Overview of the Nonclinical Development Strategies and Class-Effects of Oligonucleotide-Based Therapeutics

The objective of this chapter is to provide an overview of the chemical and mechanistic classes of oligonucleotide-based therapeutics (ONTs), to describe the general strategies used in developing the nonclinical safety program for this relatively new class of molecules, and to provide a general characterization of the class- and chemistry-dependent toxicity observed in species used for nonclinical safety assessment. The most well-described pharmacologic mechanisms for synthetic ONTs include the antisense targeting of specific RNA transcripts and aptameric targeting of proteins, although numerous others exist (eg, modulation of premRNA splicing, inhibition of mRNA translation, exon skipping, and modulation of noncoding RNA). In general, ONTs within each chemical class share similar physicochemical and pharmacokinetic properties (eg, length, solubility, charge-to-mass ratio, hydrophilicity, tissue distribution, metabolism, and protein binding, among others). Thus the toxicologic properties of ONTs are qualitatively similar within a chemical class, as a whole. To date, the preclinical and clinical experience gained with various classes of ONTs suggest that this relatively new therapeutic modality has a sufficient tolerability profile to support safe evaluation in numerous therapeutic indications.