Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Ulrike Flierl, Tracy L Nero, Bock Lim, Jane Frances Arthur, Yu Yao, Stephanie M Jung, Eelo Gitz, Alice Y Pollitt, Maria Teresa Kristina Zaldivia, Martine Jandrot-Perrus, Andreas Schafer, Bernhard Nieswandt, Robert Keith Andrews, Michael William Parker, Elizabeth Ellen Gardiner, Karlheinz Peter

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Abstract

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.
Original languageEnglish
Pages (from-to)129 - 137
Number of pages9
Journal Journal of Experimental Medicine
Volume212
Issue number2
DOIs
Publication statusPublished - 2015

Cite this

Flierl, U., Nero, T. L., Lim, B., Arthur, J. F., Yao, Y., Jung, S. M., Gitz, E., Pollitt, A. Y., Zaldivia, M. T. K., Jandrot-Perrus, M., Schafer, A., Nieswandt, B., Andrews, R. K., Parker, M. W., Gardiner, E. E., & Peter, K. (2015). Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators. Journal of Experimental Medicine, 212(2), 129 - 137. https://doi.org/10.1084/jem.20140391