Progress in antisense oligonucleotide therapeutics.

The past several years have seen substantial progress in the development of antisense oligonucleotides as pharmacological tools and as therapeutic agents. With properly designed and executed experiments, it has been possible to demonstrate selective inhibition of gene expression, owing to an antisense mechanisms of action both in cell culture-based experiments and in vivo. As the field has matured, it has also realized that oligonucleotides can produce a variety of effects in cell culture and in vivo that cannot be ascribed to an antisense mechanism of action. Nevertheless, with proper controls it has been possible to demonstrate that the pharmacological activity of an oligonucleotide is consistent with an antisense mechanism of action. The pharmacokinetic properties of first-generation phosphorothioate oligodeoxynucleotides and 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, altered pharmacokinetic properties and potentially decreased toxicological liabilities.