Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons. Motor neurons are nerve cells in the brain and spinal cord that control muscle contraction. In ALS, these neurons die off, causing muscles to atrophy and become progressively weaker.
ALS may have both genetic and environmental causes. There are several genes known to cause ALS, but the majority of cases have no known genetic cause. Exposure to environmental factors may increase the risk for ALS, but no strong environmental risk factors have been identified. It is possible that the cause of ALS in any one individual is a complex mix of genetic risk factors and environmental risk factors, all of which combine to cause the disease.
Mutations in a gene called SOD1 cause about 10 percent of familial ALS, or about 1 percent of all ALS. It is still unclear how mutations in SOD1 lead to the death of motor neurons. Potentially, the most important ALS gene, called C9ORF72, was discovered in 2011. MDA-funded scientists are still determining exactly what the normal gene does, and how the mutation causes ALS. What is known is that the mutation in the gene is in a “hexanucleotide repeat” region. The gene normally has a short region in which the DNA sequence CCCCGG repeats multiple times. In the mutant gene, this region may be expanded to hundreds or even thousands of these hexanucleotide units. Mutations in two other genes, called TDP-43 and FUS, were also recently discovered to cause ALS.
Motor neurons die in ALS, but the disease process is not limited to this one cell type. The “cascade” of effects within the motor neuron, and possibly within other cells, is complex. Likely contributors to the process include failure of protein recycling, overproduction of excitotoxic compounds, and dysfunction of cellular energy structures called mitochondria. The immune system likely contributes to the disease through the inflammation process, aggravating damage rather than healing it. Each of these processes offers a potential target for therapy.
The focus of all ALS therapy development is to slow or halt the death of motor neurons. There are a wide variety of strategies, including reducing toxic proteins or RNA; reducing excitotoxicity, inflammation, and oxidation; decreasing protein aggregation; and increasing growth factors.
For more in-depth information regarding the drugs in development for ALS, please visit the ALS Drug Development Database.