Editors' ChoicePreeclampsia

Protein silencing to stop a “silent killer”

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Science Translational Medicine  02 Jan 2019:
Vol. 11, Issue 473, eaaw0529
DOI: 10.1126/scitranslmed.aaw0529

Abstract

Delivery of a single dose of siRNA to the placenta silences proteins and may help prevent preeclampsia.

Despite first being described in ~400 BCE by Hippocrates, preeclampsia remains a disease with unknown pathophysiology that contributes to the deaths of thousands of infants and new and expectant mothers every year. This hypertensive condition originates in the placenta and has been referred to as a “silent killer” due to the difficulty of distinguishing early symptoms from normal pregnancy phenomena. The only current treatment option for preeclampsia is fetal delivery, regardless of gestational stage. Thus, the introduction of a potential therapeutic option for expectant mothers by Turanov et al. could lay the groundwork for a paradigm shift in preeclampsia treatment.

To address this vexing condition, the authors combined two critical innovations. First, they developed siRNAs targeting the predominant forms of soluble fms-like tyrosine kinase 1 (sFLT1), a circulating protein that promotes preeclampsia by dysregulating endothelial cell activity and disrupting normal angiogenesis. Second, the authors built upon their own work in the chemical modification of nucleic acids to design nuclease-resistant and long-circulating siRNAs suitable for carrier-free systemic delivery. In mice, these siRNAs were shown to accumulate substantially in the placenta (~7% of injected dose) but not in nearby maternal or—crucially—fetal tissues. In this model, circulating sFLT1 concentrations were also reduced without detectable nonspecific effects. Moving to a baboon model, which enabled evaluation in a more human-like pregnancy scenario, the authors showed that a single injection of modified siRNAs reduced sFLT1 concentrations in the blood by over 50% for up to two weeks, although there were no significant changes in blood pressure or proteinuria, clinical signs of preeclampsia.

This landmark report could set the stage for a new preeclampsia therapy. However, successful translation of this approach will require further exploration of potential off-target effects of delivered siRNAs, especially in fetal tissue. It would also be useful to explore the mechanism of placental accumulation of siRNA, and efforts to extend the duration of the therapy should be undertaken. Additional studies with higher statistical power would help clarify whether this approach significantly impacts clinical manifestations of preeclampsia. Lastly, safety considerations such as the possibility of lower infant birth weights must also be fully investigated. Nevertheless, these findings carry the potential to revolutionize treatment of preeclampsia and may signify a new frontier for extra-hepatic RNAi therapy.

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