Exon-skipping therapies

Last updated June 28, 2023, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD

Exon skipping is a treatment approach for people with Duchenne muscular dystrophy (DMD) that, while not a cure, may help to make the effects of the genetic disease less severe.

Duchenne, the most common type of muscular dystrophy, is caused by mutations in the DMD gene, which provides cells with instructions for making a protein called dystrophin. The dystrophin protein normally acts like a shock absorber in muscle cells, helping to protect muscle fibers from getting damaged during muscle contractions.

DMD-causing mutations generally result in no functional dystrophin being made. Mutations that reduce dystrophin’s function, but still allow some protein to be produced, typically cause a milder form of disease called Becker muscular dystrophy (BMD). Without a functional dystrophin protein, muscle cells accumulate damage more quickly, which ultimately leads to symptoms of muscular dystrophy such as progressive muscle weakness.

Exon skipping is a therapeutic strategy that aims to allow a shorter, but still functional, version of the dystrophin protein to be produced in people with Duchenne caused by specific mutations in the DMD gene. By allowing muscle cells to produce a functional version of dystrophin, these therapies aim to lessen muscle damage, thereby slowing disease progression.

What is an exon?

An exon is a section of a gene that provides instructions for the production of proteins. Sort of like how multiple words are combined to form a sentence, multiple exons are put together to form the full protein-coding sequence of a gene. The DMD gene, which has 79 exons, is the largest gene in the human genome.

In a person’s DNA, exons are interspersed with other sections of genetic code called introns. While these introns don’t provide instructions for making proteins, they have other functions important for regulating gene activity. When the DMD gene is used, or read, to make protein, the entire sequence —both introns and exons — is copied over from the DNA template into a temporary molecule called messenger RNA (mRNA).

The mRNA molecule then undergoes a process called splicing, in which all the introns are removed and the exons are strung together to produce a mature protein-coding sequence. Finally, this sequence is used as a template to make the dystrophin protein. Each of the exons is able to fit with its neighbors like pieces of a puzzle to form the mature sequence.

In both Duchenne and Becker muscular dystrophy, mutations typically result in one or more exons being lost from the protein-coding sequence of the DMD gene.

In the milder Becker, one or more exons are lost, but the rest of the exons are still able to fit together, resulting in the production of a shortened version of the dystrophin protein that still has some functionality. By comparison, in the more severe Duchenne, the lost exons prevent the production of any functional dystrophin protein whatsoever.

How does exon skipping work?

The general concept behind exon-skipping therapy for Duchenne is to remove certain exons in the DMD gene sequence to establish a better fit with the remaining nearby exons. This essentially results in a situation similar to BMD, where cells can produce a shortened form of the dystrophin protein that still retains some ability to function.

Existing exon-skipping therapies work to mask specific exons in the DMD gene sequence using short strands of nucleic acids (which make up DNA and RNA) called antisense oligonucleotides. By binding to specific regions on the pre-mRNA molecule, these therapies induce the cell to skip over one or more exons during mRNA splicing.

It is estimated that about 1 in 5 patients has a mutation that cannot be targeted with this strategy. Genetic testing, often used for the diagnosis of Duchenne muscular dystrophy, also can help identify an individual patient’s specific mutation.

Benefits of exon-skipping therapy

There are four exon-skipping therapies approved by the U.S. Food and Drug Administration (FDA) for Duchenne:

• Amondys 45
• Exondys 51
• Viltepso
• Vyondys 53.

All work to treat DMD caused by specific mutations.

These therapies were each approved under the FDA’s accelerated approval pathway. The regulatory agency uses this pathway to allow the marketing of therapies that have a high likelihood of benefiting patients, based on early clinical biomarker data. As a condition of accelerated approval, the therapies’ developers are required to conduct additional clinical testing to confirm that their treatment offers confirmed benefits to DMD patients.

The four were granted accelerated approval based on early data showing that they led to a statistically significant increase in dystrophin protein levels. As muscle damage in DMD is caused by a lack of this protein, boosting dystrophin levels is theoretically expected to slow the accumulation of muscle damage and the progression of DMD.

Although biomarker data indicate exon-skipping therapies are likely to provide a benefit for patients, there is not yet clinical data to confirm this definitively. Until such data become available, it’s impossible to say with certainty whether or how the progression of DMD may differ in patients who are treated with exon-skipping therapies.

