About RNAi

RNAi (RNA interference) is a revolution in biology – a breakthrough in understanding how genes are turned on and off in cells – and, represents a completely new approach to drug discovery and development.  The importance of its discovery was recognized by the award of the 2006 Nobel Prize for Physiology or Medicine, and RNAi has been heralded as “a major scientific breakthrough that happens once every decade or so.”  It is widely considered one of the most promising and rapidly advancing frontiers in biology and drug development today.

RNAi is a natural mechanism of gene silencing that occurs in organisms ranging from plants to mammals.  The genetic material, DNA, contains genes that provide cells with the instructions for making specific proteins, which are essential for the existence of the organism, but could also be involved in disease.

Proteins are made from DNA through a number of steps, including transcription from DNA to messenger RNA (mRNA) and translation of mRNA to protein. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNA, thereby preventing disease-causing proteins from being made.  Because siRNA molecules target mRNA and not DNA, the effects of RNAi are not permanent. Based on their mechanism of action, we believe RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.  RNAi therapeutics have been demonstrated to specifically silence genes in animal models of human disease and as well as in several human clinical studies.

As with other major biological discoveries, such as recombinant DNA and monoclonal antibodies, the fact that RNAi is a natural biological pathway lead many to believe that it could become a particularly safe and effective therapeutic platform.  RNAi is also widely exploited by researchers and drug developers for biological research and drug target validation.  It is therefore not surprising that there is a great deal of interest in using RNAi as a therapeutic modality itself.

The majority of drugs today, such as small molecules and monoclonal antibodies, are designed to inactivate proteins by directly binding, while not eliminating them.  Much of the interest in RNAi is based on the fact that the RNAi mechanism operates upstream of protein production by silencing the mRNA that codes for such proteins, thereby preventing the disease-causing proteins from being made in the first place.  By way of analogy, 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.”

While a natural process, an important advantage of RNAi as a therapeutic modality is that the siRNA can be chemically synthesized and then introduced into cells to achieve targeted gene silencing. Key features of an RNAi therapeutics approach 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. As a result, RNAi therapeutics can be readily designed to be potent and highly selective.

A catalytic mechanism.


RISC (RNA-Induced Silencing Complex), the enzymatic complex that mediates mRNA silencing by RNAi, requires only a single siRNA molecule to cleave a large number of target mRNAs.  In other words, the actions of an siRNA are catalytic.  We believe this gives RNAi therapeutics an advantage over other oligonucleotide-based approaches, like antisense therapeutics, that are not catalytic (they require a stoichiometric one-to-one ratio of drug molecule to target mRNA); as a result, much higher levels of antisense drugs are needed to achieve mRNA silencing.

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 to small molecules and antibodies, 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 one copy of the genetic material (a single allele), in which case a specific siRNA can target the disease-causing mutation leaving the normal allele intact. Therefore, RNAi therapeutics can 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 represents an important advantage to drugs like monoclonal antibodies since many circulating proteins are expressed at very high levels that make it difficult for enough antibody to be administered to “sop up” all the circulating protein. This is often the case with disease proteins that show a wide variation of blood levels in patients. With RNAi, we believe it is possible to achieve a consistent and tunable level of disease protein knockdown regardless of their circulating blood levels. This could have the potential to provide greater efficacy in disease control and intervention. Again, by way of analogy, 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. In addition, certain chemical modifications can be applied to confer “drug-like properties” to siRNAs, making them stable when administered into the bloodstream. Finally, approaches for delivery of RNAi therapeutics have now been engineered to enable a consistent level of target gene silencing in specific organs, such as genes expressed in the liver. There is also a highly correlated level of target knockdown observed in animal studies as compared with results in human clinical trials, ensuring what we believe to be a highly reliable translation of RNAi therapeutics from pre-clinical research into clinical studies. For these reasons, we believe RNAi therapeutics represent a highly modular and reproducible approach for drug discovery and development.