New marker could break ALS drug development deadlock

purple illustration of nerves
ALS prognosis differs with each case, but most succumb to the disease within three years.

Amyotrophic lateral sclerosis (ALS) doesn't have a cure, and the only drug approved to treat it extends life by just a few months. Now, a Mayo Clinic-led team has landed on a protein that could serve as a marker in the development of new therapies.

ALS affects motor neurons, which transmit messages from the brain or spinal cord to muscles or glands. As the disease progresses, patients lose the ability to move their muscles, which weaken and waste away, eventually leading to paralysis and death. While researchers have conducted more than 50 clinical trials in as many years, only the drug Riluzole, an incomplete solution, has earned FDA approval.

Mayo Clinic’s Tania Gendron and colleagues looked at (reg. req.) a mutation of the gene, C9ORF72, the most common genetic cause of ALS and frontotemporal dementia. They found that the mutation was also responsible for the buildup of a protein, polyGP, in the cerebrospinal fluid and blood cells of patients.


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The team found polyGP in the cerebrospinal fluid of 134 people carrying the C9ORF72 mutation, including 83 people with ALS, 27 who did not have symptoms and 24 with diseases other than ALS, such as Alzheimer’s or dementia with Lewy bodies. The protein was absent in 120 people who did not have the mutation, including those with a different type of ALS.

They injected a drug targeting the mutation into the brains of mouse models of ALS. After eight weeks, they saw a “marked decrease” in polyGP levels and a reduction in mRNA carrying the mutation.

ALS research has been stymied by the lack of pharmacologic markers to track a drug’s efficacy and its engagement with its target. Testing polyGP levels in cerebrospinal fluid could serve as such a marker in the development of ALS drugs.

Meanwhile, other ALS researchers are pursuing a range of new targets for treating the disease. A team from UC Riverside, for example, is working on an ALS drug that targets the gene EphA4, which increased survival in mouse models. And investigators from the Gladstone Institutes and and the University of Michigan identified a pathway, dubbed nonsense mediated decay, or NMD, as a new therapeutic target for ALS.

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