DNA aptamers block L-selectin function in vivo. Inhibition of human lymphocyte trafficking in SCID mice.

Abstract

Selectins participate in the initial events leading to leukocyte extravasation from the blood into tissues. Thus the selectins have generated much interest as targets for antiinflammatory agents. Therapeutic molecules based on the monomeric carbohydrate ligand sialyl Lewis X (SLe x ) have low affinities and are not specific for a given selectin. Using SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology, we have generated aptamers specific for L-selectin that require divalent cations for binding and have low nanomolar affinity. In vitro, the deoxyoligonucleotides inhibit L-selectin binding to immobilized SLe x in static assays and inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils on cytokine-activated endothelial cells in flow-based assays. These aptamers also block L-selectin-dependent lymphocyte trafficking in vivo, indicating their potential utility as therapeutics. ( J. Clin. Invest. 1996. 98:2688-2692.)

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

“…A DNA aptamer against plateletderived growth factor has been used to inhibit intimal hyperplasia in a rat carotid injury model (44) and matrix protein accumulation in a rat model of proliferative glomerulonephritis (45). Both DNA and nuclease-resistant RNA aptamers against human L-selectin have been shown to inhibit human lymphocyte trafficking in severe combined immunodeficient (SCID) mice (46,47). The most progress has been made with a polyethylene glycol-conjugated version of a nuclease-resistant RNA aptamer against VEGF, which has now shown promising results in both preclinical and clinical studies for the exudative form of agerelated macular degeneration (41,48,49).…”

Selectin ligands: will the real ones please stand up?

“…Of course, an alternate way to achieve the same end is the screening of randomized libraries composed of defined structural subcomponents. In this regard, it is interesting that the highest affinity ligands described to date for selectins are artificial ones that have been isolated by affinity selection from pools of randomized molecules belonging to yet another well-known category of acidic polysaccharides: single-stranded oligonucleotides (73,74).…”

Fucosylation of Disaccharide Precursors of Sialyl LewisX Inhibit Selectin-mediated Cell Adhesion

“…glycyrrhizin derivatives; Ref. 29), including oligonucleotides (30,31). Inhibiting the glycosyltransferases that participate in forming the carbohydrate ligands would provide another way to block leukocyte attachment to the endothelium.…”