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RNA Interference (RNAi): From Drugs to GMOs

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RNA Interference (RNAi): From Drugs to GMOs
Darryl Leja, NHGRI

What Is RNA Interference

Genes, of course, are just particular spans of the A, T, C, and G nucleotides that make up DNA, much like words are specific spans of certain letters in a book. However, unlike words, the genetic information in a DNA sequence has to be "read" through a chemical process to make the specific protein the gene encodes. Living organisms are made largely of proteins, and proteins run almost all the chemical reactions that keep living things alive.

Ribonucleic acid (RNA), specifically messenger RNA (mRNA), is used to carry a gene's information to the part of a cell that reads (or translates) the gene sequence to make a protein. In 1998, Andrew Fire and Craig Mello discovered that some plants and animals use small pieces of RNA—called short interfering RNA (siRNA)—to block, or intefere with, mRNA from certain genes from making proteins. Drs. Fire and Mello won a Nobel Prize for their groundbreaking work on RNA interference (RNAi) in 2006.

Scientists rapidly realized the potential of using this RNA interference (RNAi) approach to shut down almost any gene. They could easily design and make a short interfering RNA (siRNA) to target whatever gene they wanted to turn off. As a result the new technology quickly became a popular tool to identify the functions of genes. The concept is simple. Researchers get a sense of what a gene does by blocking it using RNA interference and seeing what the resulting effect is on a cell or organism.

RNAi Therapeutics

Beyond basic research, RNAi also had some obvious potential as a drug. Most drugs are chemicals that block the action of some protein involved in a disease. However, if you can stop disease-associated protein from even being made in the first place, then that might even be better. Not only that, but, many proteins are not so easy to block even though researchers might know they are involved in some disease. Since RNAi provides a way to turn off virtually any gene, it provides an approach to interfere with genes producing these difficult-to-drug proteins, so it provides a way to target so called undruggable genes.

As a result of these unique advantages of RNAi, many drug companies, such as Pfizer, GSK, and Merck set-up program for RNAi-based drug development. As is often the case, however, things are not as easy as they first appear and a number of challenges made developing RNAi-based drugs more difficult than initially anticipated. Some programs were shut down as practical difficulties mounted in developing drugs based on RNAi technology. However, a few companies, many which were focused only on RNAi technology such as Alnylam, Tekmira, RXi Pharmaceuticals, and Dicerna have persevered with some success.

For example, just in the past year, Isis Pharmaceuticals saw Kynamro approved for treatment of a genetic form of hypercholesterolemia. While not exactly RNAi, Kynamro is a similar sort of technology and pioneers the way for RNAi-based drug approvals.

Denmark based Santorias is also on the verge of getting approval for miravirsen to treat hepatitis C. Miravirsen is a true RNAi-based drug but it does not actually block production of a protein. The gene miravirsen blocks simply makes RNA that directly modulates the expression of other genes. In fact, many of the RNAi drugs that seem to have potential target these sort of non-protein-coding genes, rather than ones that make proteins.

RNAi in GMO Crops

In addition to the use of RNAi in research to assess gene function, and for the development of a new class of drugs, however, another commercial use of RNAi has emerged. In a recent article in Science, Kai Kupferschimdt discusses how RNAi has been engineered into plants to make them resistant to pests and pathogens.

In much the same way drugs inhibit specific proteins, pesticides also target and block the action of particular proteins. Of course, in the case of pesticides, the idea is to block a protein that is essential for the pest to survive. For example, Ortho's Bug B Gon contains bifenthrin as the active ingredient. This chemical binds to the protein in nerve cells that regulates sodium ions so it blocks the ability of these cells to send nerve impulses, and so, paralyzes bugs. The problem with bifenthrin, and many of similar chemicals in pesticides, however, is that they target most types of bugs, even beneficial ones. Also, at higher levels, they can be toxic to other animals including mammals.

For many years, now, genetic engineering has provided a way to more safely target specific pests. For example Monsanto markets several corn varieties that have been genetically modified to include a gene from a soil bacteria—Bacillus thuringiensis (Bt). The Bt gene in the corn produces the Cry protein that is toxic to worms and insect larvae that each too much of it. This approach better targets just the pests affecting the corn and minimizes the need to use broad-acting pesticides.

However, RNAi offers yet another level of specificity and safety since it can be designed to target just one particular gene only present a certain type of pest. For example, Monsanto has now developed a genetically modified corn variety that expresses an siRNA against the Western Corn Worm's Snf7 gene. Interference of this gene kills the larvae of this worm. This corn, then, is specifically toxic to this particular pest, but other organisms with slightly different versions of the Snf7 gene should be unaffected.

There are no genetically modified crops yet on the market yet that use RNAi technology as a pesticide. However, it is clear there is significant interest in this approach from agricultural companies. Syngenta acquired Devgen in September 2012 primarily to access its RNAi-based pest control program, while, around the same time, Monsanto licensed rights to Alnylam's RNAi patents.

(Published: August 27, 2013)

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