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Toshifumi Yokota and his team identified a peptide that significantly improves the effectiveness of existing treatments for Duchenne muscular dystrophy (DMD) in mice, particularly in the heart muscle, offering hope for future drug development for DMD and other neuromuscular disorders. (Photo: Supplied)

A new genetic therapy for the most common type of muscular dystrophy has been approved for human use for only a few years, but already a team of º£½ÇÉçÇø researchers is working to improve it. 

In a , medical geneticist and his team identify a human-derived peptide — a tiny protein-like molecule — that helps guide the treatment into the heart muscle cells more effectively.

“Only up to 30 per cent of patients can be treated with this type of drug and it has limited efficacy in the heart, so our goal is to expand the scope of the treatment for more patients and improve its impact on the heart muscle,” says Yokota, who holds the .

People with Duchenne muscular dystrophy (DMD) have mutations in the body’s largest gene, dystrophin, which controls the protein that cells need to build and maintain muscle tissue. Dystrophin has 79 sections, or exons. If even one is missing, the body cannot produce dystrophin and the muscles degenerate.

There is no cure for DMD, but a new class of drugs called antisense oligonucleotides acts like a Band-Aid so the body can skip over the missing exons. The drug viltolarsen was approved for use in 2020 thanks to the work of Yokota’s lab. 

Exon-skipping drugs work well in skeletal muscles, but until now they have not worked on heart muscles, because the cells in the heart are much smaller and less leaky than skeletal muscle fibres, so it’s harder for the drugs to get in.

“More than 50 per cent of DMD patients die from cardiac failure, and there is no effective treatment to restore cardiac function in muscular dystrophy, so this is a very important challenge in the field,” he says. “In this research, we treated DMD model mice using this molecule, and it worked surprisingly well. It rescued cardiac function in addition to skeletal muscle function.”

In this project, the Yokota team worked with University of Oregon chemist to test various peptides and identify the best one. They used the peptide DG9 to enhance cellular uptake of a DNA-like molecule called a morpholino that targets exon 44. They then collaborated with º£½ÇÉçÇø cardiac specialist to test its impact on heart muscle tissue. 

Yokota points out that it will take three or four years to get the new drug to the point of human clinical trials, partly because the process is so expensive. But he says it holds promise not only for DMD, but also for other neuromuscular disorders that affect the heart. He says it works to facilitate either exon skipping or exon inclusion, both of which are known as splice modulation.

Yokota’s goal is to one day develop tailored, custom-made antisense oligonucleotides to treat rare types of mutations that may affect only one or a few people. 

He credits patient groups with driving much of his work, through both funding and inspiration.  

“My study was the first to demonstrate effective exon skipping in a severe animal model of Duchenne muscular dystrophy. That led to a clinical trial and FDA approval, but the entire process took more than 10 years, so I’m grateful that they are very patient and very realistic about the process,” Yokota says.

Both Toshifumi Yokota and Gavin Oudit are members of the .

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