Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2

Abstract

Angiopoietin-2 (Ang2) appears to be a naturally occurring antagonist of the endothelial receptor tyrosine kinase Tie2, an important regulator of vascular stability. Destabilization of the endothelium by Ang2 is believed to potentiate the actions of proangiogenic growth factors. To investigate the specific role of Ang2 in the adult vasculature, we generated a nuclease-resistant RNA aptamer that binds and inhibits Ang2 but not the related Tie2 agonist, angiopoietin-1. Local delivery of this aptamer but not a partially scrambled mutant aptamer inhibited basic fibroblast growth factormediated neovascularization in the rat corneal micropocket angiogenesis assay. These in vivo data directly demonstrate that a specific inhibitor of Ang2 can act as an antiangiogenic agent.

Roles of Angiopoietins in Kidney Development and Disease

“…Another possibility would be to sequester Ang-2 by expressing a soluble Tie-2 receptor within glomeruli; this strategy has been used in tumor and arthritis models associated with aberrant Ang/Tie signaling. 68,69 Alternatively, Ang-2 could be specifically dowregulated using RNA aptamers, as reported by White et al 70 Ang-1 therapies show promise in the preservation of peritubular capillaries in chronic tubulointerstitial disease; however, such therapies may need to be tailored to specific primary kidney diseases in which endogenous Ang-1 levels are deficient; otherwise "too much of a good thing" may also cause enhanced fibrosis and inflammation. Along the same lines, we need to define whether different engineered forms of Ang-1 being used as therapies (Ang-1* versus COMP-Ang-1) have differential effects on blood endothelia versus nonendothelial cell biology.…”

The receptor tyrosine kinase Tie1 is expressed and activated in epithelial tumour cell lines

“…These findings indicate that Tie1 expressed within tumour epithelium is constitutively active and competent to signal. The angiopoietins and their better characterized receptor Tie2 have recently emerged as potentially attractive targets for anti-angiogenic therapy of tumours (34,35). The finding that Tie1 is present and constitutively active, as judged by receptor phosphorylation status, would suggest that therapeutics aimed at sequestering angiopoietins may also have effects directly on the tumour cell to limit the ability of the angiopoietins to act on Tie1 in tumour cells.…”

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

“…Those residues with double or tripple asterix are moderately and significantly varaiable, respectively, in all HIV isolates and while they make contact with the aptamer they did not significantly affect binding of the aptamer when experimentally mutated to alanine, respectively. Mi et al, 2009;Nobile et al, 1998;Ruckman et al, 1998;Rusconi et al, 2004;Rusconi et al, 2002;Vinores, 2003;White et al, 2003).…”