Tag Archives: research

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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 »

Blogs

Effects of PS ASOs on the conformations of RNAse H1 and P54.

Nucleic Acid Research Journal

Over the past several years, my group has systematically identified cellular proteins that bind PS ASOs, defined the roles of many of the proteins bound by PS ASOs, assessed the effects of PS ASO binding on those proteins and developed a thorough appreciation of the biochemistry of PS ASO protein interactions. We have also shown that PS ASO induce the formation of numerous PS ASO/protein/RNA … Continue reading Effects of PS ASOs on the conformations of RNAse H1 and P54. »

Blogs

PS ASO Induced Aggregates Undergo Phase separations.

Work from my group has demonstrated that proteins determine the fate of PS ASOs in all biological systems, identified the key proteins involved in cellular pharmacodynamics, pharmacokinetics and toxicology, characterized the binding of PS ASO to many of the critical proteins and demonstrated that most cytotoxic PS ASOs in all cells and organs studied are to interactions with paraspeckle proteins and RNAse H1 that delocalize … Continue reading PS ASO Induced Aggregates Undergo Phase separations. »

Blogs

Update on Core Antisense Research

In this paper, we continue our exploration of the molecular mechanisms by which PS ASOs enter and distribute within cells such that they can be pharmacologically active.  We show that M6PR plays a critical role in releasing PS ASOs from late endosomes. We now believe that we have identified most of the endosomal means of productive uptake and intracellular distribution of PS ASOs. We are assessing the … Continue reading Update on Core Antisense Research »

Blogs

Mechanisms that improve therapeutic index

Mechanisms of ASO toxicities and the structure activity relationships that improve therapeutic index Last year, we published a landmark paper that described a general mechanism that explains how toxic ASOs produce toxicities and provided a straightforward medicinal chemistry solution to enhance safety with little effect on potency (Shen et.al., 2019). We have now published several papers that extend our observations and broaden the understanding of … Continue reading Mechanisms that improve therapeutic index »