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

Dystrophin works with other proteins to maintain the integrity and structure of muscle fibers in skeletal muscles, those that govern movement, and in muscles of the heart. In Duchenne MD patients, a mutation in the DMD gene leads to a lack of dystrophin production and cardiac and skeletal muscles that are weak, with disease symptoms beginning in early childhood.

Becker muscular dystrophy is a  variant of Duchenne MD. In Becker patients, enough dystrophin is produced so that voluntary skeletal muscles are healthier and better retain their function.

Exon skipping works like a molecular patch so that the DMD gene can produce the dystrophin protein, at a lower than normal but working level, to help protect and maintain the strength of muscle fibers.

How do mutations in the DMD gene cause the disease?

Genes are divided into alternating pieces, called exons and introns. Exons are the section of a gene that contain the information needed to build proteins (coding areas of a gene), a process that introns (non-coding areas) are not directly involved in — with introns typically cut from a gene during protein synthesis, and exons read by the cell’s protein-making machinery. The exons that remain once the introns are removed will, in a healthy person, fit together like the pieces of a puzzle.

The DMD gene, which has 79 exons, is the largest gene in the human genome. DMD mutations can lead to certain exons being deleted or missing. This means that after the introns are removed, the remaining exons do not fit together properly and cannot be read and made into a protein. In Duchenne MD, the result is the complete absence of the dystrophin protein.

In Becker MD, even though some exons are missing due to a mutation, the remaining exons are still able to fit together and be read by the cell’s protein-making machinery. This results in the production of a shorter but still functional dystrophin protein; hence, the less severe muscular symptoms of this disease and a later age of symptom onset.

How does exon skipping work?

The idea behind exon skipping is to hide, or mask, specific exons in a gene sequence. In DMD patients, one or more exons can be masked with specific molecules called antisense oligonucleotides (AO), or “molecular patches,” near the place in the DMD gene where one or more exons are missing. Hiding select exons works to find a “fit” between remaining nearby exons, essentially resulting in a situation similar to what is seen in Becker MD. In other words, exon skipping works by  essentially — though not exactly — turning Duchenne MD into Becker MD, where a smaller but still functional dystrophin protein can be produced.

Because DMD can be caused by the deletion of different exons along the length of the DMD gene, oligonucleotides or molecular patches for a given exon will not work for all patients. For example, exon 51 skipping will only work in about  13 percent of DMD patients whose disease is amenable to skipping exon 51. Others may need skipping to take place for exons 53, or 45, etc.

Current exon skipping therapies

A number of exon skipping therapies are currently being evaluated in clinical trials.  An exon 51 treatment was given accelerated approval as a DMD therapy by the U.S. Food and Drug Administration (FDA) in September 2016, and is now available under the brand name Exondys 51 (eteplirsen) by Sarepta Therapeutics.

Exondys 51 is recommended as a once-weekly infusion treatment because oligonucleotides tend to wear off the exons they are patching after a few weeks.

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