Wave Life Sciences designs stereopure oligonucleotides using their PRISM platform, focusing on unique disease targets through innovative approaches. In her presentation, Brooke Koshel emphasised how Wave's PRISM platform centres the relationship between oligonucleotide sequence, stereochemistry, and chemistries to target unique diseases.
At Wave, they take an innovative approach: back in 2022, the company introduced PN chemistry to the literature. This, along with PS linkages make up Wave’s chiral backbone chemistries. Instead of using a predefined toolkit, Wave uses unique chemistries like PN linkages to improve PK and efficacy due to their effect of decreasing net charge.
Wave employs advanced analytical methods to study their stereopure oligonucleotides, ensuring defined stereochemistry and single molecule identity. Key quality attributes for stereopure oligonucleotides include identity, selectivity, stability, and stereopurity, confirmed through various methods like LC-MS sequencing and enzymatic digestion.
Koshel outlines how Wave uses stereospecific enzymes for enzymatic digestion to confirm sequence identity and stereochemistry, analysing digested fragments with high-resolution mass spectrometry. Dimer and shortmer modelling are also used to assess stereoselectivity and confirm data, requiring method optimization for accurate separation. Finally, Stability of stereopure oligonucleotides is assessed to ensure no interconversion between stereoisomers, using dimer pairs and anion exchange methods.
Koshel concludes by highlighting how Wave's PRISM platform enables the development of stereopure oligonucleotides with high quality, leveraging unique analytical methods and innovative approaches.