Wu Hangyu, Wahane Aniket, Alhamadani Feryal, Zhang Kristy, Parikh Rajvi, Lee SooWan, McCabe Evan M, Rasmussen Theodore P, Bahal Raman, Zhong Xiao-Bo, Manautou José E
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269, USA.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, USA.
Curr Opin Toxicol. 2022 Dec;32. doi: 10.1016/j.cotox.2022.100373. Epub 2022 Oct 21.
The field of antisense oligonucleotide (ASO)-based therapies have been making strides in precision medicine due to their potent therapeutic application. Early successes in treating some genetic diseases are now attributed to an emerging class of antisense drugs. After two decades, the US Food and Drug Administration (FDA) has approved a considerable number of ASO drugs, primarily to treat rare diseases with optimal therapeutic outcomes. However, safety is one of the biggest challenges to the therapeutic utility of ASO drugs. Due to patients' and health care practitioners' urgent demands for medicines for untreatable conditions, many ASO drugs have been approved. However, a complete understanding of the mechanisms of adverse drug reactions (ADRs) and toxicities of ASOs still need to be resolved. The range of ADRs is unique to a specific drug, while few ADRs are common to a section of drugs as a whole. Nephrotoxicity is an important concern that needs to be addressed considering the clinical translation of any drug candidates ranging from small molecules to ASO-based drugs. This article encompasses what is known about the nephrotoxicity of ASO drugs, the potential mechanisms of action(s), and recommendations for future investigations on the safety of ASO drugs.
基于反义寡核苷酸（ASO）的治疗领域因其强大的治疗应用在精准医学方面取得了进展。治疗某些遗传疾病的早期成功现在归因于一类新兴的反义药物。二十年后，美国食品药品监督管理局（FDA）已批准了相当数量的ASO药物，主要用于治疗具有最佳治疗效果的罕见疾病。然而，安全性是ASO药物治疗效用面临的最大挑战之一。由于患者和医疗从业者对治疗无法治愈疾病的药物有迫切需求，许多ASO药物已获批准。然而，对ASO药物不良反应（ADR）和毒性机制的全面了解仍有待解决。ADR的范围因特定药物而异，而作为一个整体的一部分药物很少有共同的ADR。考虑到从小分子到基于ASO的药物等任何候选药物的临床转化，肾毒性是一个需要解决的重要问题。本文涵盖了关于ASO药物肾毒性的已知信息、潜在作用机制以及对ASO药物安全性未来研究的建议。
