Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic nerve disease in men and women aged 50 years or more. It causes painless visual loss, loss of part of the visual field, and swelling of the optic nerve insie the eye. Unfortunately not only does vision rarely recover, but there is no successful treatment, despite 2 medium-sized randomized clinical trials and several small-scale studies. As part of a program to find new ways of treated optic neuropathy, we developed novel drugs that chemically reduce disulfide bonds and protect retinal ganglion cell axons, the fibers that project through the optic nerve from the eye to the brain. These phosphine- borane complexes are effective in rat optic nerve transection and experimental glaucoma. They presumably reduce intra- or intermolecular disulfide bonds in one or more critical target proteins. However, we do not know the identity of the proteins undergoing oxidative disulfide formation in diseases such as AION. If those targets can be identified, they can serve as the basis for making more specific phosphine-borane complexes, which then could be used as novel AION therapeutics. We propose to use a sensitive redox proteomic screen to identify the protein target(s) within the optic nerve that undergo sulfhydryl oxidation after rodent AION, and then use the putative target(s) to synthesize a library of 20-30 potentially more specific phosphine- borane complexes. We then will determine a lead candidate by finding which optimally reduces the critical targets, and test it in the rAION model. This lead phosphine-borane complex could then be a candidate for translation into primate models and eventually clinical trial planning.

Public Health Relevance

Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic nerve disease in men and women aged 50 years or more. Unfortunately the visual loss is usually irreversible, and there is no effective treatment. In this study we will determine how the disease causes irreversible loss of nerve cells, and develop new drugs that might be used for future treatments.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EY025074-01
Application #
8809877
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2014-12-01
Project End
2016-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
1
Fiscal Year
2015
Total Cost
$191,250
Indirect Cost
$66,250
Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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