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Jeffrey Agar, associate professor of chemistry and chemical biology, works in his lab at 140 The Fenway on Northeastern’s Boston campus. Photo by Matthew Modoono/Northeastern University
A significant advancement in the treatment of amyotrophic lateral sclerosis, known as ALS, can potentially help halt the disease’s progression in up to half of the cases in the U.S., according to a Northeastern University scientist.
Jeffrey Agar, an associate professor of chemistry and pharmaceutical sciences at Northeastern, has dedicated the past 12 years to studying the mechanism of ALS and exploring ways to prevent its advancement.
Calling it “my life’s work,” Agar shares, “I devoted over 12 years of my own life and the combined efforts of others towards something deemed risky and unlikely to succeed.
“I am relieved that it all worked out.”
ALS is an uncommon progressive disease that leads to the deterioration of nerve cells in the brain and spinal cord. The disorder impacts motor neurons, which are responsible for voluntary muscle movement, speech, mobility, chewing, and breathing. The onset of ALS is mostly sporadic, with only 10% to 20% of cases in the U.S. being inherited, also categorized as familial ALS (fALS). Agar notes that ALS can be brought on by numerous gene mutations resulting in the mutation of proteins within a cell.
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. Photo by Matthew Modoono/Northeastern University
In his research, Agar focused on the mutation of a protein called copper zinc superoxide dismutase 1 (SOD1), a major antioxidant. According to Agar, a mutation of SOD1 protein, known as A4V, is among the most common causes of familial ALS, often resulting in a patient’s death in less than a year.
The mutated protein divides into two toxic pieces called monomers, explains Agar, which can adhere to millions of other monomers. These monomers form toxic clusters in the cell that grow as the disease progresses, causing damage to the cell and ultimately leading to its demise.
The innovative treatment strategy formulated by Agar’s lab utilizes a small molecule linker, S-XL6, to prevent the separation of SOD1, thereby thwarting the mechanism that destroys cells.
“Unlike Biogen’s approach, which lessens SOD1 function, our method actually aids the protein in regaining its normal function,” highlights Agar.
His experiments confirmed that this treatment approach is effective in mice for a specific mutation of the SOD1 protein associated with familial ALS. While about 50% of all ALS cases do not involve SOD1 mutations, the protein is still being impaired in an effort to protect the cell from free radicals, notes Agar, thus indicating that, in the best-case scenario, the therapy has the potential to halt the progression of the diseases and enhance survival in half of the ALS cases in the U.S.
“We’re developing new molecules with the Roman Manetsch Research Group, a medicinal chemistry lab at Northeastern, with hopes of further improvement,” he adds.
Preliminary testing in mice, rats, and dogs shows promise, and the lab is progressing with final testing for effectiveness and safety, essential for clinical trials. The treatment engages and stabilizes 90% of SOD1 protein in blood cells, Agar states, and 60% to 70% in brain cells at a safe dosage.
“We refrained from publishing anything until we had a clear understanding of the safety aspects,” emphasizes Agar.
Previous attempts to develop a compound to stabilize SOD1 protein have not yet yielded a treatment. Agar clarifies that his treatment will not reverse the damage already inflicted on the neurons and muscles, as re-establishing vanished neuron connections is challenging.
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 attributes the success of his research to the longstanding collaboration with Roman Manetsch, professor of chemistry and chemical biology at Northeastern, and all the doctoral students who contributed to their labs over the years.
“Our expanding industry Ph.D. program made all this possible,” he contends.
Under an agreement with Northeastern, employees from major pharmaceutical companies such as Novartis, Biogen, or GSK pursue doctoral degrees at the university. They bring diverse skills and knowledge about drug development, which Agar notes academics are not typically trained in.
Conversely, the master’s level scientists from the industry are trained in analytical chemistry techniques—an essential requirement for pharmaceutical companies.
Agar’s lab is presently developing a potential ALS drug based on this breakthrough.
“We aim to expedite clinical trials with just $4 million remaining!” he declares.
In conjunction with this drug and other available treatments, such as Biogen’s Tofersen, which reduces the level of SOD1 protein in cerebrospinal fluid cells, Agar suggests that ALS patients may potentially enjoy a longer life.
“If diagnosed early, individuals might still retain their mobility, speech, and quality of life,” Agar concludes.
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