Dave Madge, Vice President of Discovery Services at WuXi AppTec, oversees the company’s business development in Europe and Israel and manages strategic initiatives across various therapeutic areas. In this presentation, he shared his expertise on building a robust discovery platform for oligonucleotide therapeutics.
The presentation began with an overview of WuXi's approach to drug discovery, Madge stressed the importance of understanding disease mechanisms, targets, and pathways to make informed modality selections. Next, he highlighted the company's comprehensive platform that supports small molecule, peptide macrocycle, and oligonucleotide therapeutics. He explained how WuXi's platform enables collaborators and clients to engage at any stage of the drug discovery process, from target selection to patient treatment.
A significant portion of the presentation focused on oligonucleotide therapeutics, detailing the various stages of mRNA and protein production where intervention is possible. Madge discussed the challenges and opportunities in delivering these therapeutics selectively to specific cells. He also elaborated on the workflow screening cascade used to discover targets, design oligos, and optimize molecules through a short iterative loop.
Madge provided an in-depth look at the four main building blocks in designing and optimising molecules: sequence selection, topology, modifications, and targeting. He described the process of predicting sequences for on-target activity, translating them into chemistry, and selecting modification patterns for stability and selective delivery. The presentation also covered various conjugation methods, including GalNAc, lipid, and peptide conjugations, and their applications in targeting specific cell types.
In addition to the technical aspects, Madge emphasised the importance of in vitro and in vivo studies for translational research. He discussed the use of humanized mice, hydrodynamic injection, viral vectors, and transgenic models to study gene knockdown in vivo. The presentation concluded with a case study on lowering LDL cholesterol using PCSK9 as a target, demonstrating the effectiveness of WuXi's workflow in producing high-quality, in vivo active molecules.
