Small interfering RNA (siRNA) is a form of genetic medicine but is not regulated as gene therapy. Since its discovery in 1998, researchers worldwide have demonstrated that RNAi is a potent methodology for reducing the expression of genes in vitro and in vivo. The US researchers who discovered it were awarded the Nobel Prize for Medicine in 2006. RNAi has the potential to be able to knock down or silence any gene which is over-expressed in disease . As a result its potential to be used as the basis of innovative therapeutics has been widely anticipated, although to date no RNAi therapeutic products have been approved for sale in the Western world. Genecon’s Britena (an siRNA-based product for skin whitening) is currently being sold in China.
The mechanism of action of RNAi involves the introduction of small interfering RNA, or siRNA, into a cell. siRNA is a dsRNA molecule (typically 19-23 nucleotides long). The siRNA’s sequence is constructed to match a short region of the target gene. The siRNA is processed by the cell’s own enzymes to destroy the target gene’s messenger RNA, or mRNA, thus preventing the disease-causing gene from being expressed. Other approaches to RNAi include DNA-directed RNAi (ddRNAi) that is used to produce dsRNA inside the cell as short hairpin RNA (shRNA), which is cleaved into siRNA by the action of Dicer, a specific type of RNAse III. MicroRNAs are derived by processing of short hairpins that can inhibit mRNAs. Expressed interfering RNA (eiRNA) is used to express dsRNA intracellularly from DNA plasmids .
RNAi can be rationally designed to block the expression of any target gene, including genes for which traditional small molecule inhibitors cannot be found. RNAi mechanisms and technologies are being extensively explored in biological applications in order to develop appropriate therapies. Several RNAi-based therapeutic candidates are currently in clinical trials, including in Phase III trials . Successful clinical trials of RNAi candidates are needed before these molecules can reach the market as therapeutics for treating serious life-threatening disorders. Areas of therapeutic applications include virus infections, cancer, genetic disorders and neurological diseases.
In order to be effective as therapeutics, efficient and specific delivery of siRNA to relevant cells and tissues is needed. This has been, and remains, an on-going challenge for the field. Delivery challenges that must be overcome include degradation of dsRNAs, off-target effects, stability issues and other factors. Thus, developers of RNAi therapeutics are focusing on producing robust, flexible and effective delivery technologies that can be customised for diverse targets with flexible modes of administration (subcutaneously, intravenous, etc.). Most of those used for siRNA are lipid/polymer/nanoparticle-based delivery systems.
The potential of RNAi has led to several companies being formed worldwide to develop novel therapeutics. Many have candidates in late-stage clinical trials including Arrowhead Research Corp., Alnylam Pharmaceuticals Inc., Arbutus Biopharma Corp., Quark Pharmaceuticals Inc., and Silenseed Ltd. Many of these therapeutics companies also develop RNAi delivery vectors and systems.
 The RNAi Web - Resources on RNA interference and microRNAs
 Alnylam achieves breakthrough RNAi success as PhIII patisiran study hits all goals, shares soar
 Li T, Wu M, Zhu YY, Chen J, Chen L. Development of RNA interference-based therapeutics and application of multi-target small interfering RNAs. Nucleic Acid Ther. 2014;24:302-312