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New Treatment Strategy Shows Promise Against ALS in Preclinical Study

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A major breakthrough in the treatment of amyotrophic lateral sclerosis, known as ALS, can potentially help stop the disease in its tracks in as much as half of the cases in the U.S., a Northeastern University scientist says.

Jeffrey Agar, associate professor of chemistry and pharmaceutical sciences at Northeastern, has spent the last 12 years studying the mechanism of ALS and researching ways to prevent its progression.

“You could consider it my life’s work,” he says. “I bet 12 years of my own life and countless number of years of others’ lives toward something that was so risky that everyone said it would never work.

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“I am relieved that it all worked out.”

ALS is a rare progressive disease that causes deterioration of nerve cells in the brain and spinal cord. The disorder affects motor neurons, which control voluntary muscle movement, talking, walking, chewing and breathing. The onset of ALS is largely sporadic — only 10% to 20% of cases in the U.S. are inherited, Agar says, and therefore are called familial ALS (fALS). ALS can be caused by dozens of different gene mutations that lead to mutation in proteins within a cell.

In his research, Agar focused on the mutation of a protein called copper zinc superoxide dismutase 1 (SOD1), a major antioxidant. A mutation of SOD1 protein called A4V, he says, is one of the most common causes of familial ALS that often results in a patient’s death in less than a year.

The mutated protein splits into two toxic pieces called monomers, Agar says, that can stick to millions of other monomers. These monomers form toxic clusters in the cell that grow with the progression of the disease, damaging the cell and causing it to die.

The novel treatment strategy developed by Agar’s lab uses a small molecule linker, S-XL6, to prevent the separation of the SOD1, stopping the mechanism that destroys cells.

“Unlike Biogen’s approach, which diminishes SOD1 function, our method actually helps the protein regain its normal function,” Agar says.

His experiments confirmed that this treatment method works in mice for a specific mutation of the SOD1 protein associated with familial ALS. In about 50% of all ALS cases there are no mutations in SOD1, but the protein is still being damaged trying to protect the cell from free radicals, Agar says, meaning that in the best-case scenario the therapy can potentially help halt the progression of the diseases and improve survival in half of the ALS cases in the U.S.

“We’re making new molecules with the Roman Manetsch Research Group, a medicinal chemistry lab at Northeastern, hoping to even improve it further,” he says.