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Silence the gene, save the cell: RNA interference as promising therapy for ALS

Scientists at the Ecole Polytechnique Fdrale de Lausanne (EPFL) in Switzerland have used RNA interference in transgenic mice to silence a mutated gene that causes inherited cases of amytrophic lateral sclerosis (ALS), substantially delaying both the onset and the progression rate of the fatal motor neuron disease. Their results will be published in the April issue of Nature Medicine, and in the journal's advanced online publication March 13.

In addition to silencing the mutated gene that causes ALS, the EPFL researchers were able to simultaneously deliver a normal version of the gene to motor neuron cells using a single delivery mechanism. "This is the first proof of principle in the human form of a disease of the nervous system in which you can silence the gene and at the same time produce another normal form of the protein," notes Patrick Aebischer, EPFL President and a co-author of the study.

ALS is a progressive neurological disease that attacks the motor neurons controlling muscles. Although its victims retain all their mental faculties, they experience gradual paralysis and eventually lose all motor function, becoming unable to speak, swallow or breathe. Known also as Lou Gehrig's disease, from the baseball player who succumbed to it, this harrowing disease has no cure and its pathogenesis is not very well understood.

An estimated 5,000 Americans are diagnosed with ALS every year, and most of these cases are "sporadic", with no identifiable cause. About 5-10% of ALS cases are inherited. Of these, 20% have been linked to any of more than 100 mutations in the gene that expresses the superoxide dismutase enzyme (SOD1).

These SOD1 mutations are "toxic gain-of-function mutations," meaning that the protein expressed by the mutated gene has, in addition to all its normal cellular functions, some additional function that makes it toxic to the cell. "Any mutation to the SOD1 gene is fatal to motor neuron cells," Aebischer notes. Recen
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Contact: Mary Parlange
mary.parlange@epfl.ch
41-21-693-7022
Ecole Polytechnique Fdrale de Lausanne
13-Mar-2005


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