Corneal &retinal angiogenesis are driven by vascular endothelial growth factor (VEGF) and are key events in corneal transplant rejection, trauma, age-related macular degeneration, and diabetic retinopathy. Current treatments for these conditions rely on chronic monthly injections of anti-VEGF agents (e.g., Avastin(R);Lucentis(R)) into the eye, with attendant risks of hemorrhage and infection. We propose to suppress VEGF using a sustained-release, intracellular, anti-angiogenic strategy. This strategy uses morpholinos which shift VEG receptor 1 or 2 (Flt-1 or KDR, respectively) expression towards their soluble isoform, essentially inhibitin membrane-bound receptor expression and increasing expression of soluble, "decoy" receptors. This strategy has potential benefit for treating corneal transplant rejection, macular degeneration and other ocular vascular disorders. During the prior funding period, we used biodegradable, nontoxic, albumin nanoparticles containing plasmids expressing anti-VEGF molecules to sustain angioinhibition for up to 6 weeks. We will next advance nanoparticle delivery through conjugation with transferrin (to facilitate topical delivery) or with arginine-glycine- aspartic acd (RGD) oligopeptides (to home to neovascular tissues). Targeted delivery of anti-angiogenics to block VEGF intracellularly selectively in neovascular tissues is a significant unmet medical need as recent data indicate that long-term use of intravitreal ranibizumab (the widely used anti-VEGF Fab fragment, which binds VEGF extracellularly) is associated with a 30% risk of developing geographic atrophy within 2 years and over 50% risk at 7 years. Based on the above rationale, our central hypotheses are that: [a] expression of morpholinos promoting soluble VEGF receptors, will inhibit corneal transplant rejection and choroidal neovascularization;and [b] nanoparticle-morpholino therapy may reduce fibrosis or atrophy.
Our specific aims are to test the following predictions based on the above hypotheses: 1. Morpholinos will inhibit angiogenesis and rejection of corneal transplants. We will test delivery using intracorneal and subconjunctival injections, as well as topical delivery of nanoparticles designed to cross the corneal epithelium. 2. Targeted nanoparticles delivering morpholinos can inhibit and regress choroidal neovascularization (CNV) in laser-induced and transgenic models 3. Long-term nanoparticle-mediated expression of morpholinos inhibits fibrosis and induces less atrophy in corneal transplants and choroidal neovascularization. The results of these studies will define whether intracellular anti-angiogenic therapy can inhibit corneal rejection and macular degeneration, and demonstrate the potential of nanoparticles for long-term anti- angiogenic therapy either by topical routes for corneal disease or targeted systemic delivery for age related macular degeneration. These may enable new treatment modalities which avoid the risks of current standard of care.

Public Health Relevance

Corneal neovascularization is a sight-threatening complication of ocular injury, and can occur from shrapnel, improvised explosive devices, or blowing sand injuries. Macular degeneration is the leading cause of blindness among the elderly, including in veterans. Preventing or regressing neovascularization in these conditions may prevent loss of or restore vision. Corneal transplantation is frequently required to restore vision after trauma to the eye (70% of battlefield eye injuries involve the cornea), but has a significantly higher risk of rejecton in younger patients and patients with eye trauma. Over a million veterans have eye conditions which would benefit from this proposal, (corneal disease, macular degeneration, diabetic retinopathy, and solid tumors) which depend on angiogenesis. Combining morpholinos with long-term targeted nanoparticles (for topical or intravenous use) is particularly promising for both corneal transplant rejection and macular degeneration. This study will enable new treatments which avoid the risks of current standard of care while preserving efficacy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000556-05
Application #
8542453
Study Section
Neurobiology C (NURC)
Project Start
2009-10-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148