Oligonucleotide, or nucleic acid-based therapeutics hold great promise and are being developed across a wide range of modalities – from antisense oligonucleotides (AON) and small interfering RNA (siRNA) molecules that make up the majority of the clinical pipeline today, to microRNA inhibitors (antiMir’s) and activators (ProMir’s), aptamers, and most recently, CRISPR-based drugs for gene editing as well as full-length messenger RNA transcripts (mRNA) for gene therapy and vaccine applications.
To enhance their stability in-vivo, nucleic acid-based therapeutics often incorporate chemically-modified nucleotides, and increasingly are being conjugated to other chemical moieties (GalNac, Cholesterol, Peptides, Antibodies, Fatty Acids, etc.), or are being encapsulated within lipid nano-particles or viral vectors (e.g.: Adeno-Associated Virus (AAV) particles) in order to achieve targeted delivery to specific cells within the body.
Like all other biologics, the biophysical characteristics and purity of these molecules must be precisely understood and controlled to meet regulatory requirements. Most oligonucleotides are produced via an automated solid-phase synthesis process, which invariably results in failure sequences and other process-related impurities that need to be separated to the greatest extent possible, and impurities as low as 0.005% of the full-length product (FLP) that co-elute or closely elute with the FLP must also be identified and fully characterized to ensure the safety and efficacy of the final drug formulation.
