Chemical Optimization of SiRNA for Safe and Efficient Silencing of Placental SFLT1

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2022 Jul 18

PMID 35847173

Authors

Sarah M Davis

Vignesh N Hariharan

Agnes Lo

Anton A Turanov

Dimas Echeverria

Jacquelyn Sousa

Nicholas McHugh

Annabelle Biscans

Julia F Alterman

S Ananth Karumanchi

Melissa J Moore

Anastasia Khvorova

Affiliations

Soon will be listed here.

Abstract

Preeclampsia (PE) is a rising, potentially lethal complication of pregnancy. PE is driven primarily by the overexpression of placental soluble fms-like tyrosine kinase 1 (sFLT1), a validated diagnostic and prognostic marker of the disease when normalized to placental growth factor (PlGF) levels. Injecting cholesterol-conjugated, fully modified, small interfering RNAs (siRNAs) targeting mRNA into pregnant mice or baboons reduces placental sFLT1 and ameliorates clinical signs of PE, providing a strong foundation for the development of a PE therapeutic. siRNA delivery, potency, and safety are dictated by conjugate chemistry, siRNA duplex structure, and chemical modification pattern. Here, we systematically evaluate these parameters and demonstrate that increasing 2'--methyl modifications and 5' chemical stabilization and using sequence-specific duplex asymmetry and a phosphocholine-docosanoic acid conjugate enhance placental accumulation, silencing efficiency and safety of -targeting siRNAs. The optimization strategy here provides a framework for the chemical optimization of siRNAs for PE as well as other targets and clinical indications.

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