1 Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka, Japan .
2 Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute , Suita, Osaka, Japan .
Nucleic Acid Ther. 2018 Feb;28(1):50-57. doi: 10.1089/nat.2017.0698. Epub 2018 Jan 23.
Recently, some studies have reported nephrotoxicity associated with a certain class of antisense oligonucleotides (ASOs) in humans. One possibility for reducing the potential nephrotoxicity of ASOs is to alter their pharmacokinetics. In this study, we investigated the effect of a ligand conjugation strategy on the renal accumulation of ASOs. We selected two ligands, cholesterol and N-acetylgalactosamine (GalNAc), with the purpose of reducing renal distribution and liver targeting, and then designed a series of cholesterol-GalNAc dual conjugated ASOs. The gene-silencing activity of the cholesterol-GalNAc dual conjugated ASO in the liver was slightly lower than that of a GalNAc-conjugated ASO. On the other hand, the renal distribution of the cholesterol-GalNAc dual conjugated ASO was considerably decreased compared with the GalNAc-conjugated ASO, as we expected. As dual conjugation was successful in reducing the renal distribution of ASO, it should be an effective strategy for reducing the nephrotoxic potential of ASOs.
最近，一些研究报告称，某些类别的反义寡核苷酸（ASO）在人体内具有肾毒性。减少 ASO 潜在肾毒性的一种方法是改变它们的药代动力学。在这项研究中，我们研究了配体偶联策略对 ASO 肾蓄积的影响。我们选择了两种配体，胆固醇和 N-乙酰半乳糖胺（GalNAc），目的是减少肾分布和肝靶向，然后设计了一系列胆固醇-GalNAc 双偶联 ASO。胆固醇-GalNAc 双偶联 ASO 在肝脏中的基因沉默活性略低于 GalNAc 偶联 ASO。另一方面，正如我们所预期的那样，胆固醇-GalNAc 双偶联 ASO 的肾分布明显低于 GalNAc 偶联 ASO。由于双重偶联成功地减少了 ASO 的肾分布，它应该是减少 ASO 肾毒性潜力的有效策略。
