The RNAi Therapeutic Mechanism View image detail

Advantages of an RNAi Therapeutics Platform

Compounds operating via the RNAi mechanism have been demonstrated numerous times to specifically silence genes with the expected biological outcome not only in cultured cells ex vivo, but also in animal models of human disease. In fact, RNAi is already being widely exploited by drug developers for drug target validation purposes. It is therefore not surprising that there is growing interest in using RNAi as a therapeutic modality itself.

RNAi therapeutics target gene expression upstream of protein production

It is known that proteins are responsible for much of the physical and dynamic properties of a cell, and defects in their function or regulation contribute to - if not cause - most diseases. The majority of drugs today are therefore designed to inactive proteins; with most attempting to neutralize disease-associated proteins through direct binding without removing them.

Much of the interest in RNAi is based on the fact that the RNAi mechanism operates upstream of protein production by eliminating the mRNAs coding for such proteins. Hence, instead of trying to stop a flood by mopping up the floor, with RNAi we can stop the flood by turning off the faucet. Moreover, as each mRNA is the template for the translation of multiple proteins, comparatively low amounts of an RNAi therapeutic should be effective in ablating protein function.

Due to the sequence specificity of double-stranded RNAs used to exploit the RNAi mechanism, it is now possible to address many of the conditions where RNA and its processing play a central role. In addition, their unique mechanism of action may allow RNAi therapeutics to work synergistically with other drug and treatment regimens, for example in conjunction with chemotherapy in cancer or statins for the treatment of hypercholesterolemia.

RNAi is an endogenous biological pathway, thus allowing for the development of safe and efficacious drugs

RNAi occurs in all human cells. As with other major biotechnologies before, like recombinant proteins and monoclonal antibodies, the fact that RNAi is an endogenous biological pathway lead many to believe that it could make a particularly safe and effective therapeutic platform. Indeed, one siRNA mediates the silencing of many mRNAs as part of the catalytic RISC complex. The catalytic nature of the RNAi mechanism allows for the use of very low concentrations of siRNAs, which minimizes the risk of adverse side effects often caused by the use of large amounts of drugs.

Another major advantage that comes from harnessing an endogenous biological pathway is the ability to translate knowledge on normal function into the development of even safer and more efficacious therapeutics. Indeed, due to their central importance in many cell biological processes, an unprecedented research effort is aimed at elucidating additional RNA biology.