Vegf or EphA2 antisense polyamide-nucleic acids; vascular localization and suppression of retinal neovascularization.
Localized gene knockdown is a valuable tool for investigating the function of gene products in tissues. It may also be a good therapeutic strategy for selective targeting of a gene product implicated in disease pathogenesis. While small interfering RNAs (siRNAs) are useful for localized gene knockdown and have achieved well-deserved attention, other strategies may also have applications. Polyamide nucleic acids (PNAs) are DNA-protein chimeric molecules that can be designed with modifications so as to allow good cell entry and high affinity binding to complementary RNA. After intraocular injection of fluorescein isothiocyanate (FITC)-labeled antisense PNAs directed against Vegf or EphA2 (genes that are highly expressed in retinal vessels), labeling was observed to persist in retinal blood vessels even after staining elsewhere in the retina had faded. This did not occur after injection of FITC-labeled antisense human cAMP responsive element binding protein 1 (hCreb) PNA. Subretinal injection of antisense EphA2 PNA was seen to label choroidal blood vessels. Intraocular injection of antisense Vegf PNA or antisense EphA2 PNA significantly reduced their respective target messenger RNAs (mRNAs) in ischemic retinas and suppressed retinal neovascularization (NV). These data suggest that signaling through EphA2 contributes to retinal NV, and that antisense PNAs may be an advantageous way to target EphA2 and other endothelial cell receptors that contribute to ocular NV.
The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Jikui
J
Shen
Bing
B
Xie
Christina M
CM
Hatara
Sean F
SF
Hackett
Peter A
PA
Campochiaro
D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000378:metabolism*; D013997:Time Factors; D042442:Vascular Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism*; D014822:Vitreous Body / Q000098:blood supply / Q000378:metabolism
D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors; D036104:Receptor, EphA2