Antisense oligonucleotides: Rational drug design for genetic pharmacology

During the seventeen years since the Zamecnik and Stephenson report [77] of antisense oligonucleotide activity, the literature describing efficacy in cell culture and animals has mushroomed. The technology has become far more sophisticated with the application of new methods for rapid oligonucleotide synthesis; for chemical modifications to improve pharmacological properties of the oligonucleotides; for detailed studies at the level of transcription and translation to define the antisense mechanisms of activity; for preclinical pharmacokinetic, pharmacology, and toxicology studies; for detailed and sensitive analysis to define oligonucleotide purity and metabolism; and for large scale synthesis to fill the needs of multiple animal studies and the human clinical studies. Clearly the application of antisense oligonucleotides has helped to validate gene targets for therapeutic intervention, and established that drug intervention can occur at the level of translation. This approach, like that of gene therapy, has heralded the new field of genetic pharmacology; and, like gene therapy, antisense oligonucleotide therapy is now being evaluated in an expanding array of clinical protocols. The focus of this review is to alert those concerned with pharmaceutical drug development to the fact that this technology has momentum and opens versatile avenues to disease control and prevention. The field is still in it infancy and many issues are yet to be addressed. However, by the nature of the opportunity to alter the expression of many genes heretofore unapproachable by traditional methods, antisense oligonucleotide therapy should have a major impact on drug development.