Ecole Polytechnique Federale de Lausanne (EPFL) scientists used RNA interference in transgenic mice to silence a mutated gene that causes inherited cases of amytrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), substantially delaying both the onset and the progression rate of the disease.
An estimated 5,000 Americans are diagnosed with ALS every year, and most of these cases are ‘sporadic’, with no identifiable cause. About five to 10% of ALS cases are inherited and, 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. Recent research also indicates that mutant SOD1 gene expression in neighboring glial cells is also implicated in motor neuron death.
The scientists targeted the cause of the disease by using RNA interference to silence the defective gene, preventing it from expressing the SOD1 protein.
In the study, 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.
Patrick Aebischer, EPFL president and a co-author of the study is optimistic about the future of gene silencing as a potential therapy, particularly in incurable progressive neurological diseases such as ALS. “I would not be surprised to see, in the next ten years, this technology used for treating diseases of the nervous system, particularly diseases that involve toxic gain-of-function, such as inherited forms of Parkinson’s disease or Huntington’s disease,” he noted.