As a result, Alnylam and others are currently developing drugs aimed at reducing PCSK9 mRNA levels in order to treat hypercholesterolemia. Such a rapid progression from genetic validation to clinical-stage drug targeting is quite unusual in the context of traditional drug development. The development of PCSK9-targeting small molecules for example would likely have been much more time-consuming and suffered from insufficient target specificity given the presence of a number of structurally very similar, yet functionally distinct proteins.

Knowing all the human genes as a result of the Human Genome Project further helps in designing siRNA sequences with optimized target specificities. As many investigational drugs fail due to off-target toxicities, RNAi, due to its high target selectivity, offers the promise for a safer class of human therapeutics with reduced development risk.

RNAi is a robust platform for drug development

In sharp contrast to small molecules which have very diverse chemical properties and therefore pharmacological challenges that are very specific to each drug candidate, the chemical uniformity of siRNAs as a class means that the know-how from the development of one siRNA drug candidate can be largely applied across the whole platform. This may include medicinal chemistries to enhance the pharmacology of siRNAs, maximize target efficacy and specificity, manufacturing expertise, and ultimately allows for the rapid expansion to generate RNAi-based drugs to multiple distinct targets.

The identification of siRNA-based drug candidates to a given target is particularly rapid and reproducible. All that is needed is the sequence information of the gene of interest, readily available from the Human Genome Project, and a number of siRNA candidates can then be rapidly designed based on simple sequence complementarity rules and chemically synthesized for initial testing. All this should facilitate fast and economical drug development attractive not only to major pharmaceutical and biotech companies, but also public agencies concerned about preparedness in the face of potential biological threats such as Ebola and pandemic flu.