Biocatalytic Approaches to Nucleic Acid Therapeutics Manufacturing
Therapeutic oligonucleotides bind to mRNA to modulate the production of disease related proteins and have emerged as a new drug modality for the treatment of a range of disease areas including genetic disorders and viral infections. Until recently, approved therapeutics were limited to the treatment of rare diseases, however in 2020 Inclisiran was approved for the treatment of atherosclerotic cardiovascular disease, which affects approximately 30 million people in the USA alone. This emergence of therapeutic oligonucleotides for common diseases now creates a significant manufacturing challenge as existing methods of chemical synthesis, which rely on iterative coupling, capping, oxidation and deprotection to achieve stepwise extension of sequences immobilized on solid supports, are not suitable for large scale applications.
This talk will describe a transformative biocatalytic approach to efficiently produce oligonucleotides in a single operation, where polymerases and endonucleases work in synergy to amplify complementary sequences embedded within catalytic self-priming templates. This approach uses unprotected building blocks, aqueous conditions and can be used to produce diverse oligonucleotide sequences containing a range of pharmaceutically relevant modifications. Our methodology is showcased through the synthesis of a range of clinically relevant molecules.