Davis Sarah M, Hariharan Vignesh N, Lo Agnes, Turanov Anton A, Echeverria Dimas, Sousa Jacquelyn, McHugh Nicholas, Biscans Annabelle, Alterman Julia F, Karumanchi S Ananth, Moore Melissa J, Khvorova Anastasia
RNA Therapeutics Institute, University of Massachusetts Medical School, AS4-1049, 368 Plantation Street, Worcester, MA 01605, USA.
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Mol Ther Nucleic Acids. 2022 Jun 22;29:135-149. doi: 10.1016/j.omtn.2022.06.009. eCollection 2022 Sep 13.
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.
子痫前期（PE）是一种日益常见且具有潜在致命性的妊娠并发症。PE主要由胎盘可溶性fms样酪氨酸激酶1（sFLT1）的过度表达所驱动，当与胎盘生长因子（PlGF）水平进行标准化时，sFLT1是该疾病经过验证的诊断和预后标志物。将靶向mRNA的胆固醇共轭、完全修饰的小干扰RNA（siRNA）注射到怀孕小鼠或狒狒体内，可降低胎盘sFLT1水平并改善PE的临床症状，为开发PE治疗方法奠定了坚实基础。siRNA的递送、效力和安全性取决于共轭化学、siRNA双链体结构和化学修饰模式。在此，我们系统地评估了这些参数，并证明增加2'-O-甲基修饰和5'化学稳定性，以及使用序列特异性双链不对称性和磷酸胆碱-二十二烷酸共轭物，可增强靶向siRNA的胎盘积累、沉默效率和安全性。本文的优化策略为针对PE以及其他靶点和临床适应症的siRNA化学优化提供了一个框架。
