Reduced retinal microvascular density, improved forepaw reach, comparative microarray and gene set enrichment analysis with c-jun targeting DNA enzyme
Retinal neovascularization is a critical component in the pathogenesis of common ocular disorders that cause blindness, and treatment options are limited. We evaluated the therapeutic effect of a DNA enzyme targeting c-jun mRNA in mice with pre-existing retinal neovascularization. A single injection of Dz13 in a lipid formulation containing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine inhibited c-Jun expression and reduced retinal microvascular density. The DNAzyme inhibited retinal microvascular density as effectively as VEGF-A antibodies. Comparative microarray and gene expression analysis determined that Dz13 suppressed not only c-jun but a range of growth factors and matrix-degrading enzymes. Dz13 in this formulation inhibited microvascular endothelial cell proliferation, migration and tubule formation in vitro. Moreover, animals treated with Dz13 sensed the top of the cage in a modified forepaw reach model, unlike mice given a DNAzyme with scrambled RNA-binding arms that did not affect c-Jun expression. These findings demonstrate reduction of microvascular density and improvement in forepaw reach in mice administered catalytic DNA.
|ISBN||1932-6203 (Electronic) 1932-6203 (Linking)|
|Authors||Chan, C. W.; Kaplan, W.; Parish, C. R.; Khachigian, L. M.;|
|Publisher Name||PLoS One|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22815700|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11752|