Identification of a DNA aptamer that inhibits sclerostin's antagonistic effect on Wnt signalling

Sclerostin is an extracellular negative regulator of bone formation that is a recognized therapeutic target for osteoporosis therapy. In the present study, we performed DNA aptamer selection against sclerostin, then characterized aptamer sclerostin binding and the ability to inhibit sclerostin function in cell culture. We show that a selected DNA aptamer was highly selective for binding to sclerostin with affinities in the nanomolar range as determined by solid-phase assays and by isothermal titration calorimetry. Binding between sclerostin and the aptamer was exothermic and enthalpically driven. CD confirmed that the aptamer had temperature-dependent parallel G-quadruplex characteristics. The aptamer was stabilized with 3 inverted thymidine to investigate efficacy at inhibiting sclerostin function in cell culture. The stabilized DNA aptamer showed potent and specific dose-dependent inhibition of sclerostin's antagonistic effect on Wnt activity using a reporter assay. Taken together, the present findings suggest an alternative approach to inhibiting sclerostin function with therapeutic potential.