Age-related macular degeneration (AMD) is the most devastating ocular neurodegenerative disorder that accounts for approximately 50% of all blindness cases in the United States and other developed nations. Three major pathological factors of its most catastrophic neovascular (wet) form include local inflammation with hypercytokinemia and retinal infiltration with immune cells, uncontrolled neovascular growth of choroidal blood vessels penetrating the retina and retinal vascular leakage that leads to degeneration of photoreceptors. All the above processes are orchestrated by pro-inflammatory/pro-angiogenic cytokines including VEGF as one of the major players. The standard-of-care anti-VEGF biologics delivered intravitreally improve visual acuity in less than half of the patient population. Both certain degree of functional redundancy between VEGF and other cytokines and poor anti-inflammatory efficacy of VEGF-blockers due to compensatory elevations in leukocyte infiltration are among the key factors that apparently account for the high proportion of non-responders. The new therapeutic approach we propose is aimed to improve both therapeutic responsiveness and drug delivery mode. The small GTPase Arf6 has been extensively validated as a promising drug target that, by virtue of its central role in destabilizig interendothelial adherens junctions, is prominently involved in promoting cytokine-mediated vascular hyperpermeability, angiogenesis and immune response. The relevant potential advantages of Arf6 over VEGF include i) its position at a convergence point of multiple cytokine signaling pathways that are associated with AMD pathogenesis;ii) demonstrated involvement in control of cytokine- mediated vascular permeability but not cytokine synthesis that opens a possibility to manage inflammation by directly targeting leukocyte infiltration while still avoidin global immunosuppression;iii) druggability with small molecules that are potentially amenable to non-invasive delivery. A first-in-class structural series of small molecule Arf6 inhibitors with demonstrated low micromolar potency, mechanistic tractability, nascent SAR, selectivity over a panel of other GTPases as well as efficacy in cellular models and, most importantly, in two mouse models of neovascular AMD has been found in HTS. Top compounds are proposed as starting point for the medicinal chemistry optimization that is aimed at development of a novel retinal neuroprotective drug candidate in collaboration with the NIH Blueprint Neurotherapeutics Network.

Public Health Relevance

Fewer than 50% of the patients with neovascular age-related macular degeneration (AMD), which is the most prevalent cause of blindness in the United States, improve visual acuity in response to the current standard-of-care treatment with anti-VEGF biologics such as Avastin and Lucentis. Our results support strong potential of a mechanistically novel therapeutic approach, which relies on negative modulation of small GTPase Arf6, to enhance overall clinical responsiveness among AMD sufferers. A first-in-class series of small molecule Arf6 inhibitors with demonstrated efficacy in the animal models is proposed as starting point for the development of a novel retinal neuroprotective drug in collaboration with the NIH Blueprint Neurotherapeutics Network.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01NS083573-02S2
Application #
8817428
Study Section
Special Emphasis Panel (ZNS1-SRB-R (61))
Program Officer
Cywin, Charles L
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$33,600
Indirect Cost
$9,600
Name
Navigen, Inc.
Department
Type
DUNS #
792046224
City
Salt Lake City
State
UT
Country
United States
Zip Code
84108
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99