Nucleic acid drugs in the clinic

Abstract

As a number of diseases are caused, or accompanied, by abnormal gene expression an understandable temptation to modulate the expression of the abnormal gene’s mRNA or protein to restore proper functioning of the cellular machinery has arisen. In addition, as many traditional therapeutic interventions are accompanied by serious side effects (because the cell killing they cause is not specific to the tumors they are intended to treat) there is a natural desire to design drugs with a very targeted mode of action so as to minimize these side effects. The motivation for developing tumor-specific therapies has now become so strong and so pervasive that we are now truly entering an era of targeted therapeutics. One of the major breakthroughs in the field of targeted therapies, and an example that many are hoping to duplicate, has been the development and successful introduction into the clinic of the first small-molecule inhibitor of the bcr-abl tyrosine kinase – imatinib. Indeed, the spectacular success of imatinib has rapidly led to the development of second-generation inhibitors, which are now either approved themselves or are in advanced clinical trials. Monoclonal antibodies have also found their way to the bedside and are being used widely to treat malignant and non-malignant diseases. In the present treatment climate, dominated as it is by small-molecule drugs and antibodies, one could wonder whether alternative approaches, such as RNA or gene-targeted nucleic acid-based drugs, are still needed. For reasons discussed in the body of this review, many colleagues believe that there is still a place for nucleic acid-based therapeutics. Here, the reason for believing that this is true is reviewed in the context of nucleic acid drug development and the early clinical experience with these new medicines.