Nonclinical Development, Sarepta Therapeutics, Inc, Cambridge, MA, USA.
Clinical Pharmacology Fellow, Ohio State University, Columbus, OH, USA.
Expert Opin Drug Metab Toxicol. 2021 Nov;17(11):1281-1292. doi: 10.1080/17425255.2021.1992382. Epub 2021 Oct 22.
Antisense oligonucleotides (ASOs) have emerged as a promising novel drug modality that aims to address unmet medical needs. A record of six ASO drugs have been approved since 2016, and more candidates are in clinical development. ASOs are the most advanced class within the RNA-based therapeutics field.
This review highlights the two major backbones that are currently used to build the most advanced ASO platforms - the phosphorodiamidate morpholino oligomers (PMOs) and the phosphorothioates (PSs). The absorption, distribution, metabolism, and excretion (ADME) properties of the PMO and PS platforms are discussed in detail.
Understanding the ADME properties of existing ASOs can foster further improvement of this cutting-edge therapy, thereby enabling researchers to safely develop ASO drugs and enhancing their ability to innovate.
2'-MOE, 2'-O-methoxyethyl; 2'PS, 2 modified PS; ADME, absorption, distribution, metabolism, and excretion; ASO, antisense oligonucleotide; AUC, area under the curve; BNA, bridged nucleic acid; CPP, cell-penetrating peptide; CMV, cytomegalovirus; CNS, central nervous system; CYP, cytochrome P; DDI, drug-drug interaction; DMD, Duchenne muscular dystrophy; FDA, Food and Drug Administration; GalNAc3, triantennary N-acetyl galactosamine; IT, intrathecal; IV, intravenous; LNA, locked nucleic acid; mRNA, messenger RNA; NA, not applicable; PBPK, physiologically based pharmacokinetics; PD, pharmacodynamic; PK, pharmacokinetic; PMO, phosphorodiamidate morpholino oligomer; PMOplus, PMOs with positionally specific positive molecular charges; PPMO, peptide-conjugated PMO; PS, phosphorothioate; SC, subcutaneous; siRNA, small-interfering RNA; SMA, spinal muscular atrophy.
反义寡核苷酸（ASO）已成为一种有前途的新型药物模式，旨在满足未满足的医疗需求。自 2016 年以来，已有 6 种 ASO 药物获得批准，更多的候选药物正在临床开发中。ASO 是 RNA 治疗领域中最先进的一类。
本综述重点介绍了目前用于构建最先进 ASO 平台的两种主要骨架——磷酸二酰胺吗啉寡聚物（PMO）和硫代磷酸酯（PS）。详细讨论了 PMO 和 PS 平台的吸收、分布、代谢和排泄（ADME）特性。
了解现有 ASO 的 ADME 特性可以促进这种尖端疗法的进一步改进，从而使研究人员能够安全地开发 ASO 药物，并提高他们的创新能力。
2'-MOE，2'-O-甲氧基乙基；2'PS，2 位修饰 PS；ADME，吸收、分布、代谢和排泄；ASO，反义寡核苷酸；AUC，曲线下面积；BNA，桥接核酸；CPP，细胞穿透肽；CMV，巨细胞病毒；CNS，中枢神经系统；CYP，细胞色素 P；DDI，药物-药物相互作用；DMD，杜氏肌营养不良症；FDA，美国食品和药物管理局；GalNAc3，三触角 N-乙酰半乳糖胺；IT，鞘内；IV，静脉内；LNA，锁核酸；mRNA，信使 RNA；NA，不适用；PBPK，基于生理学的药代动力学；PD，药效学；PK，药代动力学；PMO，磷酸二酰胺吗啉寡聚物；PMOplus，具有位置特异性正分子电荷的 PMO；PPMO，肽偶联 PMO；PS，硫代磷酸酯；SC，皮下；siRNA，小干扰 RNA；SMA，脊髓性肌萎缩症。
