Silencing genes with RNA interference to treat human disease
Occasionally genes can have a harmful effect producing proteins that result in diseases or cancer . But what if you could simply shut down the unwanted gene? Advances in genetics have shown that if you know the harmful gene’s sequence, you can shut it down, with a gene silencing mechanism called RNA interference (RNAi) .
Figure 1 RNA interference (Nature.com 2008)
The technique, which can target any known gene, involves small segments of double stranded RNA that are added to cells where they are split into single strands of short interfering RNA (siRNA) . The siRNA, once forming a complex with specific proteins, then binds to a complimentary sequence of mRNA which it degrades, or it simply blocks the translation and production of the unwanted protein .
Gene silencing is not a new concept; in fact it is actually a naturally occurring process that is thought to have protected the genome from viruses in early organisms . It was unexpectedly discovered in plants in the early 1990s and has been followed by growing research in plants, fungi, viruses, animals and human cells indicating great promise for the technology [1;4]. But only recently have we seen the first successes in humans .
Recent studies by John DeVincenzo and the staff at the University of Tennessee Health Science Centre have been aimed at targeting respiratory syncytial virus (RSV) in humans with RNAi. RSV largely effects infants, but because it is quite harmless in adults and delivery directly to the lungs is viable via nasal spray it presented an excellent opportunity to test the effects of siRNA. The trial involving 85 healthy adults given siRNAs or a placebo, and being exposed to RSV, showed promising results. Only 44% of those given the siRNA developed an infection in comparison with 71% of the group given the placebo .
Most scientists agree that the challenge facing RNAi in humans is the delivery. To carry out their function, siRNA molecules need to get to the targeted tissue and cross the cell membrane into the cytoplasm before they are degraded. Organs affected by disease such as the lungs, eyes or skin can be accessed more readily, and it is for this reason that researchers have had recent successes treating such areas in humans .
Figure 2 RNAi mechanism within the human cell (Aldrigde 2011)
Many existing drugs used to combat disease are designed to attack the protein that causes the disease. This usually requires large doses of the drugs . Comparatively, when using RNAi, only a small amount is required to stop the harmful protein being produced in the first place with lasting effects .
The effectiveness of RNAi in silencing harmful genes in plants and animals, and now in humans, leaves little doubt that the tool will become a formidable treatment of human disease . While we witness success with ‘accessible’ diseases in local tissues like the lungs, the big challenge remains in the delivery to other target areas within the body . Hopefully, in overcoming such a challenge, scientists will soon open the door to the full potential of gene silencing in treating humans.
A detailed animation of the RNAi process can be viewed on the Nature Reviews Genetics website at the following link: http://www.nature.com/nrg/multimedia/rnai/animation/index.html
1. Abdolhamid Angaji, S., Hedayati, S.S., Poor, R.H., Madani, S., Poor, S.S. & Panahi, S. 2010, "Application of RNA interference in treating human diseases", Journal of Genetics, vol. 89, no. 4, pp. 527-37.
2. Aldridge, S. 2011, RNA interference – still the great white hope?viewed 15 March 2012, <http://www.inpharm.com/news/149829/rna-interference-still-the-great-white-hope
3. Reece, J.B., Meyers,N., Urry, L.A., Cain, M.L., Wasserman, S.A., Minorsky, P.V., Jackson, R.B., Cooke, B.N., 2011, Campbell Biology, 9th edn (Australian version), Pearsons Education.
4. Dykxhoorn, D.M. & Lieberman, J. 2005, "THE SILENT REVOLUTION: RNA Interference as Basic Biology, Research Tool, and Therapeutic", Annual Review of Medicine, vol. 56, no. 00664219, pp. 401-23.
5. Holmes, B. 2010, Gene silencing prevents first human disease, Reed Business Information UK, London, United Kingdom, London. ORIGINAL SOURCE
6. Holmes, B. 2007, Switched on, Reed Business Information UK, London, United Kingdom, London.
7. Nature Reviews Genetics 2012, Video Animation: RNA interference 2012, Veiwed 15 March 2012, <http//http://www.nature.com/nrg/multimedia/rnai/animation/index.html>
8. Wilson, J.F. 2005,"Gene Therapy Yields to RNA Interference", Annals of Internal Medicine, vol. 143, no. 2, pp. 161-4.