Antisense Oligonucleotide Therapies: The Promise and the Challenges from a Toxicologic Pathologist's Perspective
Antisense Oligonucleotide Therapies: The Promise and the Challenges from a Toxicologic Pathologist's Perspective
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DOI：
10.1177/0192623314551840
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发表时间：
2015-01-01
影响因子：
1.5
通讯作者：
Frazier, Kendall S.
中科院分区：
文献类型：
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作者：
Frazier, Kendall S.
来自几类分子的许多反义寡核苷酸（ASO）目前正在药物开发中。尽管有超过20年的药物研究，但由于临床疗效或临床前毒理学挑战的问题，很少有ASO上市。然而，最近的一些发展重新引起了人们对这类药物的兴趣，包括米泊美生的注册，成功筛选策略的出现，以消除更多的毒性分子，以及对脱靶核苷酸结合风险和减轻潜在脱靶效应的新认识。骨架化学、与其他部分的缀合和新的递送系统的最新进展允许更好的组织渗透、增强的细胞内靶向和更少的给药频率，从而导致更少的毒性。虽然这些新的发展使人们对这些平台产生了更大的兴趣，但一些挥之不去的挑战和临床前/临床毒性问题仍有待完全解决，包括：（1）促炎作用（血管炎/炎性浸润）;（2）与溶酶体蓄积无关的肾毒性和肝毒性;以及（3）血小板减少症。几个实验室最近的研究工作有助于阐明这些问题的机制，从而更好地理解特定毒性的临床相关性和影响。重要的是，毒理学家，病理学家和监管审查人员要熟悉阿索领域的新发展及其影响，因为越来越多的新型反义分子正在进行临床前毒性测试。
Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Despite over 20 years of pharmaceutical research, few ASOs have been marketed due to problems with clinical efficacy or preclinical toxicologic challenges. However, a number of recent developments have renewed interest in this class including the registration of mipomersen, the advent of successful screening strategies to eliminate more toxic molecules, and new understanding of the risks of off-target nucleotide binding and mitigation of potential off-target effects. Recent advances in backbone chemistries, conjugation to other moieties, and new delivery systems have allowed better tissue penetration, enhanced intracellular targeting, and less frequent dosing, resulting in fewer toxicities. While these new developments provide invigorated interest in these platforms, a few lingering challenges and preclinical/clinical toxicity issues remain to be completely resolved, including: (1) proinflammatory effects (vasculitis/inflammatory infiltrates); (2) nephrotoxicity and hepatotoxicity unrelated to lysosomal accumulation; and (3) thrombocytopenia. Recent investigative work by several laboratories have helped elucidate mechanisms for these issues, allowing a better understanding of the clinical relevance and implications of particular toxicities. It is important for toxicologists, pathologists, and regulatory reviewers to be familiar with new developments in the ASO field and their implications, as a greater number of new types of antisense molecules undergo preclinical toxicity testing.