Phillip A. Sharp
Koch Institute for Integrated Cancer Research and Department of Biology, MIT, USA
RNA interference was discovered a little over ten years ago and subsequently was shown to be mediated by intracellular double stranded small RNAs approximately 21 nucleotides in length (siRNA). In mammals, these RNAs enter the microRNA pathway, present in all cell types, are loaded into a complex containing the critical Argonaute protein, and target its activity to cleave and cause degradation of specific complimentary mRNA. Thus, in principle with the appropriate design of the siRNA any target gene could be silenced. Over the past years, the challenge of effective delivery of the hydrophilic siRNAs to cells has been advanced to where it is now possible in a therapeutically attractive fashion to silence genes expressed in the liver of humans with a sugar-based conjugate of a chemically modified siRNA. These therapeutic agents are modular in structure, where one constituent provides a gene-specific component whose modulation of expression is beneficial, while the other agent targets and facilitates delivery to the inside of cells. This modular property greatly reduces the time required to develop therapeutics to new disease modifying genes and is an example of future developments in pharmaceuticals. Examples of these types of agents will be discussed. The activities of small RNA based agents will be set in the context of the known biology of small non-coding RNAs.