Exon Skipping for Duchenne Muscular Dystrophy

Exon skipping is a treatment approach for people whose Duchenne muscular dystrophy (DMD) is due to certain mutations in its causative gene.

Duchenne is the most common and severe type of muscular dystrophy (MD), marked by progressive muscle degeneration. Mutations in the DMD gene, which encodes for a protein called dystrophin, cause DMD, which mostly affects boys.

Dystrophin works with other proteins to maintain the integrity and structure of muscle fibers in skeletal muscles and in muscles of the heart. (Skeletal muscles are those that control movement.) In DMD 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 disease symptoms beginning to be evident in early childhood.

Becker muscular dystrophy (BMD) is a variant of DMD with a slower progression. In Becker patients, the body produces a short version of dystrophin. Skeletal and heart muscles are somewhat healthier and better retain their function, but they also slowly degrade over time.

Exon skipping works like a molecular patch, so that the DMD gene can produce a shorter version of the dystrophin protein to help protect and maintain the strength of muscle fibers.

How do DMD mutations cause the disease?

When cells are making protein, they first make a copy of the gene that encodes for that protein. This copy is called messenger RNA or mRNA. Genes consist of alternating pieces, called exons and introns. Exons contain the information necessary to build proteins. Introns do not, and cells typically cut them from the mRNA before protein synthesis. They then fit the remaining exons back together, like pieces of a puzzle, to make them into a protein.

The DMD gene, which has 79 exons, is the largest gene in the human genome. DMD mutations can cause one or more exons to be missing. With Duchenne, once cells remove the introns, the remaining exons do not fit together properly, and they cannot be made into a working protein. A complete absence of the dystrophin protein results.

Exons can also be missing due to DMD mutations in Becker, but 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 MD.

How does exon skipping work?

The idea behind exon skipping is to mask specific exons in a gene sequence. In DMD patients, one or more exons can be masked with artificial pieces of mRNA that work like patches at the place in the DMD gene where one or more exons are missing, breaking the ability of the remaining exons to link together. Masking (or skipping) one or more exons at that break works to establish a “fit” with nearby exons, essentially resulting in a situation similar to BMD. Cells can again produce a smaller but functional dystrophin protein.

Because the deletion of different exons along the length of the DMD gene can cause Duchenne, mRNA patches for a given exon will not work for all patients. For example, exon 51 skipping will only work in about 13% of DMD patients, because the disease in these people is amenable to masking exon 51. Other patients may need exons 53 or 45, for instance, to be skipped for their remaining exons to fit together and protein production to resume.

Current exon skipping therapies

To date, the U.S. Food and Drug Administration (FDA) has approved three exon skipping therapies for DMD.

Exondys 51 (eteplirsen) by Sarepta Therapeutics is an exon 51 skipping therapy.

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

Viltepso (viltolarsen), developed by Nippon Shinyaku, was given conditional FDA approval in August 2020. It is also approved for patients in Japan.

A number of potential exon skipping therapies are also under testing in clinical trials.

 

Last updated: Jan. 29, 2021

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