ALS Mutation Affects Key Pathway, But Asthma Treatment Seen to Offer Protection in Early Study

A possible new target for treating amyotrophic lateral sclerosis (ALS) may be the nonsense-mediated mRNA decay (NMD) pathway, which helps cells remove potentially harmful RNA, like RNA that’s been improperly processed or comes from viruses.

Researchers in this early study also suggest that an asthma treatment known as tranilast (marketed in Japan as Rizaben) may be able to reactivate the NMD pathway, to potentially treat ALS.

The study, “Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity,” was published in the journal Brain.

Most inherited ALS cases, and around 1 in 10 sporadic cases, involve a mutation in the C9orf72 gene wherein a six-nucleotide sequence is essentially “copied and pasted” too many times. This is called a hexa-nucleotide repeat expansion or HRE.

How exactly this mutation contributes to ALS isn’t fully understood, but it is known that this change can interfere with the way cells process RNA. (RNA is transcribed from DNA, as it is the template for protein production.)

The NMD pathway is a surveillance system in our cells that degrades selected RNA molecules, to prevent the accumulation of defective proteins.

Researchers in China and the U.S. first performed a bioinformatics analysis using gene expression data. Results showed that cells with defective NDM pathways express many of the same genes  expressed in brain tissue of ALS patients carrying the C9orf72 expansion, suggesting a link between the two.

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Next, they found that the presence of this mutation in cells in dishes and in the brains of mice led to a decrease in NMD, suggesting a causal relationship rather than just a correlation. In a casual relationship, the existence of one event “causes” the other (i.e., the mutation leads to defective pathways); a correlation is a link between two things, but without a definite “cause and effect” process.

When the researchers genetically re-activated NMD in cells and in Drosophila (fruit fly) models of ALS, they found that cells were protected from neurodegeneration — the decay of brain cells that takes place in ALS.

Such results suggest that reactivating this pathway might be a viable way of treating ALS.

To further explore this idea, the team tested several experimental compounds to see whether they could activate NMD, and tranilast was the most promising. This small-molecule compound holds particular promise because it can easily cross the blood-brain barrier. Additionally, the “long track record of Tranilast as a well-tolerated, low toxicity drug would make it a highly promising choice for ALS therapy,” the study notes.

Tests of tranilast in cell and fly models of ALS showed it could protect brain cells from neurodegeneration.

Further research, both in animal models and in ALS patients, is needed to better judge the potential benefits of tranilast, or other therapies designed to activate NMD .

“With validation of its protective effect against C9orf72 HRE, tranilast may also be used in individuals carrying C9orf72 HRE at pre-symptomatic [before symptoms] stage to delay or prevent the disease onset,” the researchers said.

Tranilast ( (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) has been used in Japan, South Korea and China to treat bronchial asthma since 1982, they noted in the study’s concluding section.