AstraZeneca works with a range of drug modalities with a particular focus on picking the right modality for the target of choice. In the oligonucleotide therapeutic space, Anna Rydzik is a Principal Scientist at AstraZeneca, working within medicinal chemistry.
Her presentation begins with an introduction to oligonucleotide therapeutics, specifically focusing on microRNA mode of action and microRNA therapies. Rydzik highlights the role of chemical modifications in microRNA therapeutics, emphasising their importance for stability, potency, selectivity, and uptake of oligonucleotides. Rydzik’s presentation illustrates these points with examples from AstraZeneca's internal work on microRNAs.
MicroRNA therapeutics are a new and emerging technology, with a growing number of publications and drugs in the development pipeline. The mechanism of action for this modality is a form of RNA interference (RNAi) which interferes with the body’s protein making machinery for therapeutic effect. The main benefit here is to vastly broaden the druggable space. Rydzik also highlights differences between siRNA and microRNA, particularly in terms of target specificity.
The presentation then delves into the design of microRNA mimics, discussing the optimisation of guide and passenger strands, as well as the overall duplex architecture. Various chemical modifications and duplex architectures were tested to determine their impact on the activity and selectivity of the microRNA mimics. Rydzik highlights the example of miR200c as a model system to illustrate these experimental findings.
Finally, the presentation concludes with future aspirations, aiming to build knowledge on how chemical modifications affect the properties of microRNA mimics. The ultimate goal is to develop tool compounds for in vitro target validation and eventually move into the design space for therapeutics.