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By using the RNA interference technique (RNAi) for which the American scientists Andrew Fire and Craig Mello won the Nobel Prize for Medicine and Physiology this year, a German team led by Alexander Pfeifer of the University of Bonn has been able to prolong the life expectancy of mice infected with Scrapie.
Transmissible spongiform encephalopathies (TSEs) are a heterogeneous group of fatal neurodegenerative diseases for which no effective treatment currently exists.
TSEs include Creutzfeldt-Jakob disease in humans, spongiform encephalopathy in cattle (so-called Mad Cow disease),and Scrapie in sheep.
TSEs all commonly present an abnormal protein, Prion Protein (PrP), that multiplies inside the organism as a result of an autocatalytic process that can cause neuronal degeneration.
The gene for Prionic Protein is normally found in healthy organisms. The pathology arises when a mutation of the gene occurs or when the abnormal protein enters the organism from outside, triggering a pathological transformation of the endogenous protein itself.
Prion disease can therefore be either genetic or infective.
All efforts to find drugs capable of limiting modified PrP diffusion have so far been in vain.
Results obtained by Alexander Pfeifer represent the first concrete therapeutic approach to treating prion disease in humans, and were recently published in the Journal of Clinical Investigation.
Using the RNA interference technique, the German scientists succeeded in silencing the prion protein expression in mouse, thereby significantly extending the lifespan of Scrapie infected mice.
RNAi is a selective gene-silencing mechanism, highly conserved in plant and animal evolution. It blocks the conversion of messenger RNA into protein and can be experimentally induced via injection of a specific double strained RNA.
Once inside the cell, RNA molecules fragment into small pieces able to selectively block the synthesis of the specific protein encoded by the RNA sequence injected.
The possibility of selectively silencing specific genes in adult mammal cells has immediately lead to new and interesting approaches to the therapy of cancer, neurodegenerative diseases – such as Parkinson or Huntington’s Corea – and generally in the field of genetic diseases unresponsive to traditional pharmacological approaches.
The main problem in clinical application of RNAi lies in administering it. Different approaches have been explored, the more promising being those based on viral vectors as they have been shown to be highly effective in carrying RNA fragments into cells.
This is the strategy adopted by Pfeifer’s group.
However, optimism for therapeutic applications of RNAi has been tempered by worries about possible side effects. Nature recently reported a high percentage of fatalities in mice treated using the RNAi technique.
Furthermore, any aspecific interference with the expression of other genes and/or side effect caused by the viral vector should be ruled out by careful preclinical evaluation.
In particular, in relation to prion disease, the main issue in the paper by Pfeifer’s group is the high percentage of cells that RNA interference must involve in order for it to have a significant therapeutic effect.
Their data show that to improve survival in Scrapie infected mice, at least two third of total animal cells need to be treated.
Scaling-up to humans, the amount of RNA required would be so large that it would simply be impossible to inject it.
In summary, although these results are very encouraging, the time for therapeutic application in humans is still some way off. Meanwhile, approaches eradicating the disease from the original source of infection by creating transgenic livestock with the prion gene removed are producing the first positive results.
Clayton J., The silent treatment, Nature, 431:-605, 30 September 2004
Grimm D. et al., Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways, nature, 441:537:541, 25 May 2006 ,
Kong Q., RNAi: a novel strategy for the treatment of prion disease, Journal of Clinical Investigation, 116(12):3101-3103, 2006
Pfeifer A. et al., Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice, The Journal of Clinical Investigation, 116(12):3204-3210, 2006
Andrew Fire - Faculty & Researcher Profiles
http://med.stanford.edu/profiles/Andrew_Fire
Andrew Zachary Fire - From Wikipedia(italy), the free encyclopedia
http://it.wikipedia.org/wiki/Andrew_Zachary_Fire
Andrew Z.Fire - Wikipedia
http://de.wikipedia.org/wiki/Andrew_Z._Fire
Nobel prize for genetic discovery - BBC News
http://news.bbc.co.uk/2/hi/health/5398844.stm
The Nobel Prize in Physiology or Medicine 2006
http://nobelprize.org/nobel_prizes/medicine/laureates/2006
Youthful duo snags a swift Nobel for RNA control of genes
http://www.nature.com/news/2006/061002/full/443488a.html
RNAi scoops medical Nobel - Gene silencers get something to shout about.
http://www.nature.com/news/2006/061002/full/061002-2.html
Prion - Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Prion
Scrapie - From Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Scrapie
Bovine spongiform encephalopathy - From Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy
Transmissible spongiform encephalopathy - From Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Spongiform_encephalopathy
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