Preclinical Safety Assessment of Therapeutic Oligonucleotides

During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated into successful clinical applications. Depending on the specific OND mechanism, chemistry, and design, the DMPK and toxicity properties can vary significantly between different OND classes and delivery approaches, the latter including lipid formulations or conjugation approaches to enhance productive OND uptake. At the same time, with the only difference between compounds being the nucleobase sequence, ONDs with same mechanism of action, chemistry, and design show relatively consistent behavior, allowing certain extrapolations between compounds within an OND class. This chapter provides a summary of the most common toxicities, the improved mechanistic understanding and the safety assessment activities performed for therapeutic oligonucleotides during the drug discovery and development process. Several of the considerations described for therapeutic applications should also be of value for the scientists mainly using oligonucleotides as research tools to explore various biological processes.