Single-moleucle analysis of RNA-based therapeutics

Research Project, 2023 – 2026

Nucleic Acid Therapies (NATs) are emerging as the next generation of drugs, with the hope of treating diseases that today are undruggable. The main benefit of treating diseases at RNA level instead of the protein level is that the complexity potentially is reduced from 3D to 2D – from the surface/cavity of a protein to the sequence of the RNA. However, when targeting RNA, for example via antisense oligonucleotides (ASOs), the folding of the RNA is important. ASOs work by binding to a target RNA and recruiting Rnase H1 that degrades the target and then the ASO is recycled. The project is a collaboration between AstraZeneca, who currently have a strong focus on NATs, including several ASOs, and two groups at Chalmers University of Technology that are experts in single molecule biophysics, nucleic acid chemistry and fluorescence. The goal is to understand the ASO-target interaction on the molecular level, using single RNA molecule analysis. We will investigate the structure and dynamics of the ASO-target complex, and its interactions with Rnase H1, using optical tweezers and complementing techniques. We will analyze all steps of the cycle of the ASO mechanism from a biophysical perspective, with the goal of establishing general principles that will be implemented in the pharmaceutical industry as design optimizations of ASO drugs. This will in turn pave the way for next-generation therapeutics for a variety of difficult-to-treat diseases.