Duchenne muscular dystrophy, or DMD, is a severe genetic disorder characterized by progressive muscle degeneration and weakness. It is one of the most common forms of muscular dystrophy, primarily affecting boys. The condition arises from flaws in the genetic instructions for building a protein for muscle cell integrity. As our understanding of the human genome deepens, therapeutic strategies are shifting towards addressing the root genetic cause of such diseases.
The Genetic Basis of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy is caused by mutations in the DMD gene, which provides the instructions for making a protein called dystrophin. The DMD gene is one of the largest in the human genome, containing 79 distinct segments called exons. These exons can be thought of as individual paragraphs in a long instruction manual; for the final protein to be assembled correctly, all paragraphs must be present and in the correct order.
The cellular machinery reads these exons in a specific sequence, known as the “reading frame.” The most common mutations causing DMD are deletions, where one or more exons are missing from the gene. If a deletion disrupts the reading frame, it’s called a “frameshift” mutation. This disruption leads to an early “stop” signal in the genetic code, halting the production of the dystrophin protein. The absence of functional dystrophin is what leads to the severe symptoms of DMD.
The Mechanism of Exon Skipping
Exon skipping is a therapeutic strategy designed to address the genetic errors that cause Duchenne muscular dystrophy. This approach uses small, synthetic molecules called antisense oligonucleotides (AONs). These AONs are engineered to bind to a specific exon in the pre-messenger RNA (pre-mRNA), which is the initial transcript of a gene. By binding to the target exon, the AON masks it from the cell’s splicing machinery, causing that exon to be “skipped” or left out of the final messenger RNA (mRNA) instructions.
The goal of this process is to restore the genetic reading frame that was disrupted by the initial mutation. For example, if the deletion of exon 50 causes exon 49 to connect improperly with exon 51, it disrupts the reading frame. An AON can be designed to hide exon 51, forcing the cellular machinery to skip it and instead connect exon 49 directly to exon 52. If this new connection restores the reading frame, the cell can once again produce a dystrophin protein.
This resulting protein is shorter than normal but is often partially functional. The outcome is similar to what occurs naturally in Becker muscular dystrophy, a much milder form of the condition. In Becker, patients have mutations that keep the reading frame intact, allowing for the production of a shortened but functional dystrophin.
Approved Exon Skipping Therapies
Regulatory bodies have approved several exon-skipping drugs, each targeting a specific exon within the DMD gene. These therapies are not a one-size-fits-all solution; they are designed for patients with particular genetic mutations that are amenable to being corrected by skipping a designated exon. The approvals have largely been granted through accelerated pathways, based on the drugs’ ability to increase dystrophin production in muscle tissue.
Eteplirsen (Exondys 51) was the first such therapy to receive approval from the U.S. Food and Drug Administration (FDA). It is designed to skip exon 51 of the dystrophin gene. Other therapies have become available, including Golodirsen (Vyondys 53) and viltolarsen (Viltepso), which both target exon 53 for skipping. Another approved treatment, casimersen (Amondys 45), is designed to skip exon 45. Each drug is a phosphorodiamidate morpholino oligomer (PMO), and their clinical benefit is still being evaluated in ongoing confirmatory studies.
Patient Eligibility and Treatment Outcomes
Eligibility for exon-skipping therapies is highly specific and depends entirely on a patient’s unique genetic mutation. A patient must have a deletion in the DMD gene that can be corrected by skipping the specific exon targeted by an approved drug. For instance, only patients whose genetic reading frame can be restored by skipping exon 51 are candidates for eteplirsen. Genetic testing is a necessary step to determine if a patient is eligible for one of these treatments.
It is estimated that the currently approved drugs targeting exons 45, 51, and 53 could treat up to 30% of all individuals with DMD. The primary goal of exon skipping is not to cure Duchenne muscular dystrophy but to act as a disease-modifying treatment. The main outcome measured in clinical trials for these drugs is an increase in dystrophin production within muscle cells, which is confirmed through muscle biopsies.
Clinical responses to these therapies can vary among patients. While the treatments have demonstrated an ability to increase dystrophin levels, the functional benefits and long-term outcomes are still under investigation in confirmatory trials.