Category Archives: Uncategorized

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Unravelling why some PS ASOs activate the innate immune system

Working out the step by step molecular mechanism to explain why some PS ASOs of all chemical classes are cytotoxic led directly to medicinal chemical solutions that are enhancing the therapeutic index  of many PS ASOs significantly by dramatically reducing their potential cytotoxic effects without materially altering their potency (Shen, W., et.al., NAR, 2018; Migawa, M., et.al., NAR, 2019; Vasquez, G., et.al., NAR, 2021; Anderson, … Continue reading Unravelling why some PS ASOs activate the innate immune system »

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Insights into innate immune activation via PS-ASO-Protein-TLR9 Interactions

July 15, 2022 : Pollak,A.J., et al, NAR https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac618/6644951 It has long been known that nucleic acids that have CpG motifs can activate the immune system and that DNA like nucleic acids do that by interacting with TLR9 located in late endosomes. It has also been shown that PS ASOs that do not have CpG motifs can activate the innate immune system in a TLR9 … Continue reading Insights into innate immune activation via PS-ASO-Protein-TLR9 Interactions »

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Establishing an environment in which rigorous scientific inquiry is practiced: a personal journey

In the fall of last year, I received a very unusual request from two associated editors, David Corey, Ph.D. and Helle Ulrich, Ph.D. for Nucleic Acid Research (NAR), a highly regarded and highly cited scientific journal. They asked if I would be willing to provide a manuscript describing how I established a rigorous scientific environment at Ionis. I was pleased to have two scientists for whom I … Continue reading Establishing an environment in which rigorous scientific inquiry is practiced: a personal journey »

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RNA modifications can affect RNase H1-mediated PS-ASO activity

Thanks to decades of work, we have a great deal of detailed knowledge about how various chemical modifications of a PS ASO can affect hybridization to target RNAs and how those modifications affect the interactions of the heteroduplex with RNAseH1, including binding, catalytic rate and sites of cleavage of the target RNA. However, it is now clear that cellular RNAs may be modified post-transcriptionally with … Continue reading RNA modifications can affect RNase H1-mediated PS-ASO activity »

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What next? Questions to consider in assessing the response to COVID-19 and the risks of future pandemics

The study of risk, the perception of risk and the management of risk is an important area of scholarship that I believe all leaders in positions of authority should study. I am certainly not an expert, but over the years I have invested in some scholarship in this area. There are, of course, numerous ways to categorize risks. One simple exercise is to think about … Continue reading What next? Questions to consider in assessing the response to COVID-19 and the risks of future pandemics »

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Ionis papers provide insight into the characteristics of antisense medicines

Not long ago, I wrote about an important paper that we published (Shen et. al, NBT, 2019) which, for the first time, provides a step-by-step molecular mechanism explaining most of the toxicities of ASOs and a straightforward medicinal chemical solution that dramatically enhances the therapeutic index of toxic ASOs. As you might imagine, we will be publishing a number of papers that provide more detail … Continue reading Ionis papers provide insight into the characteristics of antisense medicines »