Abstract

Introduction Continuous advancement in human genome sequencing led us to a better understanding of biological pathways and their links to disease-related targets. However, most existing targets are still under-exploited or considered “undruggable” with traditional small molecules. Expansion of the chemical modality toolbox provides beneficial opportunities in drug discovery. RNA-based drugs, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), are successful examples of these new modalities. Discussion RNA-based therapeutics enable us to address new modes of action (MoA) via a range of processes. Recent clinical approvals of RNA-based drugs have attracted extensive investigation in oligonucleotide drug discovery. Compared to traditional small molecule drug discovery, the oligonucleotide drug discovery process can be more straightforward and cost efficient. Although there are many variations on siRNA therapeutics, the typical workflow for siRNA design and sequence selection are well defined. To further support and advance oligonucleotide drug discovery process, we at WuXi AppTec have been creating a comprehensive toolbox covering the early stages of hit finding as well as toxicology, manufacturing and formulation, . For example, by using a portfolio of state-of-the-art technologies we have created a “one-stop shop” for oligonucleotide synthesis to support multiple scale production and to ensure high quality and fast turnaround. We have established a variety of in vitro cell-based knockdown assessments that can fit different screening requirements. Our humanized mouse models and NHP models provide resources for pharmacodynamic assessments of RNA-based drug candidates. In addition, we have established a set of tools for off-target and safety assessment, including cytotoxicity assays, in vitro immunogenicity assays and off-target profiling by RNA sequencing. Considering the unique physicochemical properties of oligonucleotides and the bioanalytical challenges, we have also developed unique bioanalytical platforms for oligonucleotides in DMPK studies. Conclusion To conclude, we have created a comprehensive toolbox for rapid and efficient oligonucleotide drug discovery and made it available, accessible and achievable.