Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1.
Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1.
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DOI：
10.1016/j.omtn.2022.06.009
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发表时间：
2022-09-13
期刊：
影响因子：
--
通讯作者：
Khvorova, Anastasia
中科院分区：
文献类型：
--
作者：
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
先兆子痫（PE）是一种上升的，潜在的致命的妊娠并发症。PE主要由胎盘可溶性fms样酪氨酸激酶1（sFLT 1）的过表达驱动，sFLT 1是一种经验证的疾病诊断和预后标志物，当标准化为胎盘生长因子（PlGF）水平时。将靶向sFLT 1 mRNA的胆固醇缀合的、完全修饰的小干扰RNA（siRNA）注射到妊娠小鼠或狒狒中，可减少胎盘sFLT 1并改善PE的临床体征，为PE治疗剂的开发提供了坚实的基础。siRNA递送、效力和安全性由缀合物化学、siRNA双链体结构和化学修饰模式决定。在这里，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，并使用序列特异性双链体不对称性和磷酸胆碱-二十二烷酸缀合物增强胎盘积累，沉默效率和sFLT 1靶向siRNA的安全性。这里的优化策略为PE以及其他靶标和临床适应症的siRNA的化学优化提供了框架。Davis，Hariharan，and Lo et al.本发明提供了疏水性siRNA缀合物和化学结构以及修饰模式的系统优化，以增强选择性靶向sFLT 1（用于治疗先兆子痫的治疗靶标）的化合物的靶标沉默、胎盘积累和安全性。保留字：siRNA治疗，寡核苷酸，先兆子痫，寡核苷酸药物设计，肝外递送，血管生成疾病，siRNA优化，临床前开发，富甲基siRNA
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. Davis, Hariharan, and Lo et al. present a systematic optimization of hydrophobic siRNA conjugate and chemical architecture and modification patterns to enhance target silencing, placental accumulation, and safety of compounds selectively targeting sFLT1, a therapeutic target for the treatment of preeclampsia. Keywords: siRNA therapeutics, oligonucleotides, preeclampsia, oligonucleotide drug design, extrahepatic delivery, angiogenic disorders, siRNA optimization, pre-clinical development, methyl rich siRNA
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影响因子：
158.5
作者：
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