Mol Ther Nucleic Acids. 2022 Sep 13. 29
135-149
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.
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.
Keywords: angiogenic disorders; extrahepatic delivery; methyl rich siRNA; oligonucleotide drug design; oligonucleotides; pre-clinical development; preeclampsia; siRNA optimization; siRNA therapeutics