DMD exon skipping is a targeted genetic therapy for some individuals with Duchenne Muscular Dystrophy. It enables the body to produce the muscle protein dystrophin in a modified form. This approach uses molecular patches to bypass genetic errors that would otherwise halt dystrophin production entirely. By doing so, it helps create a shorter but still functional version of the protein.
What is Duchenne Muscular Dystrophy?
Duchenne Muscular Dystrophy (DMD) is a severe, progressive muscle-wasting genetic disorder caused by mutations in the DMD gene. This gene provides instructions for making dystrophin, a protein that maintains the structural integrity of muscle cells during contraction and relaxation. Without functional dystrophin, muscle cells are easily damaged, leading to inflammation and the gradual replacement of muscle tissue with fat and scar tissue.
DMD is an X-linked condition, as the responsible gene is located on the X chromosome. Because males have only one X chromosome, a single mutated copy of the DMD gene will result in the disorder. Females, having two X chromosomes, are typically carriers and often do not exhibit the severe symptoms of the disease, as their second X chromosome usually carries a functional copy of the gene.
The Science of Exon Skipping
Genes contain coding sections called exons and non-coding sections called introns. During a natural process called RNA splicing, introns are removed from the pre-messenger RNA (pre-mRNA), and exons are joined to form a messenger RNA (mRNA) blueprint. This blueprint is read by the cell’s machinery in a specific sequence known as the reading frame.
In many Duchenne cases, a mutation such as a deleted exon disrupts this reading frame. This scrambles the genetic code, creating a premature stop signal that halts protein production. The result is little to no functional dystrophin.
Exon skipping uses synthetic molecules called antisense oligonucleotides (AOs) to correct this. These AOs bind to a specific exon in the pre-mRNA, acting as a molecular patch. This patch masks the targeted exon from the cell’s splicing machinery, causing it to be skipped, which can restore the reading frame of the final mRNA.
How Exon Skipping Aims to Treat DMD
The goal is to produce a dystrophin protein that is shorter than normal but still partially functional. This concept is modeled after Becker Muscular Dystrophy (BMD), a much milder condition. Individuals with BMD also have mutations in the DMD gene but naturally produce a shortened, functional form of dystrophin, leading to less severe symptoms.
This strategy is not a cure for DMD but aims to change the disease’s trajectory into a milder one. By enabling the production of a truncated dystrophin protein, the goal is to slow the progression of muscle weakness and preserve muscle function. This can help maintain mobility and delay other complications.
Current Exon Skipping Therapies
Exon skipping therapies are highly specific to an individual’s genetic mutation, so they are only effective for certain patients. Detailed genetic testing is required to determine if a patient is a candidate for an existing treatment. It is estimated that different exon skipping drugs could potentially treat a significant portion of the DMD population.
The medications are phosphorodiamidate morpholino oligomers (PMOs) administered via regular intravenous infusions. Several therapies approved by the U.S. Food and Drug Administration (FDA) target different exons.
- Eteplirsen (Exondys 51) is designed for patients with mutations amenable to skipping exon 51, which applies to about 13-14% of the DMD population.
- Golodirsen (Vyondys 53) and Viltolarsen (Viltepso) are both designed to skip exon 53 and are suitable for approximately 8% of patients.
- Casimersen (Amondys 45) targets exon 45 for a different subset of patients.
Ongoing research is looking into treatments for other exons to expand the number of patients who can benefit.
Real-World Impact of Exon Skipping
The real-world impact of exon skipping therapies shows both promise and limitations. Clinical studies confirm these treatments lead to dystrophin production in the muscles of treated individuals. However, the amount produced is often a small fraction of normal levels, and the response varies significantly among patients.
Regarding clinical benefits, some studies and patient reports indicate a slowing of disease progression. This is often measured with functional assessments like the 6-minute walk test. For some patients, the therapy helps maintain muscle strength and mobility for longer than would be expected without treatment.
The therapies face challenges. The drugs may not be delivered effectively to all muscle tissues in the body, particularly the heart and the diaphragm. The molecules also do not cross the blood-brain barrier, so they do not address cognitive aspects associated with the lack of dystrophin in the brain. Treatment is a lifelong commitment of regular infusions, and like any medication, there is a risk of side effects.