Exon-skipping therapies for Duchenne muscular dystrophy

Exon skipping therapy is a treatment strategy for Duchenne muscular dystrophy (DMD) that, while not a cure, may help ease symptoms of the disease. Several DMD exon-skipping therapies have accelerated approval in the U.S., and others are in various stages of clinical testing.

What is exon-skipping therapy for DMD?

Mutations in the DMD gene cause Duchenne by disrupting production of the protein dystrophin, which helps protect muscles from damage. DMD-causing mutations typically result in cells making little to no functional dystrophin, leading to progressive muscle weakness and other symptoms.

A related condition called Becker muscular dystrophy (BMD) occurs when mutations in the DMD gene lead to the production of a shorter, but still partially working, version of dystrophin. People with BMD generally have milder symptoms than those with DMD.

The aim of DMD exon-skipping therapy is to allow people with DMD to produce a partially working version of dystrophin, similarly to people with BMD. Researchers believe this may help slow muscle damage and reduce the severity of DMD symptoms.

Exon-skipping therapy is not a cure for DMD. It does not stop the disease entirely, nor does it reverse muscle damage that has already occurred.

How exon-skipping therapies work

Exon-skipping therapies are designed to help a person’s cells make a shortened, but partially functional version of dystrophin that can still help protect muscles from damage. Understanding how these therapies work starts with knowing how cells use genetic information to make proteins.

Genes contain alternating sections called exons and introns. Exons carry instructions for making proteins, while introns do not directly code for proteins but have other regulatory functions. With 79 exons, DMD is one of the largest genes in the human genome.

Under normal circumstances, cells follow three main steps to produce dystrophin from DMD:

• Transcription: the information in the DMD gene is copied into a temporary molecule called pre-messenger RNA (pre-mRNA)
• Splicing: the pre-mRNA is edited to remove introns, leaving the exons joined together in a protein-coding sequence called messenger RNA (mRNA)
  
• Translation: the cell’s protein-making machinery reads the mRNA template to produce dystrophin
  

To properly translate mRNA, cells need the exons to fit together like pieces of a puzzle. In DMD and BMD, mutations often cause the loss of one or more DMD exons.

In BMD, the remaining exons can still fit together in a way that allows the cell to read the sequence and make a partially functional dystrophin protein. In DMD caused by mutations that disrupt this reading sequence, however, the exons don’t fit properly. The cell’s protein-making machinery can’t read the mRNA template correctly and produces little or no functional dystrophin.

The goal of exon-skipping for DMD is to skip certain DMD exons when processing RNA, allowing the remaining exons to fit together properly. This allows cells to produce a shortened, but still partially functional form of dystrophin, much like what occurs in BMD.

Existing exon-skipping therapies achieve this with antisense oligonucleotides (ASOs), which are short pieces of genetic material that bind to pre-mRNA and alter splicing to remove specific exons from the final mRNA template.

Who is eligible for exon-skipping therapies?

Researchers estimate that about 80% of people with DMD have a mutation that could theoretically respond to exon skipping. 

Each exon-skipping therapy targets one specific exon. Whether a person’s disease-causing mutation can be treated with that specific therapy depends on how the remaining exons would fit together after the target exons are removed.

Genetic testing, which is often part of the diagnostic process for DMD, can help determine if someone may be eligible for specific exon-skipping therapies.

Potential benefits of exon-skipping therapies

Evidence about the long-term clinical benefits of exon-skipping therapies remains limited. All exon-skipping therapies available in the U.S. initially received accelerated approval from the Food and Drug Administration (FDA) based on clinical trial data showing they increased dystrophin levels in muscles.

While an increase in dystrophin may help improve muscle health and motor function, data on how exon-skipping therapies affect DMD progression and motor function over the long term remain limited.

Ongoing clinical trials aim to answer these questions, with some data suggesting that these therapies may lead to improvements in motor function for people with DMD.

FDA-approved exon-skipping drugs

Among the approved DMD treatments in the U.S. are four exon-skipping therapies:

About 13% of people with DMD have mutations amenable to exon 51 skipping. Mutations amenable to skipping exons 45 and 53 each account for about 8% of the DMD population.

All four exon skipping drugs use ASO technology and are given through weekly intravenous (IV) infusions administered by a healthcare professional.

Experimental exon-skipping therapies

Many experimental exon-skipping therapies are in development. Several of these target the same exons as approved medications. Others target exons 44 and 50 — about 6% and 4% of people with DMD have mutations amenable to skipping these exons, respectively.

It is not yet known if or when these experimental exon-skipping therapies will be approved for DMD.

Potential risks and side effects

The full range of potential risks from exon-skipping therapies and other ASO therapies is not yet understood. Based on currently approved medications, possible exon-skipping side effects could include:

• Upper respiratory tract infections
• Cough
• Fever
• Headache
• Vomiting

However, the precise side effect profiles vary between therapies.

Some exon-skipping therapies, as well as certain other ASO-based medications, carry warnings about potential kidney problems. The reasons for this aren’t entirely clear, but close monitoring of kidney function is important to help reduce the risk of serious complications.

Exon-skipping therapies may cause allergic reactions during the infusion. Depending on the severity of the reaction, the healthcare provider administering the medication may slow the infusion rate or stop the treatment.

---

Muscular Dystrophy News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.