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2017 ; 27
(2
): 70-77
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Molecular Mechanisms of Antisense Oligonucleotides
#MMPMID28080221
Crooke ST
Nucleic Acid Ther
2017[Apr]; 27
(2
): 70-77
PMID28080221
show ga
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.
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