Chandra Vargeese, PhDSVP, Head of Drug Discovery at WAVE Life Sciences
Wave Life Sciences has developed PRISMTM, our proprietary discovery and drug development platform, which enables us to generate stereopure oligonucleotides to target genetically defined diseases. Stereopure oligonucleotides are those in which the chiral configuration of backbone-modified oligonucleotides is precisely controlled at each linkage. We have demonstrated that, in addition to sequence and other chemical modifications, control over backbone stereochemistry provides an important new dimension for the optimization of oligonucleotide therapeutics. PRISM combines our unique ability to construct stereopure oligonucleotides with a growing knowledge of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacologic properties. Using PRISM, we optimize stereopure oligonucleotides to meet pre-defined product profiles. We illustrate by example that optimized, stereopure oligonucleotides exhibit the desired activity across multiple modalities, for example those that depend on RNase H and those that promote exon skipping. We demonstrate that the potencies of stereopure oligonucleotides in cellular models under free-uptake conditions help predict their potencies in animal models in multiple tissues. We also show that stereopure oligonucleotides can potently engage and durably impact the expression of their targets in animal models.