Molecular Mechanisms of Antisense Oligonucleotides

© Stanley T. Crooke, 2017; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Address correspondence to: Stanley T. Crooke, MD, PhD, Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA 92010, E-mail: [email protected]

Introduction

Throughout my career, my primary research interests have focused on understanding the molecular mechanisms by which drugs work, molecular pharmacology. Early in my career, I focused on the molecular mechanisms of antineoplastic drugs such as bleomycin, cisplatinum, and anthracyclines [1-3]. I then focused on more traditional receptor biological questions with a particular emphasis on leukotriene receptor signaling pathways and other G-protein-coupled receptors [4]. 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 Pharmaceuticals (formerly, Isis Pharmaceuticals). 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. That progress has also been chronicled in a number of books that I have edited [5-8]. (Although it...