MuSK and ALS

WASHINGTON, D.C.—Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a neurodegenerative disease typified by the loss of motor neurons in the brain and spinal cord, eventually resulting in the loss of voluntary muscle movement, paralysis and death. While progress has been made in understanding the disease, there is still no cure, nor treatments to slow or reverse disease progression.

But in an encouraging development, a recent study funded by The ALS Association’s Lawrence and Isabel Barnett Drug Development Program has found a way protect synapses and slow muscle paralysis in mouse models of ALS. The work was led by Dr. Steven Burden, professor at the Skirball Institute of Biomolecular Medicine in the Department of Neuroscience and Physiology at New York University School of Medicine, who was joined by colleagues at Columbia University Medical School. Their work was published in eLife under the title “Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody.”

Patients with ALS also experience loss of neuromuscular synapses—the meeting point of motor neurons and muscles—which takes place before motor neurons are lost and is another leading cause of paralysis. MuSK, a receptor tyrosine kinase, is pivotal in the maintenance of neuromuscular synapses. Given this, the research team tested a MuSK-stimulatory antibody (SODI G93A, produced by Genentech Inc.) that binds to MuSK and increases its activity at the site of neuromuscular synapses. They found that administration of the antibody to mice with ALS “decreased detachment of motor endings from muscles, improved function of the diaphragm muscle, reduced the loss of spinal motor neurons and modestly extended survival,” as noted in a press release.

“The therapeutic strategy described here targets a disease mechanism, namely the loss of neuromuscular synapses, which is common to familial and sporadic forms of ALS and is based on a therapeutic antibody format with considerable clinical precedence,” Burden explained in a press release. “Although the MuSK agonist antibody cannot override the many pathological pathways that occur in motor neurons and in non-neuronal cells, therapeutic interventions that preserve neuromuscular synapses have the potential to improve the quality of life for a majority of ALS patients.”

Additional studies are in the works to explore the MuSK antibody in mice with a milder form of ALS to see if treatment efficacy improves. As for moving beyond mice, The ALS Association notes in a summary page of this research project that the researchers have confirmed that the antibody developed for the murine form of MuSK does not bind to the human version of the protein, and as such, work is underway to “characterize the molecular differences that account for this difference in binding ability, and using that information, an antibody will be designed that will work with human MuSK.”

“The overall goal of this project is to identify imaging markers of ALS that can be used to accelerate ALS diagnostic timelines and the pace of ALS drug discovery,” the Association notes. “This project will focus on studying the role of brain inflammation in people with ALS. In this project, investigators plan to use innovative MRI and positron emission tomography (PET) tracer (contrast) that will show them the location and degree of nerve damage and brain inflammation in people with ALS. They plan to compare MRI signals between 50 people with ALS and 50 healthy volunteers, and to study these MRI signals over time in relationship with ALS clinical presentation and disease progression. In a subgroup of patients, investigators plan to compare brain inflammation between 20 people with ALS and 20 healthy volunteers, and to study brain inflammation over time in relationship with ALS clinical presentation and disease progression.”

“The ALS Association is excited about the promising data from this study and grateful to the Greater Philadelphia Chapter for their generous support of this drug development contract,” stated Dr. Lucie Bruijn, chief scientist at The ALS Association. “This study is part of the Lawrence and Isabel Barnett Drug Development Program, which is focused on building partnerships with academia and industry to bring new treatments to people living with ALS.”