PROGRESS IN ANTISENSE OLIGONUCLEOTIDE THERAPEUTIC

The past several years have seen substantial progress in the developme nt of antisense oligonucleotides as pharmacological tools and as thera peutic agents. With properly designed and executed experiments, it has been possible to demonstrate selective inhibition of gene expresssion , owing to an antisense mechanisms of action both in cell culture-base d experiments and in vivo. As the field has matured, it has also reali zed that oligonucleotides can produce a variety of effects in cell cul ture and in vivo that cannot be ascribed to an antisense mechanism of action. Nevertheless, with proper controls it has been possible to dem onstrate that the pharmacological activity of an oligonucleotide is co nsistent with an antisense mechanism of action. The pharmacokinetic pr operties of first-generation phosphorothioate oligodeoxynucleotides an d their toxicological limitations have been characterized in rodents, primates, and humans. Finally, it has been demonstrated that medicinal chemistry can improve the properties of oligonucleotides, as several modifications have been identified that have increased potency, altere d pharmacokinetic properties and potentially decreased toxicological l iabilities.