One of my interests is to understand the fine details of the molecular mechanisms for which antisense oligonucleotides (ASOs) may be designed. Today, we have a very high-level understanding of many of the molecular mechanisms and have successfully expanded the repertoire of well-understood mechanisms of action. This knowledge enables the design of better performing RNA-targeted medicines and expands the therapeutic potential of antisense technology.
In my laboratory, an abiding interest has been to understand the robust and specific ribonuclease H1 (RNaseH1) mechanism. We have contributed to numerous papers that expand our knowledge of the roles of RNaseH1 in the cell and the characteristics of the molecular mechanism for RNaseH1-designed ASOs. This mechanism has proven to be extraordinarily important, as this work led to a range of important advances in the performance of ASOs in the clinic. I summarize the current state of knowledge and discuss the characteristics of other post-RNA binding mechanisms in a review published in Nucleic Acid Therapeutics. However, important progress has continued after the review was written. For example, we reported the creation of a viable RNaseH1 knock-out mouse that added substantially to the understanding of the biological roles of RNaseH1 and the mechanisms for which this enzyme mediates ASO activity. (Lima et. al., Nucleic Acid Res 44:5299-312, 2016).
We also have identified new mechanisms that can be used to create ASOs that increase protein levels. (Liang et. al., Nature Biotech 34:875-882, 2016; Liang et. al., Nucleic Acid Res, 1-19, 2017.) This is a vital step because it broadens the potential use of ASOs in drug discovery and development by enabling the creation of ASOs that can selectively increase the production of specific proteins rather than just reduce protein production.