RNAi is a naturally occurring phenomenon by which short double-stranded RNAs interfere with the expression of targeted genes. The development of therapeutics based on RNAi technology takes advantage of this phenomenon and potentially allows us to reduce the expression of particular genes within living cells. The discovery of RNAi is regarded as a significant advancement in the scientific community, as evidenced the selection of RNAi as the “Breakthrough of the Year” in 2002 by the journal Science and by the 2006 Nobel Prize in Medicine being awarded to the co-discoverers of RNAi, including Dr. Craig Mello, a founder of RXi. RNAi offers a novel approach to the drug development process because RNAi compounds can potentially be designed to target any one of the thousands of human genes, many of which are undruggable by other modalities.
The RNAi Mechanism
The human genome is made of double-stranded DNA (the double helix) that acts as an instruction manual for approximately 21,000 human proteins. Proteins are important molecules that allow cells and organisms to live and function. With rare exceptions, each cell in the human body has the entire complement of genes. However, only a subset of these genes directs the production of proteins in any particular cell type. For example, a muscle cell produces muscle-specific protein, whereas a skin cell does not. In order for a gene to guide the production of a protein, it must first be copied into a single-stranded chemical messenger (messenger RNA or mRNA), which is then translated into protein. Abnormal expression of certain genes (too much or too little) can result in disease, as can expression of an abnormal protein from a gene with a mutation.
RNAi is a naturally occurring process by which a particular mRNA can be destroyed before it is translated into protein. The process of RNAi can be artificially induced by introducing a small double-stranded fragment of RNA that corresponds to a particular mRNA into a cell. A protein complex within the cell called RISC (RNA-Induced Silencing Complex) recognizes this double-stranded RNA fragment and uses one strand, the guide strand, to bind to and destroy its corresponding cellular mRNA target. If the mRNA is destroyed in this way, the encoded protein cannot be made. Thus, RNAi provides a way to potentially block the expression of specific proteins. Since the overexpression of certain proteins plays a role in many diseases, the ability to inhibit gene expression with RNAi provides a potentially powerful tool to treat human disease.
- High specificity for targeted genes;
- High potency (low doses);
- Ability to interfere with the expression of potentially any gene;
- Accelerated generation of lead compounds; and
- Low toxicity, natural mechanism of action.