Developing new therapies to fight muscle disease

Biophysicist Alireza Mashaghi and his collaborators are taking up the fight against muscular dystrophy: genetic disorders that cause muscle weakness. They want to inhibit the clumping of proteins that results in toxic aggregates. For this, the team receives 550,000 euros from Health Holland. The team includes cell biologist Vered Raz and electron microscopist Thom Sharp from the Leiden University Medical Centre (LUMC).

‘Muscular dystrophy greatly impacts a patient’s live and can even be fatal,’ says Mashaghi. ‘Current therapies are not sufficient enough. At the Leiden Academic Centre for Drug Research, we are therefore working hard to find new treatments.’ Mashaghi gets help from the Raz group at LUMC and Argenx, a biopharmaceutical company that develops human antibodies in the lab. The project will officially start at 1 October 2022.

Decreased muscle function

Mashaghi: ‘We focus on Oculopharyngeal muscular dystrophy, or OPMD. Initial symptoms are drooping upper eyelids and swallowing difficulties. As the disease progresses, it affects the function of additional skeletal muscles, severely impacting all aspects of the patients life.’

A single gene

OPMD is a monogenic disease. Meaning it is caused by an error in a single gene. Furthermore, it is also autosomal dominant: if you get the abnormal gene from only one parent, you can get it. Often, one of the parents may also have the disease.

Stop the clumping of proteins

‘Our goal is to learn more about the role of a specific protein in the nucleus of the muscle cells,’ Mashaghi explains. ‘A small mutation in the recipe for this protein in our DNA, results in a protein that likes to clump together.’ In the nucleus, these malformed proteins then clump together into insoluble aggregates, depleting the levels of functional proteins. This eventually leads to muscle dysfunction. Mashaghi: ‘By efficiently suppressing the formation of protein aggregates, we hope to halt the loss of muscle function.’

A promising drug, but how does it work?

The team has found a potential drug that shows some promising results. ‘Biotech company Argenx and the group of Vered Raz at LUMC developed special antibodies to target the malformed proteins in the nucleus of muscle cells,’ says Mashaghi. ‘In the first tests with fruit flies, it dramatically reduced protein aggregation and even restored muscle function. We are very keen to find out the mechanisms that underlie this therapeutic effect. In the next step, we will test these antibodies in the human muscle system, mimicked on a chip.’

‘How wonderful would it be if find a better therapy for OPMD and other muscular diseases as well’

Contributing to better treatment

Mashaghi: ‘Hopefully our research will help our industrial partner Argenx, to further develop new drugs for a better treatment of muscular dystrophy. How wonderful would it be if the same concept not only worked for OPMD, but for other muscular diseases as well!’

Developing innovative tools

The team will apply state-of-the-art technologies to study single muscle cells and proteins, such as optical tweezers and acoustic force spectroscopy. They combine these experiments with computational analyses supported by Mashaghi’s speciality: topological modelling. This is a way to describe and analyse how a protein is folded. The team is developing a workflow for modelling highly dynamic proteins, such those they study for this project.

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