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Development of universal antidotes to control aptamer activity

Nature Medicine volume 15, pages 1224–1228 (2009)Cite this article

Abstract

With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.

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Figure 1: The structures of aptamers used in this study and protamine-mediated reversal of anticoagulant aptamer function.
Figure 2: Polymer-mediated reversal of anticoagulant aptamer function.
Figure 3: Polymer-mediated reversal of antiplatelet aptamer function.
Figure 4: In vivo aptamer and antidote activity.

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Acknowledgements

We thank S.M. Nimjee and J. Layzer for helpful discussions and Calando Pharmaceuticals for providing the CDP and CDP-Im polymers. This work was supported by a grant from the US National Institutes of Health (HL065222 to B.A.S.), a predoctoral fellowship from the American Heart Association (0615443U to S.O.) and a grant from the US National Cancer Institute (CA 119347 to M.E.D).

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Author notes

  1. Sabah Oney

    Present address: Present address: b3bio, Inc., Research Triangle Park, North Carolina, USA.,

Authors and Affiliations

  1. Duke Translational Research Institute, Duke University Medical Center, Durham, North Carolina, USA

    Sabah Oney, Kristin M Bompiani, Charlene M Blake, George Quick & Bruce A Sullenger

  2. University Program in Genetics and Genomics, Duke University, Durham, North Carolina, USA

    Sabah Oney, Kristin M Bompiani, Charlene M Blake & Bruce A Sullenger

  3. Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

    Sabah Oney, Kristin M Bompiani, Charlene M Blake & Bruce A Sullenger

  4. Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA

    Ruby T S Lam & Kam W Leong

  5. Calando Pharmaceuticals, Pasadena, California, USA

    Jeremy D Heidel & Joanna Yi-Ching Liu

  6. Department of Chemical Engineering, California Institute of Technology, Pasadena, California, USA

    Brendan C Mack & Mark E Davis

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Contributions

S.O. designed and performed research, analyzed data and wrote the manuscript; R.T.S.L designed and performed research and analyzed data; K.M.B. performed research; C.M.B. performed research and analyzed data; G.Q. performed research; J.D.H. designed and performed research, provided useful reagents, analyzed data and provided useful discussions; J.Y.-C.L. performed research; B.C.M. performed research; M.E.D. provided useful reagents and discussions; K.W.L. provided useful reagents and discussions; B.A.S. suggested the universal antidote idea, designed and coordinated research, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Bruce A Sullenger.

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Competing interests

B.A.S. and M.E.D. are scientific founders of Regado Biosciences, Inc. and Calando Pharmaceuticals, Inc., respectively.

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Supplementary Tables 1 and 2 and Supplementary Figs. 1–3 (PDF 1018 kb)

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Oney, S., Lam, R., Bompiani, K. et al. Development of universal antidotes to control aptamer activity. Nat Med 15, 1224–1228 (2009). https://doi.org/10.1038/nm.1990

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