Molecular Mechanisms of Antisense Oligonucleotides.
Molecular Mechanisms of Antisense Oligonucleotides.
复制标题
DOI：
10.1089/nat.2016.0656
复制
发表时间：
2017-04
影响因子：
4
通讯作者：
Crooke ST
中科院分区：
文献类型：
--
作者：
Crooke ST
1987年，当我对反义技术的概念产生兴趣时，我回到了RNA生物化学的根源上，并开始研究寡核苷酸在生物系统中的行为。自1989年以来，我的研究主要集中在这个主题上，尽管我参与了反义技术的大多数领域的研究。我认为，优秀科学的艺术是，构思用现有知识和方法可能无法立即回答的重大重要问题，然后构思一项长期(多年)研究战略，从回答通往长期目标的道路上最紧迫的可回答问题开始。然后，必须实施一条循序渐进的研究路径，解决提出的战略问题，随着新事物的学习而调整计划。这是我们在IONIS采取的方法。显然，为了创造反义技术，我们必须解决一系列的战略问题，例如，寡核苷酸的药物化学、制造和分析方法、药代动力学和毒理学，以及关于反义寡核苷酸(ASO)的分子药理学问题。这些努力中的每一项都耗费了近30年的科学努力，在很大程度上仍然是一项正在进行的工作，并已发表了数百篇论文。作为2016年由寡核苷酸治疗学会颁发的终身成就奖的获得者，在本笔记中，我的目标是总结我的团队对理解ASOS分子机制的贡献。
In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs.