Advantages of RNAi

Small interfering RNA — or "siRNA", the molecules that mediate RNAi — can be synthesized chemically in the lab and then introduced into cells to achieve targeted gene silencing. This opens up enormous possibilities for using siRNAs as potential drug candidates. Key features of siRNAs as RNAi therapeutics include the following:

The ability to harness a natural pathway

RNAi is a natural pathway involved in regulation of gene expression in all mammalian cells. This natural pathway can be harnessed to create a new class of innovative medicines. Since this pathway is catalytic, RNAi therapeutics can be readily designed to be potent and highly selective.

The ability to target virtually any protein

A key limitation of traditional medicines is that they can only target certain classes of proteins. Targets for currently marketed small-molecule drugs include G-protein-coupled receptors, ion channels, enzymes and nuclear hormone receptors. Despite much effort, attempts to find small-molecule drugs targeting other classes of proteins have been largely unsuccessful. The range of targets for protein drugs, such as monoclonal antibodies, is also limited mainly to cell-surface receptors or to circulating proteins. In contrast, given the sequenced human genome, it is possible to design siRNAs for any gene and its mRNA transcript. This capability opens up the possibility of developing siRNA drugs for proteins that do not fit into the so-called "druggable target classes." Further, certain diseases may be caused by the mutation in a single allele, in which case a specific siRNA can target the disease-causing mutation leaving the normal allele intact. Therefore, RNAi therapeutics could be designed targeting any gene in the genome involved in the cause or pathway of disease.

Acting "upstream" of today's medicines

With RNAi therapeutics, it is possible to block the production of disease-causing proteins before they are made. This has the potential to provide greater efficacy in disease control and intervention. The RNAi approach is akin to "stopping a flood by turning off the faucet" as compared with today's medicines that simply "mop up the floor."

Simplified discovery of drug candidates

Identification of appropriate drug candidates can be more straightforward using siRNAs. In contrast to the extensive lead optimization steps required in small molecule and protein drug discovery, RNAi drug candidates can be identified using bioinformatic tools to select sequences complementary to the target mRNA. The process of choosing an RNAi-based drug candidate then involves the synthesis and testing of siRNAs. Further, and quite importantly siRNA lead candidates can be designed to be active across a broad range of species, greatly simplifying the translation of animal model data to human disease applications. With simple chemical modifications, siRNAs can be made to be stable and also to avoid unwanted activation of immune cells.