Preclinical Development of Antisense Therapeutics

Phosphorothioate oligodeoxynucleotides appear to be an important new class of human therapeutic agents and are the first compounds shown to have the properties required of antisense drugs. They have well-demonstrated antisense modes of drug action, are stable in vitro and have very acceptable half-lives in vivo. When administered by injection, phosphorothioate oligodeoxynucleotides distribute rapidly to tissues and show excellent pharmacokinetics. To date, they have exhibited mild and manageable toxicities at projected and demonstrated therapeutic doses. Phosphorothioate oligodeoxynucleotides are readily taken up by cells in vivo without need for added uptake enhancers. At lengths of 20–21 nucleotides or less, they exhibit messenger RNA (mRNA) affinities sufficient to inhibit gene expression at doses which, in turn, can provide good therapeutic indices and acceptable cost to the patient.