PERSPECTIVES IN ANTISENSE THERAPEUTICS

Modulation of gene expression using oligonucleotides (oligos) is curre ntly an area of intense activity, both from therapeutic, as well as re search perspectives. To develop oligos as therapeutic agents, in addit ion to demonstrable biological activity, in vico metabolic stability, tissue disposition and pharmacokinetics are important considerations. Oligodeoxynucleoside phosphorothioates are the first-generation antise nse analogs that have been studied extensively, and are in clinical tr ials against a number of disease indications. In an effort to improve the antisense properties of these compounds, mixed-backbone oligos inc orporating different chemical modifications have been synthesized and evaluated for antisense activity, The present review will provide an o verview of the pharmacokinetics and toxicology following intravenous, intraperitoneal, subcutaneous and oral administration of mixed-backbon e oligos as second-generation antisense therapeutics. (C) 1997 Elsevie r Science Inc.