Oligonucleotide therapeutics: clothing the emperor

Oligonucleotides (ON) have been used in vitro, in vivo and clinically for the treatment viral infections, malignancies and inflammatory diseases. This review will focus on the application of ON-based therapeutics for hematological disease. The primary application of ONs has been as sequence specific inhibitors of gene expression, ie, antisense oligonucleotides (AS ON) and ribozymes. Based upon the unique expression of the Bcl-Abl neogene in CML cells, numerous studies have targeted this product with AS ONs and ribozymes. These studies demonstrate that ON targeting the breakpoint region selectively inhibit the proliferation of CML cells. Subsequent studies suggest that this effect may not be due to a true antisense effect of the ON. Other targets, which are being exploited for the treatment of hematological malignancies, include ON targeting c-myb gene, p53 and Bcl-2. All three have entered clinical trials and have been shown to be tolerated by patients. In addition to inhibition of gene expression, ON can be selected for sequence specific binding to proteins (aptamer). In particular an ON that binds to thrombin with high affinity is being explored as a potential anticoagulant. These early studies have identified limitations for first generation ON which may be solvable with newer ON chemistries and/or formulations. Although the technology is still nascent it continues to show promise.