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

research also indicates that mutant SOD1 gene expression in neighboring glial cells is also implicated in motor neuron death.

Lead author Cedric Raoul and colleagues targeted the cause of the disease by using RNA interference to silence the defective gene, preventing it from expressing the SOD1 protein.

RNA interference is part of a complex cellular housekeeping process that protects cells from invading viruses or other genetic threats. It works by interrupting messenger RNA as it transfers the genetic code for a protein from the nucleus to the site in the cell where the protein is synthesized.

To trigger RNA interference and silence a gene, short bits of double-stranded RNA are introduced in the cell, where they bind with matching sections of messenger RNA. The cell identifies the resulting messenger RNA strand as faulty and chops it up. As a result, the genetic blueprint isn't delivered and the protein never gets made.

"Gene silencing is an example of using "molecular scissors" at its most advanced level," Raoul explains.

Raoul and colleagues used RNA interference to reduce levels of mutant SOD1 protein in the spinal cords of transgenic ALS mice (mice bred to express the human SOD1 gene). Short strands of RNA that targeted multiple mutated and normal forms of the human SOD1 gene were delivered in a specially engineered lentivirus. Expression of the SOD1 protein was knocked down in the affected motor neurons and neighboring glial cells, and both the onset and the rate of progression of the disease in the treated mice were substantially reduced. In addition, the mice showed a significant improvement in neuromuscular function.

"This is the first demonstration of therapeutic efficacy in vivo of RNA interference-mediated gene silencing in an ALS model," notes Raoul.

Because the normal form of the SOD1 protein may be necessary for the survival or function of adult human motor neurons, the Swiss researchers designed
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Source:Ecole Polytechnique F茅d茅rale de Lausanne


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