Therapeutic MuSK Antibody Stabilizes Nerve-Muscle Synapses in a Mouse Model of ALS

Researchers funded through The ALS Association’s Lawrence and Isabel Barnett Drug Development Program, uncovered a new way to prevent muscle paralysis in an ALS mouse model. Dr. Steven Burden at New York University Medical School and colleagues at Columbia University Medical School used a stimulatory antibody to increase the activity of MuSK, a protein critical for maintaining the connections between muscle and motor neurons.

This treatment preserved nerve-muscle synapses, improved diaphragm muscle function, and modestly extended lifespan of the mice. Their findings reveal a novel therapeutic strategy using an antibody to potentially target ALS and other neuromuscular diseases.

“Our findings reveal a new therapeutic strategy for ALS that protects a pathway essential for keeping nerves and muscles connected. There are few treatments for ALS, and the two FDA-approved drugs extend survival for only a few months in a subset of patients. We believe that this approach, mostly likely in combination with other drugs, may extend the quality of life during the early phases of this devastating disease.” – 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.

People living with ALS progress from muscle weakness to a more severe decline in motor function and, eventually, to lethal respiratory muscle paralysis. Motor neuron death is one of the most talked about causes of muscle paralysis. Loss of neuromuscular synapses, the place where motor neurons and muscle connect, happens prior to motor neuron loss and is also a primary cause of muscle paralysis.

At the neuromuscular synapse, a motor neuron transmits signals to the muscle, causing it to contract. Loss of these synapses prevents communication between the muscle and motor neuron, causing muscle paralysis.

What is MuSK?
Signaling pathways between the muscle and motor neuron play an important role in keeping the neuromuscular synapse intact and muscle health. MuSK is a receptor tyrosine kinase that plays a critical role in maintaining neuromuscular synapses.

Some types of mutations in MuSK cause congential myasthenia, a group of neuromuscular disorders that lead to muscle weakness and fatigue, which are distinct from ALS. In addition, inhibitory autoantibodies to MuSK cause an autoimmune disease, called myasthenia gravis, which is also distinct from ALS.

The study
Dr. Burden and team asked the question of whether increasing MuSK activity in SOD1 (G93A) mice, a common ALS mouse model that demonstrates severe disease, could keep synapses intact and preserve neuromuscular function to improve the health and lifespan of the mice. To accomplish this, they used a genetically engineered stimulatory agonist antibody to MuSK, produced by Genentech, Inc., that binds to MuSK and increases MuSK activity at the neuromuscular synapse.

Major findings
Injecting the MuSK antibody in SOD1 (G93A) mice resulted in the following:
• Decreased detachment of motor endings from muscles
• Improved function of the diaphragm muscle – the principle muscle for respiration
• Reduced loss of spinal motor neurons
• Modest extension of survival of the mice

Study conclusions and impact
The improvements in mice were observed even when the antibody was first introduced after disease onset, a time when neuromuscular synapses are already compromised. This suggests that targeting a pathway essential for maintaining attachment of motor neurons to muscle could be a potential novel therapeutic strategy for ALS.

Synaptic loss and muscle denervation are common to both familial (inherited) and sporadic (non-inherited) forms of ALS. Therefore, increasing MuSK could impact both forms of ALS. Other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinal Muscular Atrophy, and Frontotemporal dementia, all show synaptic loss early in disease progression, suggesting that treatments that specifically address the loss of affected synapses rather than neuronal loss could be beneficial for these diseases, as well.

How could people with ALS benefit?
ALS is a heterogenous disease, caused by multiple disease pathways. Although the MuSK antibody cannot override many of these pathological pathways that can lead to motor neuron death, combination therapy interventions that include those that preserve neuromuscular synapses, like increasing MuSK, have the potential to improve the quality of life for many people living with ALS.

This work was generously supported by the Greater Philadelphia Chapter of The ALS Association through the Lawrence and Isabel Barnett Drug Development Program.

For more information about Dr. Burden’s project, click here.

To read our news release about this research paper, click here.

Click here to read full article.

Paper Citation

Cantor S., Zhang W., Delestrée N., Remédio L., Mentis G., Burden S. Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody. eLife. 2018 Feb. 20; 14-12-2017-RA-eLife-34375R1