If you’re a parent or caregiver of a child with Duchenne muscular dystrophy (DMD), you’re all too familiar with the challenges this condition presents. DMD is a genetic disorder that causes muscles to get weaker over time. But there’s good news — researchers are making progress on new treatments that can offer hope to children with DMD. One of these emerging treatments is called exon-skipping therapy.

This article will cover what exon-skipping therapy is, how it works, and how it can help treat DMD.

What Is Exon-Skipping Therapy?

Imagine your child’s muscles as a set of building blocks. Each block represents a segment of a protein called dystrophin, which helps keep muscles strong. In DMD, one or more of these blocks are broken or missing because of a mutation (variation) in the DMD gene. This means the muscles can’t hold together well, leading to muscle atrophy (muscle loss), degeneration, and damage.

Exon-skipping therapy works like a repair kit for these broken blocks. Although it doesn’t replace the missing pieces, it helps the body skip over the faulty parts, allowing it to produce a shorter but still functional version of dystrophin. This helps the muscle cells hold together better and can slow down the weakening of the muscles.

For genetic disorders like DMD and similar ones — including Becker muscular dystrophy (BMD) — exon-skipping therapy offers a new way to fight these diseases at their root cause.

How Does Exon-Skipping Therapy Work?

Think of the dystrophin gene as a set of instructions for how to make the dystrophin protein. This set of instructions (or pieces of RNA) is divided into 79 segments called exons. In DMD, one or more of these exons are missing or mutated, causing the instructions to become scrambled. As a result, the body can’t build the functional dystrophin protein.

Exon-skipping therapy is a type of gene therapy that uses a special kind of molecule called antisense oligonucleotides (AONs). These AONs act like a sticky note that covers up the mutated part of the gene. By skipping over the faulty part, the body can still read the rest of the instructions and make a shorter but functional version of the dystrophin protein. Although this isn’t a perfect solution, it can improve muscle function and help preserve muscle strength for a longer period.

Exon-Skipping Therapy May Help People With DMD

People with specific genetic mutations in the DMD gene might benefit from exon-skipping drugs, which work at the precursor messenger RNA (pre-mRNA) stage of gene expression. This means they can change the faulty instructions before the muscle cell “reads” them to build new dystrophin proteins.

These treatments can be used when a mutation affects a specific exon in the DMD gene. Normally, during pre-mRNA splicing, cells “read” the gene to make the dystrophin protein. Exon-skipping drugs tell cells to skip over the mutated part of the exon. As a result, they can string together the remaining parts, allowing the cell to read the instructions more clearly and produce higher levels of dystrophin expression. In people with DMD, this helps stabilize muscle cells and can slow down muscle degeneration.

Clinical Trials and New Developments in DMD

The research into exon-skipping therapy is moving quickly. Several exon-skipping drugs have already been approved, and more are in the works in ongoing clinical trials.

Exondys 51

Eteplirsen (Exondys 51) is the first exon-skipping drug in its class to be approved by the U.S.Food and Drug Administration (FDA) for the treatment of DMD. It was approved in 2016 and works for people who have mutations in exon 51 of the DMD gene. This makes up about 14 percent of people with DMD.

Vyondys 53 and Viltepso

The FDA approved two more exon-skipping drugs — golodirsen (Vyondys 53) and viltolarsen (Viltepso) — in 2019 and 2020. These two treatments work for people with mutations in exon 53 of the DMD gene. About 8 percent of people with DMD have this specific mutation and may benefit from one of these therapies.

Amondys 45

In 2021, casimersen (Amondys 45) also gained FDA approval. This version targets mutations in exon 45 of the DMD gene, which affects about 8 percent of people living with DMD. If your child is affected by this part of the gene, they may be a good candidate for this type of exon-skipping therapy.

About 1 in 3 people living with DMD may benefit from one of these exon-skipping drugs. If your child has genetic deletions in other exons on the DMD gene, these therapies won’t help. However, the good news is that researchers are already working on similar versions of these treatments that target other exons.

AOC 1044

AOC 1044 is an experimental therapy for people with DMD being studied in clinical trials. It works on mutations in exon 44 of the DMD gene. The FDA hasn’t yet approved it but has granted it designations that reflect its potential as a new therapy for people with DMD. Talk to your health care provider if you or a loved one is interested in joining a clinical trial for DMD treatments.

You can also learn more about participating in ongoing research studies for DMD by going online. Review this list of clinical trials from the Muscular Dystrophy Association to see if there are any that are relevant or accessible to you.

Potential Benefits and Limitations of Exon-Skipping Therapy for DMD

Exon-skipping therapy won’t cure DMD, but it could significantly slow the disease progression and make a real difference in your child’s life.

Potential Benefits of Exon-Skipping Therapy for DMD

Some DMD treatments can only manage the symptoms that come along with the condition, but exon-skipping therapies target the root cause at the genetic level. It’s not a cure, but it helps the body make a working version of dystrophin and build stronger muscles. This can help to prevent or slow the weakening of muscles that happens over time, potentially keeping children longer than they would without treatment.

Genetic therapies such as exon-skipping therapy can be used in combination with other treatments for DMD. These can include mobility aids, medications, surgery, and exercise or occupational therapies. Talk to your health care team about what combination of therapeutic approaches is best for your child — together, they could make a big difference in slowing the progression of DMD.

Limitations of Exon-Skipping Therapy for DMD

Exon-skipping drugs are new treatments, so the long-term effects are still unknown. As research continues, experts will learn more about what long-term consequences could result from these types of therapies.

As with any medical treatment, there are side effects that could happen, too. Some of the most common adverse side effects of exon-skipping therapy are:

• Upper respiratory tract infections
• Kidney toxicity
• Injection site reactions
• Cough
• Fever

Be sure to talk with your health care team about all the possible side effects of exon-skipping therapy before making final treatment decisions.

So far, exon-skipping therapies are only approved for three specific deletions of the DMD gene — exons 51, 53, and 45. This means that 2 out of 3 people living with DMD are unlikely to benefit from the exon-skipping drugs that are currently available.

Long-Term Outlook for Exon-Skipping Therapy in DMD

For parents and caregivers, staying in the know about the latest developments in exon-skipping therapy is crucial. Exon-skipping therapy isn’t a perfect solution, but it’s a big step forward in the fight against DMD. Researchers are making a lot of progress, and new treatment options are on the horizon.

If you think your child might benefit from exon-skipping therapy or want to learn more about ongoing clinical trials for DMD, talk to your health care team about it.

Talk With Others Who Understand

On myDMDcenter, people with Duchenne muscular dystrophy and their loved ones come together to gain a new understanding of DMD and share their stories with others who understand life with DMD.

Have you or a loved one undergone exon-skipping therapy for DMD? What has your experience been like? Share more in the comments below.