ALS patient at his room
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Researchers were able to suppress a rare aggressive form of amyotrophic lateral sclerosis (ALS) gene using antisense in mice. Their work suggests the therapy could treat cases of the disease caused by mutations in the fused in sarcoma (FUS) gene. The study was recently published in Nature Medicine.

“The study is an example of a precision medicine, bench-to-bedside effort,” said Neil Shneider, senior author and director of the Eleanor and Lou Gehrig ALS Center at Columbia University, New York City. “We began with the mouse model to establish a rationale for the drug, conducted efficacy studies in the mouse, moved the drug into a human, and collected valuable data that was ultimately used to support a larger Phase III clinical trial.”

ALS, also known as Lou Gehrig’s disease, is a fatal neurological disorder that causes the degeneration of motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, but at least 10% of cases are familial. Mutations in the gene FUS cause severe forms of ALS, referred to as FUS-ALS, including a rare type that begins in adolescence or young adulthood.

In the study, Shneider and his team delayed the onset of motor neuron degeneration in mice by using an antisense oligonucleotide drug designed to silence FUS by blocking cells from making specific proteins. Following encouraging results, they administered the drug to a patient with ALS.

Compared to normal mice, mice with a mutated FUS gene had higher levels of insoluble FUS and other ALS-related proteins in their brains and spinal cords. Mice with higher doses of mutant FUS in motor neurons experienced rapid neurodegeneration that began early in life, much like FUS-ALS patients.

“The study establishes a mouse model that is highly disease-relevant,” said Shneider. “In mice, we found that FUS toxicity was due to a gain of function and was dose-dependent, suggesting that we could treat FUS-ALS by silencing the FUS gene.”

This work was started by a personal interaction. In 2019 Shneider met an individual with ALS in search of therapies. Inspired by her story, he teamed up with a pharmaceutical company to develop a personalized therapy designed to target the FUS mutation.

In mice, injecting a single dose of the drug into the ventricles, fluid-filled spaces surrounding the brain, delayed the onset of inflammation and motor neuron degeneration by six months. The drug also knocked down levels of FUS by 50% to 80% in the brain and spinal cord. Following drug administration, insoluble forms of other ALS-associated proteins were also cleared.

Under a compassionate use protocol reviewed by the FDA, Shneider administered the drug to the patient it had been designed for. She received repeated infusions of the drug into her spinal canal for 10 months. During the treatment, her rate of motor function deterioration slowed. She tolerated the treatment well and there were no medically adverse effects.

Treatment began more than six months after clinical onset, by which time the disease had already significantly advanced. As is typical with juvenile-onset FUS-ALS, the disease progressed rapidly, and the patient died from complications of the disease.

By studying the patient’s brain and spinal cord tissue, researchers found that the drug silenced FUS throughout the nervous system and reversed the toxic nature of FUS and other disease-related proteins. Compared to tissue from untreated FUS-ALS patients and healthy controls, FUS protein aggregates—a pathological hallmark of this form of ALS—were sparse, suggesting that they may have been cleared by the drug. Tissue samples were provided by the New York Brain Bank of Columbia University.

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