“In the context of clinical applications, RNAi-based reagents have the potential to target genes whose protein products could not be targeted by conventional drugs.”

There is a lot of interest in RNA interference (RNAi) from both a basic science and a clinical perspective in both academia and the biotech and pharmaceutical industries. This is because RNAi reagents are used as experimental tools for the analysis of gene function and they also have potential as therapeutics. As a result, there is a wide target audience for a review paper such as this that summarizes progress in this field.

RNAi exploits an evolutionary conserved endogenous biological pathway which was first identified in plants and lower organisms and is now being exploited in mammalian systems. This discovery was recognized by the award of the 2006 Nobel Prize for Physiology or Medicine to its discoverers Andrew Z. Fire of the Stanford University School of Medicine and Craig C. Mello of the University of Massachusetts Medical School.

In this approach, double-stranded RNA (dsRNA) reagents are used to bind to and promote the degradation of target RNAs, resulting in knockdown of the expression of specific genes. As a result, it can be used as a research tool to study gene function and, potentially, as a way of silencing genes that promote disease. The first clinical trials of an RNAi reagent to treat a common form of blindness are currently in progress.

With the completion of the sequencing of the human genome, a key goal in recent years has been to convert this information into new, more effective, and safer drugs. However, actually achieving this is not a trivial task. Only a portion of the estimated 25,000 genes in the human genome will be therapeutically relevant, dependent on having a role in the disease process and having an activity that can be modulated therapeutically.

A major bottleneck in the drug discovery process, therefore, is identifying genes that are relevant to a given disease (target identification) and showing that interfering with the action of the protein products of these genes through using drugs, is likely to have a therapeutic effect (target validation).

RNAi can be used to simulate the effects of target inhibition by drugs in cellular and animal models of the disease by knocking down the expression of putative drug targets and so providing valuable information on their validity. In the context of clinical applications, RNAi-based reagents have the potential to target genes whose protein products could not be targeted by conventional drugs.

So far, the pharmaceutical industry has targeted only around 500 of the protein targets encoded by the genes in the human genome, using small molecule inhibitors (conventional drugs). However, there are estimated to be approximately 3,000 targets that are "druggable," with an additional 4,500 or so other targets addressable by non-conventional approaches such as RNAi therapeutics.

It came about through my involvement in target discovery and validation in drug discovery. Also, the pharmaceutical company I work for (Novartis) is currently exploring the use of RNAi reagents as therapeutics in several disease areas. There are limitations to RNAi as it stands, but these wrinkles are being ironed out as more is learned of the biology of RNAi in mammalian systems and as improvements to the stability, delivery, and the reduction of off-target and non-specific effects are made.

RNAi has the potential to expand the pharmaceutical arsenal by targeting genes whose protein products would not be "druggable" using small molecule drug inhibitors.