Exon Skipping for Duchenne Muscular Dystrophy

Exon skipping is a treatment approach for people with Duchenne muscular dystrophy (DMD) that is caused by certain genetic mutations.

Duchenne, the most common type of muscular dystrophy, is marked by progressive muscle degeneration. DMD is caused by mutations in a gene called DMD, which provides cells with instructions for making a protein called dystrophin.

Dystrophin works with other proteins to maintain the integrity and structure of muscle fibers in skeletal and heart muscles. (Skeletal muscles are those that control movement.) In Duchenne patients, a mutation in the DMD gene leads to a lack of dystrophin production. As a result, cardiac and skeletal muscles weaken and are progressively damaged, with symptoms beginning to be evident in early childhood.

DMD-causing mutations generally result in no functional dystrophin being made, whereas 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). As the DMD gene is located on the sex-determining X-chromosome, both DMD and BMD primarily affect males.

Exon skipping works like a “molecular patch,” so that the DMD gene in people with Duchenne can produce a shorter, but still functional version of the dystrophin protein to help protect and maintain the strength of muscle fibers.

What is an exon?

Protein-coding genes such as DMD are made up of alternating pieces, called exons and introns. Exons contain the instructions to build proteins, whereas introns are regions between exons that do not code for protein, but may have other functions (for instance, regulating gene expression). The DMD gene, which has 79 exons, is the largest gene in the human genome.

When the DMD gene is “read,” the cell makes a temporary copy of the genetic code called messenger RNA (mRNA), which is shuttled from the nucleus where DNA is housed out to the cell’s protein-making machinery, called ribosomes. At first, the gene’s mRNA contains the exons as well as the introns, but before the mRNA is “read” to produce a protein, the introns all are removed through a process called splicing. The exons are strung together to produce the mature mRNA that is “read” by the ribosomes to produce dystrophin protein.

Disease-causing mutations in the DMD gene can cause one or more exons to be missing. In Duchenne, once cells remove the introns, the remaining exons do not fit together properly; as a result, they cannot be “read” to produce a working protein, leading to a complete absence of the dystrophin protein.

By contrast, in Becker, the remaining exons are still able to fit together and the cell’s protein-making machinery can read them. This results in the production of a shorter, but still functional, dystrophin protein — and a less severe form of muscular dystrophy.

How does exon skipping work?

The idea behind exon skipping is to mask specific exons in a gene sequence. This involves using short strands of nucleic acids (which make up DNA and RNA) called antisense oligonucleotide to induce the cell to remove one or more exons, along with all the introns, during mRNA splicing.

In patients with specific disease-causing mutations, skipping or masking certain exons can work to establish a “fit” with nearby exons, essentially resulting in a situation similar to BMD where cells can produce a shortened but functional form of the dystrophin protein.

Exon-skipping therapies that target a given exon will not work for all patients. For example, exon 51 skipping will work in about 13% of DMD patients, because the disease they have is amenable to masking exon 51. Skipping either exon 45 or 53 may be beneficial in about 8% of DMD patients.

An estimated 80% of DMD patients have genetic mutations that are amenable to exon-skipping, while the remaining 20% have mutations that cannot be targeted with this strategy.

Current exon-skipping therapies

To date, the U.S. Food and Drug Administration (FDA) has approved four exon-skipping therapies for DMD. All have been given conditional authorization under the accelerated approval pathway based on early clinical evidence that the treatments can increase dystrophin levels in patients with amenable mutations. Accelerated approval is granted to therapies where early biological data indicate the treatment is likely to benefit patients, but where hard evidence of a clinical benefit has not yet been established.

Exondys 51 (eteplirsen) is an exon 51 skipping therapy, sold by Sarepta Therapeutics, that received accelerated approval from the FDA in 2016 — the first therapy to be approved in the U.S. to treat DMD.

Another Sarepta treatment, called Vyondys 53 (golodirsen), was approved in December 2019 for DMD patients amenable to exon 53 skipping.

Sarepta also markets Amondys 45 (casimersen) for patients amenable to exon 45 skipping and which received accelerated approval from the FDA in early 2021.

Viltepso (viltolarsen), developed by Nippon Shinyaku, was given accelerated FDA approval in August 2020. The therapy, which works to skip exon 53, is also approved for patients in Japan.

 

Last updated: Feb. 14, 2022, by Marisa Wexler MS

 


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