RNAi and chimeric dimers – our best hope for future therapeutics

There is a revolution in progress in biotechnology. We are always being attacked by other organisms and have a number of defense mechanisms at our disposal. The most obvious is our skin. But we have other biochemical tricks including our immune response composed of both a cellular seek and destroy army and a macromolecular antibody defense force. Recently, a new mechanism has been discovered. It is amazing, as we have spent billons of dollars on trying to understand the components and capabilities of our bodies but missed this one until almost the end of the millennium.

Some viruses are composed of double stranded RNA. Double stranded RNA is unique as we are loaded with double stranded DNA and single stranded RNA but not much in the way of double stranded RNA. So a mechanism that could detect and destroy double stranded RNA would not hurt us but would protect us from this class of viruses. Such a mechanism was identified in plants in the 1980s but due to technical difficulties was not confirmed in mammals until 1998. When double stranded RNA enters the cell an nuclease called dicer cuts it up into 21 nucleotide lengths. These oligonucleotides then complex with a system that chops up any RNA with that sequence which effectively keeps the virus from replicating and we are saved. Using the tools of modern biochemistry we can make any RNA at will so it is possible to use this system to turn of the expression of any gene we want. One makes a 21 or so nucleotide strip of double stranded RNA that is unique to the gene of interest and the system will turn off that gene. If one has a nucleotide sequence from sequencing some genome like ours that is for a gene whose function is unknown; one can make the appropriate double stranded RNA and turn off the gene to see what happens. One can also make double stranded RNA that will turn off the expression of critical genes for other viruses such as HIV even if the virus does not itself contain double stranded RNA. The key is that one procedure can do all these things. Instead of looking for a different drug to protect against each type of virus one can use easily made double stranded RNA made by a common procedure to turn off anything.

Things are not really as simple as this sounds but they are certainly much better than having a different chemical to treat each disease. Here, slight modifications of a single chemical can be used to treat anything from HIV to cancer. However, one problem is delivery. How do you get it into the cell and especially into the correct cell. An article by SONGCHUAN GUO,1 NUSKA TSCHAMMER,2 SULMA MOHAMMED1 and PEIXUAN GUO1,* HUMAN GENE THERAPY 16:1097–1109 (September 2005) describes an ingenious technique. They have constructed a molecule composed of two modified double stranded virus units that each contain the 21 base pair sequence required for the RNAi process. To one of these units they add a molecule that will bind to the surface of certain types of cells. This surface binding helps the double stranded RNA select the desired cell type and to enter the target cell. The beauty of this technique is that the ”turn it off signal” will not be added to all cell types and that its uptake in the desired cell type will be enhanced. So if you want to turn off a gene in stomach tissue but not muscle tissue it should be possible. The beauty of this technique is that a single process can turn off practically anything. All the drugs would be made the same way containing approximately the same components. This should be especially useful for combating influenza as the virus would not have to be grown in chicken eggs and a switch from one strain to another would be straightforward. There is hope for the future.