June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Mechanism of disease selective vision restoration by small molecule photoswitches.
Author Affiliations & Notes
  • Ivan Tochitsky
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA
  • Victor Meseguer
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA
  • Zachary Helft
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA
  • Aleksandra Polosukhina
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA
  • Richard Kramer
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA
  • Footnotes
    Commercial Relationships Ivan Tochitsky, None; Victor Meseguer, None; Zachary Helft, None; Aleksandra Polosukhina, None; Richard Kramer, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2265. doi:
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      Ivan Tochitsky, Victor Meseguer, Zachary Helft, Aleksandra Polosukhina, Richard Kramer; Mechanism of disease selective vision restoration by small molecule photoswitches.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2265.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Degenerative blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) affect millions of patients around the world. These disorders cause the progressive loss of photoreceptors from the retina, while sparing the remaining amacrine, bipolar and retinal ganglion cells (RGCs). We have developed a series of chemical "photoswitches" that selectively photosensitize retinal ganglion cells in retinas suffering from photoreceptor degeneration, while leaving healthy retinas unaffected. We now identify the mechanism of these photoswitches' disease selective action.

Methods: We have created several small molecule photoswitches that can be used to control the activity of neurons by reversibly blocking native ion channels in response to light. Using imaging and electrophysiological methods, we identify the mechanism of these compounds' disease selectivity.

Results: We have previously demonstrated that chemical photoswitches restore light responses to blind retinas in vitro and also enable innate and learned visual behaviors in blind mice. Here, we characterize the action of four different photoswitches on the retina, which target overlapping but different sets of ion channels. All of the compounds exhibit a disease selective effect, photosensitizing retinal ganglion cells from blind mouse, rat and dog retinas, while leaving healthy retinas unaffected. We find that large-pore ATP (P2X) receptors are responsible for the disease selective action of these photoswitches by mediating photoswitch uptake into RGCs. While the photoswitches quickly accumulate in RGCs from blind retinas, they don't enter RGCs from healthy retinas nearly as well. We confirm these findings by imaging the retinal loading of the large, permanently charged dye molecule YO-PRO, which also requires the activity of large-pore ion channels for permeation into neurons. Like the photoswitches, YO-PRO also preferentially loads into RGCs from the blind retina.

Conclusions: Our findings identify a change in P2X receptor expression or function in RGCs in animal models of RP. The selectivity of our photoswitches for diseased but not healthy retinas implies that our pharmacological therapy could not only restore vision in patients with end stage RP, but also improve vision in less advanced RP and AMD patients, by selectively acting on the parts of the retina undergoing photoreceptor death.

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