Toxicological evaluation of oligonucleotide therapeutics.

In this brief review, guidance is provided for the safety evaluation of phosphorothioate oligonucleotides. This novel class of compounds has proved to be challenging for the preclinical development scientist, as systemic exposure can evoke sometimes dramatic responses, in terms of general functional parameters, laboratory data (hematology, clinical chemistry) and histopathology of target organs. The polyanionic profile of these compounds is discussed vis-à-vis historical data for related structures. Dose-related responses in various laboratory test species are described. The liver, kidneys and immune system are major target organs, and an experimental perspective is provided for understanding each of these in determining a safe starting dose for clinical trials with novel compounds.