Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the rest of the visual system intact but unable to respond to light. A synthetic chemical photoswitch, named DENAQ, can restore visual responses in blind mouse models of RP. Previous studies showed that DENAQ imparts light-sensitivity on action potential firing in retinal ganglion cells (RGC), but how this occurs is unclear. The goal of this project is to elucidate the mechanism of DENAQ photosensitization, crucial for enabling discovery of improved drug candidates and for optimizing photo- stimulation strategies for vision restoration.
The first aim i to understand why DENAQ selectively photosensitizes retinas from mice with dead rods and cones while having no effect on healthy retinas with intact rods and cones. We will test the hypothesis that degeneration leads to enhanced entry of DENAQ into RGCs and/or enhanced action on ion channels underlying spontaneous firing in RGCs.
The second aim i s to identify which RGCs are photosensitized by DENAQ. In the healthy retina, some RGCs fire at light onset, some at offset, and some at onset and offset. Studies will determine which are photosensitized by DENAQ, and whether local degeneration of rods and cones leads to spatially constrained RGC photosensitization, of particular relevance for AMD, a localized degenerative disease. Other studies will reveal whether DENAQ photosensitization applies to human RGCs in tissue samples obtained during surgical retinectomy.
The third aim i s to exploit our findings to optimize vision restoration. Information about the ion channels targeted by DENAQ will enable development of more specific photoswitches. Subcellular localization of these channels in RGCs will enable more spatially-precise photo-control. Finally imaging studies in vivo will reveal signals transmitted from the DENAQ-treated retina to the brain of blind mice, validating the functional integrity of the visual system and providing a platform for optimizing retinal stimulatin patterns to best recapitulate normal visual responses.

Public Health Relevance

We have developed a compound called DENAQ, which has properties that make it potentially useful as a drug for patients with degenerative blinding diseases, such as retinitis pigmentosa and macular degeneration. The goals of this project are 1) to understand the mechanism by which DENAQ works, and 2) to understand how well DENAQ can restore vision to blind mice.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024334-05
Application #
9770872
Study Section
Neuroscience and Ophthalmic Imaging Technologies Study Section (NOIT)
Program Officer
Shen, Grace L
Project Start
2015-09-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94710
Ko, Kwang Woo; Rasband, Matthew N; Meseguer, Victor et al. (2016) Serotonin modulates spike probability in the axon initial segment through HCN channels. Nat Neurosci 19:826-34
Tochitsky, Ivan; Helft, Zachary; Meseguer, Victor et al. (2016) How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina. Neuron 92:100-113
Tochitsky, Ivan; Kramer, Richard H (2015) Optopharmacological tools for restoring visual function in degenerative retinal diseases. Curr Opin Neurobiol 34:74-8
Lin, Wan-Chen; Tsai, Ming-Chi; Davenport, Christopher M et al. (2015) A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABA(A) Receptors and Synaptic Inhibition. Neuron 88:879-891
Lin, Wan-Chen; Davenport, Christopher M; Mourot, Alexandre et al. (2014) Engineering a light-regulated GABAA receptor for optical control of neural inhibition. ACS Chem Biol 9:1414-9
Tochitsky, Ivan; Polosukhina, Aleksandra; Degtyar, Vadim E et al. (2014) Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81:800-13