Breakthrough that can halt the progression of familial amyotrophic lateral sclerosis (fALS) developed by a Northeastern University scientist

Bosto, Mass. – 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.

“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 alter 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.

Testing in mice, rats and dogs is promising, and the lab is moving forward with final testing for effectiveness and safety necessary for clinical trials. The treatment engages and stabilizes 90% of SOD1 protein in blood cells, Agar says, and 60% to 70% in brain cells at a safe dose.

“We made sure to never publish anything until we actually had an idea of the safety,” Agar says.

Previous efforts of developing a compound that would stabilize SOD1 protein have not yet resulted in a treatment. Agar’s treatment won’t reverse the damage already done to the neurons and muscles, he says, because it is hard to reestablish vanished neuron connections.

This research was financially supported by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health; the ALS Association; Johnston Educational Ventures; and the National Science Foundation.

Agar also credits the success of his research to the longtime collaboration with Roman Manetsch, professor of chemistry and chemical biology at Northeastern, and all the doctoral students who worked in their labs over the years.

“The thing that made all this possible was our growing industry Ph.D. program,” he says.

Under an agreement with Northeastern, employees of major pharmaceutical companies such as Novartis, Biogen or GSK come to the university to get a doctoral degree. They bring a variety of skills and knowledge about drug development, Agar says, that academics are not trained in.

In exchange, he says, the master’s level scientists from the industry are trained in analytical chemistry techniques — an exigent need for the pharmaceutical companies.

Agar’s lab is now developing a potential drug for ALS based upon this breakthrough.

“We want to get to clinical trials as fast as we can, only $4 million to go!” he says.

With this drug and other treatments currently available, such as Biogen’s Tofersen, which reduces the level of SOD1 protein in cerebrospinal fluid cells, Agar says, ALS patients potentially will be able to live a long life.

“If you are diagnosed early, people might be able to still walk, talk and move on about life,” Agar says.

 

Contacts

 

Alexa Kummrow