Duchenne muscular dystrophy (DMD) is a fatal genetic disease without a cure. A study from Yale University researchers brings hope after researchers identify a new compound that could treat the condition.

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Scientists have inched closer to a treatment for Duchenne muscular dystrophy.

DMD is an X-linked recessive disease that occurs primarily in boys and leads to progressive muscle loss. Around 16 in every 100,000 males in the United States are born with DMD.

Females who have one altered gene are carriers. While most female carriers have no signs or symptoms of the condition, they may experience some mild signs or symptoms in rare cases.

The muscle wastage of DMD causes difficulty walking and speaking, and eventually, breathing. There is currently no cure for the disease, and patients with DMD have an average life expectancy of just 26 years old.

A mutation in the dystrophin gene, which is important for maintaining muscle fibers, causes DMD. Muscle fibers in people with DMD are highly susceptible to injury and are also unable to regenerate. Fibrotic (scar) tissue replaces the fibers.

There is also a role for an enzyme called MKP5, which, when deleted in animals, stops mice from developing the disease. However, until now, the medical community has considered the enzyme to be ‘undruggable.’

A new study led by Yale University, New Haven, CT, and appearing in the journal Science Signaling, describes for the first time a compound that effectively targets the MKP5 enzyme.

The researchers say the results open up avenues for the treatment of DMD and other conditions associated with fibrosis. Fibrosis is involved in the death of many tissues, including muscle, liver, and lung tissue, and contributes to almost a third of natural deaths worldwide.

The new study relies on earlier results, which showed that genetically deleting MKP5 in a mouse model of DMD protected the animals from developing muscular dystrophy and significantly reducing fibrosis. The results suggested that a drug blocking MKP5 could help treat DMD in people.

Then came the challenge of finding such a compound. The researchers screened more than 160,000 compounds to find one that could effectively block MKP5.

Of 391 compounds that inhibited the enzyme by more than 30%, the team found one with real therapeutic potential. This compound, which researchers had never explored before, potently and selectively inhibited MKP5.

“There have been many attempts to design inhibitors for this family of enzymes, but those compounds have failed to produce the right properties. Until now, the family of enzymes has been considered ‘undruggable.'”

– Anton Bennett, Professor of Pharmacology at Yale University School of Medicine and senior author of the study

Further experiments showed that the compound works by binding to the enzyme at a previously undiscovered site, away from its primary binding site.

This is called an allosteric site, a site other than the active site of the enzyme. Previous research had focused on the active site without success, but by targeting this allosteric site, the team found an ‘excellent starting point for drug development,’ says senior author Prof. Anton Bennett.

After further isolated tests of the compound, the researchers went on to test it in muscle cells, showing that the compound can effectively block MKP5 within the muscle.

The compound also significantly increased the differentiation of the muscle cells, suggesting it could help the muscle regenerate.

The research team is hopeful their discovery could be a promising new treatment for people with DMD, and they are already working with a major pharmaceutical company to progress the new treatment.

Beyond DMD, they say that targeting the MKP5 enzyme could also be a treatment strategy for fibrosis.

Scientists already know that MKP5 plays a role in fibrosis. Therefore, an MKP5 inhibitor could benefit diseases associated with tissue scarring, such as pulmonary fibrosis and chronic liver disease.

“We believe this enzyme could be a target more broadly for fibrotic tissue disease,” says Professor Bennett.

Future work will focus on optimizing the compound’s structure and testing whether the inhibitor works on other enzymes in the MKP class, which play a role in many disorders, including cardiovascular disease, colorectal cancer, and metabolic syndrome.