New cocktail drug provide an effective and economical treatment to Duchenne muscular dystrophy

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Up to 45% of patients with the most common inherited neuromuscular disease could benefit from a new “cocktail” drug being developed at the University of Alberta, according to research published this week in the Proceedings of the National Academy of Sciences.

The drug could provide an effective and economical treatment to lessen symptoms for the six of every 100,000 people – usually boys – affected by Duchenne muscular dystrophy, a chronic muscle-wasting disease, according to lead researcher Toshifumi Yokota, professor of medical genetics in the Faculty of Medicine & Dentistry.

A Band-Aid for damaged genes

People with Duchenne muscular dystrophy, referred to as DMD, have various mutations in the body’s largest gene, dystrophin, which is a protein that cells need to stay intact. 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 uses an approach called “exon skipping,” which acts like a Band-Aid over the missing exons so the body can skip over the damaged instructions and produce the protein needed to rebuild muscle tissue.

The U.S. Food and Drug Administration has approved four exon-skipping molecules, including viltolarsen, based on Yokota’s research, but each has only limited applicability.

Now the U of A’s team of medical genetics researchers has combined six such DNA-like exon-skipping molecules to create a “cocktail” treatment that could help many more patients.

“Each of the previously developed exon-skipping molecules has been able to treat only around 10% of DMD patients, because they have different mutations to their exons in different locations within the gene,” said Yokota.

“Our approach is to skip over 11 exons all at once, which would allow us to treat approximately 45% of patients,” he explained.

Yokota is also the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair.

Treatment could help improve heart muscle

The new cocktail also addresses another limitation of existing exon-skipping treatments, which is that they don’t penetrate the heart muscle, Yokota explained. While DMD patients often suffer from extreme skeletal body weakness, most die from heart failure.

“Our cocktail combines the antisense oligonucleotides with a new peptide, a short chain of amino acids, which allows the drug to penetrate the heart muscle,” he said.

Yokota’s team tested the new synthetic drug in patient-derived muscle tissue in test tubes and in mice. They found signs of dystrophin production, muscle building and improved heart function.

The next step will be to undertake toxicology testing and go through the regulatory steps to conduct clinical trials. Yokota and his colleagues recently launched a company that will help to commercialize the drug.

Rimeporide in Duchenne Muscular Dystrophy (DMD) | Fondation EspeRare

Duchenne muscular dystrophy (DMD) is primarily caused by out-of-frame deletions in the dystrophin gene. Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) converts out-of-frame to in-frame mutations, producing partially functional dystrophin.

Four single-exon skipping PMOs are approved for DMD but treat only 8 to 14% of patients each, and some exhibit poor efficacy. Alternatively, exons 45 to 55 skipping could treat 40 to 47% of all patients and is associated with improved clinical outcomes. Here, we report the development of peptide-conjugated PMOs for exons 45 to 55 skipping.

Experiments with immortalized patient myotubes revealed that exons 45 to 55 could be skipped by targeting as few as five exons. We also found that conjugating DG9, a cell-penetrating peptide, to PMOs improved single-exon 51 skipping, dystrophin restoration, and muscle function in hDMDdel52;mdx mice.

Local administration of a minimized exons 45 to 55–skipping DG9-PMO mixture restored dystrophin production. This study provides proof of concept toward the development of a more economical and effective exons 45 to 55–skipping DMD therapy.


More information: Kenji Rowel Q. Lim et al, Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2112546119

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