Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

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

Molecular Therapy: Nucleic Acids (Sep 2022)

Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

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

Sarah M. Davis: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Vignesh N. Hariharan: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Agnes Lo: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Anton A. Turanov: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Dimas Echeverria: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Jacquelyn Sousa: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Nicholas McHugh: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Annabelle Biscans: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
Julia F. Alterman: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA
S. Ananth Karumanchi: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Deparment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Melissa J. Moore: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA; Moderna Therapeutics, Cambridge, MA, USA
Anastasia Khvorova: RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA; Department of Molecular Medicine, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA; Corresponding author Anastasia Khvorova, PhD, University of Massachusetts Medical School, RNA Therapeutics Institute, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 29
pp. 135 – 149

Abstract

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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 sFLT1 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′-O-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 sFLT1-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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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