title: Reduced retinal microvascular density, improved forepaw reach, comparative microarray and gene set enrichment analysis with c-jun targeting DNA enzyme.
abstract: 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.
authors: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors: Cecilia W S
authors: CW
authors: Chan
authors: Warren
authors: W
authors: Kaplan
authors: Christopher R
authors: CR
authors: Parish
authors: Levon M
authors: LM
authors: Khachigian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D021881:DNA, Catalytic / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005128:Eye Diseases / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D005552:Forelimb / Q000502:physiology; D006801:Humans; D018496:Hyperoxia / Q000150:complications; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D012160:Retina / Q000187:drug effects* / Q000503:physiopathology; D059467:Transcriptome / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D021881:DNA, Catalytic; C485475:Dz13 DNAzyme; D042461:Vascular Endothelial Growth Factor A; D048031:JNK Mitogen-Activated Protein Kinases