Antisense Oligonucleotide Therapies: Are They the “Magic Bullets”?

The recent commencement of clinical trials using antisense oligonucleotide therapy for leukemias and viral infections has heralded a new era in drug therapy [1-4]. Antisense oligonucleotides are short chains of nucleic acids, usually 10 to 30 residues long, and are intermediate in size compared with smaller-size conventional drugs, such as β-blockers, and the much larger therapeutic polypeptides, such as growth factors or monoclonal antibodies. Conventional drugs generally affect cellular functions by interacting with proteins.

Despite substantial advances in the understanding of molecular interactions between proteins and their ligands, it is difficult to design drugs based on the amino acid sequences of proteins because ligand-protein interactions involve multiple chemical bonds. In contrast, regardless of the gene function, antisense oligonucleotides can be designed based on the nucleotide sequences of the targeted genes and on the concept of base-pairing of nucleic acids, which is governed by one set of physical-chemical principles. The mechanism of recognition between two nucleic acid strands is through hydrogen bonding of the four nucleotide bases that make up the genetic alphabet. A properly designed antisense oligonucleotide, with a specified complementary base sequence, binds selectively to a targeted region of the messenger RNA (that is, the sense strand) and prevents RNA translation into protein. The specificity and stability of an oligonucleotide also depend on its length. The therapeutic aim is to inhibit genes that are vital to the survival or the function of the target cell or organism. Theoretically, these synthetic oligonucleotides can be more specific than most conventional drugs and can inhibit mutated genes or foreign …