Exon-skipping therapies

Exon-skipping therapy is a treatment strategy for Duchenne muscular dystrophy (DMD) designed to help muscle cells produce a functional, albeit shorter, version of the dystrophin protein. While not a cure, it aims to slow the progression of muscle weakness and damage.

How It Works

DMD is caused by mutations in the DMD gene that disrupt the "reading frame" of genetic instructions, preventing the production of functional dystrophin. Exon skipping uses molecules called antisense oligonucleotides to "mask" specific sections of the gene (exons) during the splicing process.

  • By skipping a specific exon, the cell can bypass the mutation and restore the reading frame.

  • This converts a severe "out-of-frame" mutation (typical of Duchenne) into an "in-frame" mutation, resulting in a protein similar to the one found in patients with Becker muscular dystrophy, a much milder form of the disease.

Approved Therapies

The FDA has granted accelerated approval to four therapies, each targeting specific mutations:

  • Exondys 51 (eteplirsen): Targets exon 51; applicable to about 13% of DMD patients.

  • Vyondys 53 (golodirsen): Targets exon 53; applicable to about 8% of DMD patients.

  • Viltepso (viltolarsen): Also targets exon 53.

  • Amondys 45 (casimersen): Targets exon 45; applicable to about 8% of DMD patients.

Benefits and Limitations

  • Production of Dystrophin: Clinical data shows these treatments successfully increase dystrophin levels in muscle tissue.

  • Slowing Progression: Some studies suggest these therapies can help maintain lung function and improve survival rates, especially when started early.

  • Genetic Specificity: These treatments are "personalized" in that they only work for patients with specific genetic deletions. Approximately 20% of DMD patients have mutations that cannot currently be treated with this approach.

Safety and Administration

  • Administration: These drugs are typically administered via weekly intravenous (IV) infusions.

  • Side Effects: Common side effects include balance issues, vomiting, headache, and fever. Some therapies require monitoring for potential kidney toxicity or allergic reactions

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