Introduction to RNAi
RNAi (RNA interference) is a naturally occurring mechanism whereby short, double-stranded RNA molecules interfere with the expression of genes in living cells. It is believed that this mechanism can be harnessed to ‘silence’ or specifically block the production of disease causing proteins before they are made. This technology can potentially be used to treat human diseases by “turning-off” genes that lead to disease in the first place.
RXi Pharmaceuticals is using RNAi technology to develop RNA-derived molecules targeting disease causing genes.
The RNAi Mechanism
The human genetic code (human genome) is made of a double-stranded DNA (the double helix) that acts as an instruction manual for the production of the roughly 30,000 to 50,000 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 messenger (messenger RNA, mRNA), which then is translated into protein (see figure below). RNA interference (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 triggered by introducing a small double-stranded fragment of RNA corresponding 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 splits the double-strands apart, retaining one strand in the RISC complex. The RISC then helps this guide strand of RNA bind to and destroy its corresponding cellular mRNA target. By destroying the mRNA target the production of the protein is blocked. Thus, RNAi provides a method to potentially block the creation of the proteins that cause disease, as depicted in the following figure.
Figure - Mechanism of RNA interference within a cell
Since gene expression controls most cellular processes, the ability to inhibit gene expression provides a potentially powerful tool to treat human disease. Furthermore, since the human genome has recently been decoded, RXi believes that RNAi compounds can readily be designed to interfere with the expression of any specific gene, many of which are considered “undrugable” by alternative approaches. This capability may enable the development of new therapies for diseases that are otherwise under treated, or not treated at all.
The potential market for RNAi therapeutic drugs is substantial. RXi believes that the use of RNAi technology could lead to significant advantages over traditional drug development approaches and result in a successful new class of therapeutic compounds. Important advantages of this technology include the potential to develop new drugs for currently untreated or under-treated diseases, high specificity for targeted genes, high potency, and accelerated development of lead compounds.
RNAi is regarded as a significant scientific advancement. RNAi was selected as the “Breakthrough of the Year” in 2002 by the journal Science, and the 2006 Nobel Prize in Medicine was awarded to the co-discoverers of RNAi, including Dr. Craig Mello, an RXi founder and scientific advisory board chairman.
RXi’s scientific team and advisors have been leaders in the development of RNAi from its discovery through practical research applications, and now potentially into new therapeutic products. A timeline of these achievements is presented in the figure below.
