Corneal and 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. We propose to suppress VEGF using an intracellular, anti-angiogenic strategy relying on plasmids which express Flt23k intraceptors, recombinant subunits of Flt-1 (VEGF receptor 1) domains 2 and 3 coupled with KDEL at C-terminal which sequester VEGF within cells, in concert with a targeted nanoparticle delivery system. We previously demonstrated biodegradable, nontoxic, albumin nanoparticles containing plasmids expressing Flt-intraceptors sustained angioinhibition for up to 6 weeks. We will now advance nanoparticle delivery through conjugation with transferrin (to facilitate topical delivery) or with arginine-glycine-aspartic acid (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. We hypothesize that targeted expression of Flt23K "intraceptors", will inhibit corneal transplant rejection and choroidal neovascularization, while mitigating development of fibrosis or atrophy.
Our specific aims are to determine whether: 1. Plasmids expressing intraceptors will inhibit angiogenesis and rejection of corneal transplants. We will test delivery using subconjunctival injections or topical delivery of nanoparticles designed to cross the corneal epithelium. 2. Targeted nanoparticles delivering plasmids expressing intraceptors can inhibit and regress choroidal neovascularization (CNV) in laser-induced and transgenic models. 3. Long-term nanoparticle expression of intraceptors affects tissue re-epithelialization in corneal transplant and tissue fibrosis or atrophy in CNV models.

Public Health Relevance

The project seeks to determine whether very small particles encapsulating a drug can block the development of vision-threatening new vessels (angiogenesis) at the cellular level in for the protection of corneal transplants and age-related macular degeneration (AMD). This study will demonstrate the potential of nanoparticles for long-term therapy;either as a topical drop (for corneal disease) or targeted intravenous injection (for AMD), resulting in new treatments which avoid the risks of current standard of care treatments (injections inside the eye) and improve outcomes for patients.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY017182-06A1
Application #
8630598
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2005-12-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$392,028
Indirect Cost
$122,500
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Bogdanovich, Sasha; Kim, Younghee; Mizutani, Takeshi et al. (2016) Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther 1:
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Bosco, Alejandra; Romero, Cesar O; Ambati, Balamurali K et al. (2015) In vivo dynamics of retinal microglial activation during neurodegeneration: confocal ophthalmoscopic imaging and cell morphometry in mouse glaucoma. J Vis Exp :e52731
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Kim, Younghee; Tarallo, Valeria; Kerur, Nagaraj et al. (2014) DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc Natl Acad Sci U S A 111:16082-7

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