Several clinical trials are ongoing to collect more data on the approved exon-skipping therapies in patients with amenable mutations. Among them:

• The Phase 3 ESSENCE study (NCT02500381) is testing Amondys 45 and Vyondys 53 against a placebo.
• An open-label Phase 2 trial (NCT04179409) is collecting data on patients treated with Amondys 45, Exondys 51, or Vyondys 53.
• The Phase 3 trial RACER53 (NCT04060199) is assessing Viltepso versus a placebo.
• A Phase 3 study called MiS5ION (NCT03992430) is comparing multiple doses of Exondys 51.

Approved exon-skipping therapies

Exondys 51

Exondys 51 (eteplirsen) was developed by Sarepta Therapeutics as a treatment for DMD patients with mutations amenable to exon 51 skipping. That’s about 13% of all people with DMD. The FDA granted Exondys 51 accelerated approval in 2016. The therapy is administered once weekly via an infusion into the bloodstream that takes 35 minutes to one hour.

Although clinical trials to confirm the efficacy of Exondys 51 are still in progress, analyses of available data have indicated that it may slow the decline in respiratory function for amenable patients — particularly when started early. It’s also been seen to prolong survival, by more than five years in one study.

The most common side effects of Exondys 51 include balance problems and vomiting.

Vyondys 53

Vyondys 53 (golodirsen), also sold by Sarepta, received accelerated approval from the FDA in late 2019. It is indicated to treat patients with mutations amenable to exon 53 skipping, which accounts for roughly 8% of all people with DMD.

The therapy has been shown to increase the levels of dystrophin in muscle cells.

It is given via weekly infusions that take 35 to 60 minutes, and its most common side effects include headache, fever, fall, abdominal pain, the common cold, cough, vomiting, and nausea.

Viltepso

Viltepso (viltolarsen), sold by Nippon Shinyaku through its subsidiary NS Pharma, was given accelerated approval by the FDA in 2020 to treat DMD patients amenable to exon 53 skipping. It is administered via once-weekly infusions that take about one hour.

Although Phase 3 testing to confirm the clinical efficacy of Viltepso is still ongoing, long-term data from the Phase 2 study that supported accelerated approval suggested that the therapy may slow motor function decline compared with what’s typically seen without treatment.

The most common side effects of Viltepso include upper respiratory tract infections, injection site reactions, cough, and fever.

Amondys 45

Amondys 45 (casimersen), by Sarepta, is intended to treat people with DMD caused by mutations amenable to exon 45 skipping, estimated to affect about 8% of DMD patients. Granted accelerated approval by the FDA in 2021, it is the newest of the four treatments.

The therapy has been shown to increase the levels of dystrophin in muscle.

Amondys 45 is administered once weekly via an infusion lasting 35-60 minutes. Upper respiratory tract infections, cough, fever, headache, and pain in the throat and/or joints were the most common side effects of this medication.

Experimental exon-skipping therapies

Many potential exon-skipping therapies for DMD are being developed, and several are in early clinical testing.

• NS-089/NCNP-02, from NS Pharma, is designed for patients with mutations amenable to exon 44 skipping.
• NS-050/NCNP-03, also from NS Pharma, is a potential therapy for patients with mutations amenable to exon 50 skipping.
• Avidity Biosciences is developing AOC 1044 for patients amenable to exon 44 skipping.
• DYNE-251, by Dyne Therapeutics, is being developed for patients amenable to exon 51 skipping.
• WVE-N531 is being developed by Wave Life Sciences for patients amenable to exon 53 skipping.
• PepGen is developing PGN-EDO51 to treat patients amenable to exon 51 skipping.
• Sarepta is developing a next-generation version of Exondys 51, called SRP-5051 (vesleteplirsen), for patients amenable to exon 51 skipping.

Potential risks and issues

Some patients have experienced allergic reactions to approved exon-skipping therapies, including Exondys 51, Vyondys 53, and Amondys 45. If an allergic reaction occurs, it may be necessary to slow the therapy infusion rate or discontinue treatment.

Several exon-skipping therapies — including Viltepso, Vyondys 53, and Amondys 45 — also have been reported to cause kidney toxicity in some patients. Thus, kidney function should be monitored regularly while patients are on these treatments.

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