On future's doorstep: RNA interference and the pharmacopeia of tomorrow

Abstract

Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current generation of targeted therapies, and in a small but growing number of patients, resistance to initially successful treatments evolves. This Review Series on the medicinal promise of posttranscriptional gene silencing with small interfering RNA and other molecules capable of inducing RNA interference (RNAi) is motivated by the hypothesis that effectors of RNAi can be developed into effective drugs for treating malignancies as well as many other types of disease. As this Review Series points out, there is still much to do, but many in the field now hope that the time has finally arrived when "antisense" therapies will finally come of age and fulfill their promise as the magic bullets of the 21st century.

Figure 1. The RNAi pathway.

The enzyme Dicer processes dsRNA molecules into shorter dsRNA fragments, typically 21–23 bp in length, termed siRNA. The siRNA duplexes are incorporated into the RISC, where the sense strand is degraded, leaving the antisense “guide” strand free to hybridize with its complementary sequence in the mRNA. This initiates mRNA strand cleavage by an enzyme native to RISC.