Angiogenesis is a blinding complication of many eye diseases including diabetic and sickle cell retinopathy, retinopathy of prematurity (ROP) and exudative age-related macular degeneration (ARMID). Although over 50 antiangiogenic factors are currently being evaluated in clinical trials for eir effect on tumors, only two are in clinical trial for angiogenesis in the eye. One needed stepping stone towards antiangiogenic therapy in the eye has been the delivery of the agents to the nieovascularization selectively. This proposal will evaluate the delivery of genes encoding for antiangiogenic agents to sites of angiogenesis in the eye by non-viral means. The genes will be encapsulated in chitosan nanoparticles and the particles injected into vitreous or the subtenon's space. This gene delivery system has several attractive features: 1) ligands can be conjugated to the nanoparticles to stimulate receptor-mediated endocytosis (ex: acetylated LDL); 2) lysosomolytic agents can be incorporated to reduce degradation of the DNA in the endosomal and lysosomal compartments (ex: chloroquine); 3) other bioactive agents (proteinacious or non-proteinacious) or multiple plasmids can be co-encapsulated; 4) bioavailability of the DNA can be improved because of protection from nuclease degradation by the matrix; 5) the nanoparticles can be lyophilized for storage without loss of bioactivity. Pigment epithelial-derived factor (PEDF) will serve as the prototypic gene to be evaluated initially by this novel antiangiogenic therapeutic approach. In summary, chitosan nanoparticles are nontoxic, biodegradable particles that have the potential of delivering large genes to target cells of the eye. The goal of this proposal is to deliver genes for endogenous antiangiogenic agents to sites of ocular neovascularization.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY013744-03
Application #
6605691
Study Section
Special Emphasis Panel (ZEY1-VSN (04))
Program Officer
Dudley, Peter A
Project Start
2001-07-02
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$163,500
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Prow, Tarl W; Bhutto, Imran; Grebe, Rhonda et al. (2008) Nanoparticle-delivered biosensor for reactive oxygen species in diabetes. Vision Res 48:478-85
Prow, Tarl W; Bhutto, Imran; Kim, Sahng Y et al. (2008) Ocular nanoparticle toxicity and transfection of the retina and retinal pigment epithelium. Nanomedicine 4:340-9
Prow, Tarl; Smith, Jacob N; Grebe, Rhonda et al. (2006) Construction, gene delivery, and expression of DNA tethered nanoparticles. Mol Vis 12:606-15
Prow, Tarl; Grebe, Rhonda; Merges, Carol et al. (2006) Nanoparticle tethered antioxidant response element as a biosensor for oxygen induced toxicity in retinal endothelial cells. Mol Vis 12:616-25