Researchers take new step toward promising therapy against muscle diseases

In developing the therapy, researchers started with one of the rarest forms of MG: myasthenia gravis with MuSK antibodies, abbreviated as MuSK-MG. In this autoimmune disease, muscles cannot properly process signals from nerves. This leads to muscle weakness and sometimes severe symptoms such as breathing problems, drooping eyelids and problems chewing, speaking and swallowing. The muscle disease is very rare and has a huge impact on a person's life: about two hundred people in the Netherlands have it.

Communication between nerve and muscle

For muscles to work properly, it is important that there is good communication between nerve and muscle. This is where the so-called MuSK protein plays a crucial role. This protein, which is on the outside of the muscle fiber, has the important task of preparing the muscle to process signals from the nerve. But the protein can only do this if it pairs with another MuSK protein.

Jan Verschuuren, neurologist and professor of muscle diseases at LUMC: “People with MuSK-MG have antibodies that block the formation of those duos. The communication between nerve and muscle is therefore disturbed. As a result, the muscle becomes 'deaf' to the signal from the nerve. As a result, these people cannot - or cannot properly - contract their muscles. They experience this as muscle weakness.”

On/Off button

In MuSK-MG, the antibody called IgG4 is the culprit, previous research has shown. In recent years, thanks partially to funding from the Princess Beatrix Spierfonds, LUMC has done a lot of research into how IgG4 antibodies cause muscle weakness in patients. That has ensured LUMC scientists, in collaboration with NYU and biotech company argenx, have now created a therapy that can independently make MuSK-MuSK duos.

LUMC researcher Dr. Maartje Huijbers: “This means that we can turn the MuSK signal ‘on’ or ‘off’ ourselves which can strengthen or weaken the communication between nerve and muscle and enable the muscles to function better again. This has the potential to treat other muscle diseases in which the communication between nerve and muscle is disturbed.

After successful laboratory tests, the therapy is now being tested on patients with rare muscle diseases, including ALS and SMA.

Longer preservation of muscle strength

While the therapy is unlikely to cure the diseases completely, it offers hope for a better life for patients with certain muscle diseases. Huijbers: “We don't solve the underlying problem in ALS, for example. We are aiming to preserve function of the contact between nerve and muscle for longer. If you can make those 'talk' to each other longer, that could theoretically contribute to making that nerve and muscle live longer and to longer preservation of muscle strength.”

Verschuuren says: “We have a drug in hands that in theory can be used for many different muscle diseases and can ensure longer function retention and a better quality of life. This is an important step for muscle diseases that currently lack a good treatment.”

More info:

1. Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models: iScience
2. ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome | Science Translational Medicine
3. Agonist antibody to MuSK protects mice from MuSK myasthenia gravis - PubMed