Photoreceptor cell death from age-related or hereditary retinal degeneration remains the leading cause of blindness in the developed world. The inner retina is largely spared in these diseases. Photoswitch chemicals are specific pharmacologic agents whose activity can be modulated using visible light. We propose utilizing this class of compounds as an approach to reverse blindness from outer retinal degeneration. Preliminary work from our laboratories has demonstrated that the photoswitchable voltage gated potassium channel antagonist AAQ is able to restore electrophysiological retinal responses to several mouse models of outer retinal blindness, and is able to restore pupillary light responses and behavioral responses to light in blind mice. However, AAQ has limitations in terms of its wavelength sensitivity, kinetics, and potential toxicity. Two 'second generation'photoswitch compounds, DENAQ and PhENAQ, show improved spectral response, kinetics, and tolerance in the eye. We propose rigorously testing these two compounds against each other in vitro and in in vivo in mouse, rat, dog, and primate models to determine which to take forward into clinical development;propose an in depth analysis of their effects on the primate retina in vitro, in order to understand their potential for rescue of human blindness;and propose performing required preclinical toxicology and efficacy tests with the goal of applying for a new drug application to allow human clinical studies at the conclusion of this grant.

Public Health Relevance

Photoswitch compounds offer a small-molecule approach to the treatment and reversal of outer retinal blindness. Successful development of this approach would offer a well-defined path to clinical treatment of currently irreversible blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
1R24EY023937-01
Application #
8608067
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
2014-09-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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