Key Milestones in the Development of RNAi Therapeutics View image detail

RNAi opens up many new targets for drug development

Drug development has traditionally focused on the so called “druggable genome.” This includes genes coding for extracellular proteins, cell-surface receptors, and enzymes with well-defined catalytic sites which are physically accessible and have structures that allows them to be bound with sufficient strength and specificity. As these represent only a small subset of our genome, the identification of suitable druggable targets has become a major bottleneck in the development of new, innovative drugs.

RNAi is different. As dsRNAs can be designed to target essentially any protein-coding mRNA independent of protein structure and localization, it opens up the many genetically validated, yet previously deemed “undruggable targets” for RNAi-based drug development. One example is Huntington’s disease where the genetic cause has long been known, but efforts to neutralize the harmful effects of the mutated huntingtin protein have failed. By being able to suppress huntingtin expression, drugs based on RNAi promise to be the first modality that may slow or even prevent the progression of this devastating disease.

To be sure, the discovery of RNAi comes at a good time. Less than five years after the sequencing of the human genome, genetic research is booming with a record number of potential drug targets being uncovered, all of which can theoretically be addressed through RNAi.

An example of one such gene that has consequently attracted interest for the treatment of hypercholesterolemia is PCSK9, a gene that encodes for a protein involved in the metabolism of LDL-cholesterol. Genetic studies have shown that individuals who lack this protein are far less likely to develop cardiovascular disease without any overt side effect, while those that have a genetic disposition that causes an increase in PCSK9 production are at an elevated risk of cardiac disease.