Synthetic oligonucleotides: The development of antisense therapeutics

Antisense therapeutics using synthetic oligodeoxynucleotides (ODNs) are cur rently being evaluated in clinical trials for cancer, inflammation, and vir al diseases. These macromolecules afford a unique opportunity to treat dise ase at the molecular level. The specificity of these compounds is derived f rom the genetic code and Watson-Crick base pairing, utilizing an antisense paradigm for the inhibition of translation and the regulation of protein ex pression. Currently, most antisense ODNs in development contain a phosphoro thioate (P=S) backbone. Additional modifications primarily involve the 2' p osition on the ribose or modification of the nucleotide linkages of the bac kbone. To date, no toxicities in animal models appear related to inhibition of the pharmacologic target, rather toxicities induced by P=S ODNs appear similar and are independent of pharmacologic target. In general, toxicities correlate well with pharmacokinetic or tissue distribution parameters. In primates, the primary acute effects are associated with complement activati on and the systemic effects associated with accumulation of high concentrat ions of P=S ODNs in the kidneys. In rodents, the primary effect is an immun e stimulation characterized by splenomegaly, lymphoid hyperplasia, and mono nuclear cell infiltrates in multiple tissues. At extraordinarily high doses (15-50 times the targeted clinical doses), hepatocellular and renal tubula r degeneration are evident in rodents. Second generation antisense compound s, new routes of administration, and new formulations appear to broaden and improve the application of antisense technology.