds to generate visual responses in blind retinas. These molecules restore retinal responses to white light with an intensity equivalent to ordinary daylight in a mouse model of RP. A single intraocular injection photosensitizes blind retinas for weeks, restoring electrophysiological responses with no apparent toxicity. The photoswitches also restore visual exploratory behavior and enable visual learning in blind mice in vivo. Experiments on wild-type mouse retinas show that the compounds have no effect on intrinsic, photoreceptor-mediated light responses. The preferential action of our photoswitch compounds on degenerated but not healthy retinas suggests they may selectively photosensitize regions of the retina undergoing degeneration, for example, in AMD patients, and not interfere with these patients’ remaining vision. The safety, high light sensitivity, and selective targeting of the photoswitch compounds to diseased tissue make them prime drug candidates for vision restoration in patients with end-stage RP and AMD.

    Lay Language Summary: We have developed light-sensitive small molecules that restore retinal light responses in blind mice and blind dogs and also allow these animals to perform visual behavioral tasks.
    Millions of patients around the world suffer from vision loss due to the degeneration of light-sensitive rod and cone photoreceptors in the retina. The most common degenerative blinding disorders include retinitis pigmentosa (RP) and age-related macular degeneration (AMD). A number of approaches, including optoelectronic retinal implants and stem cell transplants, as well as gene therapy, are being explored in order to restore visual function to blind patients. However, the above approaches are either invasive, irreversible or both. Thus, we have developed and tested a conventional drug-based therapy for retinal degeneration.
    We have synthesized light-sensitive small molecules, called “photoswitches”, that can make any neuron they enter respond to light, by blocking and unblocking ion channels responsible for the activity of neurons. We found that treating retinas from blind mice with our compounds restored robust light responses in every cell we recorded from using a multielectrode array. Our latest photoswitches, DENAQ and BENAQ enable blind retinas to respond to white light about as bright as ordinary daylight. The compounds persisted in the eye for several weeks after injection, making the retinas sensitive to light throughout that period.
    When we injected DENAQ into the eyes of blind mice, they explored their environment more in the light than in the dark, presumably because they were now able to sense light. The blind mice were also able to associate a light flash with an aversive conditioned stimulus, indicating they could use their novel light perception to learn and perform a standard behavioral response (freezing in a fear conditioning assay).
    Perhaps most surprisingly, our compounds have little to no effect on healthy retinas, leaving normal photoceptor- mediated light responses unchanged. This is rather important because many patients suffering from AMD have some remaining peripheral vision. The fact that our compounds are selective for diseased retinal tissue suggests they may target only the blind parts of the retina in these patients, while not interfering with their remaining vision.
    We are currently trying to understand why our photoswitches work only on diseased and not healthy retinas. One possibility is that a molecular target of these compounds is present only in or is upregulated during retinal degeneration. Once we identify the target, we can then develop even more potent and selective molecules. We are also testing the restoration of more sophisticated visual behaviors to determine what sort of vision the blind mice we’ve treated now have. Finally, we are continuing to treat blind dogs with our photoswitches and testing whether we can also restore visual function in large blind animals. Once we have demonstrated safety and efficacy in two different animals models of retinal degeneration, we can then plan and apply for a possible clinical trial.