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

• Main Authors: Sarah M. Davis (Author), Vignesh N. Hariharan (Author), Agnes Lo (Author), Anton A. Turanov (Author), Dimas Echeverria (Author), Jacquelyn Sousa (Author), Nicholas McHugh (Author), Annabelle Biscans (Author), Julia F. Alterman (Author), S. Ananth Karumanchi (Author), Melissa J. Moore (Author), Anastasia Khvorova (Author)
• Format: Book
• Published: Elsevier, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

2162-2531
10.1016/j.omtn.2022.06.009