Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision-threatening retinal edema and/or neovascularization. The main therapeutic strategies that have been successful to date have focused on reducing the signals from the destabilizing pathways. This is the basis of anti-VEGF therapies which are costly biologics administered by intraocular injection, typically once monthly. Navigen seeks to explore an alternative and innovative approach to treating the pathologic angiogenesis and endothelial hyperpermeability of the retinal and choroidal vascular beds. Our approach restores the balance toward vascular homeostasis by stimulating vascular stabilization signals. Through its work on guidance cues, the laboratory of Navigen's scientific co-founder, Dr. Dean Li, identified a novel endothelial- specific receptor, Robo4, that when activated by its cognate ligand, Slit2, stabilizes the endothelium and inhibits pathologic cytokine- and growth factor-induced angiogenesis and vascular leak by inhibiting the activation of ADP-ribosylation factor-6 (Arf6). These findings suggest that Robo4 activation, and specifically inhibition of Arf6, provides vascular stabilization signals that actively instruct the endothelium to maintain cell- cell junctions and limit vascular leak and invasion. Our preliminary data and the published literature support the relevance of Arf6 in vascular eye disease. This proposal outlines a strategy to identify novel small molecule inhibitors of Arf6 and to test these in in vitro models of vascular eye disease. By adopting an approach based on identifying small molecule inhibitors of Arf6, we anticipate that potential market advantages include: a small molecule for which topical or oral administration are feasible;a broad based approach to blocking VEGF and other cytokine mediated leak and angiogenesis, and a distinct biochemical pathway that may either replace or augment current anti-VEGF centric therapies.

Public Health Relevance

Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision threatening retinal edema and/or neovascularization. There is abundant evidence that small G protein ADP ribosylation factor 6 (Arf6) is of therapeutic interest in vascular eye disease;however, no small molecule inhibitors exist to this highly relevant target. The goal of this Phase I SBIR project is o identify clinically and commercially viable structural classes of Arf6 inhibitors that are effectiv at reducing the pathologic angiogenesis and hyperpermeability associated with vascular eye diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43EY022516-01A1
Application #
8453229
Study Section
Special Emphasis Panel (ZRG1-ETTN-G (12))
Program Officer
Wujek, Jerome R
Project Start
2013-02-01
Project End
2014-07-31
Budget Start
2013-02-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$150,640
Indirect Cost
Name
Navigen, Inc.
Department
Type
DUNS #
792046224
City
Salt Lake City
State
UT
Country
United States
Zip Code
84108