Exon Skipping

Exons are segments of a gene that encode for protein. The DMD gene, which is responsible for the production of the key muscle protein dystrophin, is one of the largest human genes known and contains 79 individual exons.  
 
Mutations, such as deletions, duplications, or point mutations in the DMD gene, may prevent the production of dystrophin, leading to the progressive muscle degeneration seen in Duchenne muscular dystrophy (DMD). Treatments like exon skipping aim to allow the production of a truncated but functional dystrophin protein.

Our genes are divided into exons and introns which contain the instructions for making proteins like the dystrophin protein. Exons (also referred to as the coding regions) contain the information to make the protein, whereas introns (also referred to as non-coding regions), get removed.   

The DMD gene has 79 exons that together make up the complete coding region for producing dystrophin, a protein that is crucial to maintain muscle strength and structure. In Duchenne, there are mistakes or mutations in the genetic code of the DMD gene that result in the inability to make dystrophin protein. Most of these mutations or errors take place in the coding regions of the gene. 

What is Exon Skipping?

Exon skipping is a way to treat DMD. This approach involves bypassing (or skipping over) a specific section of the genetic code, called an exon, to help the body create a slightly shorter but still functional dystrophin protein.

Watch this video about Exon Skipping  >>>

How Does Exon Skipping Work?

  • Exons need to fit together in a precise way to make the complete protein.  The “shape” of the boxes indicates how each exon has to fit precisely with the next one.  
  • When you have a deletion in one or more exons, the boundaries may now not match up exactly, so the reading frame is disrupted.  In that case, the dystrophin protein is not made.  
  • Exon skipping attempts to “skip” over another exon adjacent to where the deletion is, to set the reading frame back on track (or get the shapes to match up.)
  • This process doesn’t cure DMD but may slow the progression of muscle weakness and other symptoms. 

Who Could Benefit?

Currently, there are a few FDA-approved exon skipping drugs (see below) and more in clinical trials. The approved drugs skip exons 51, 53 and 45, which could treat up to 29% of all DMD patients. It is thought that up to 80% of DMD could potentially benefit from exon skipping if it is applied to other mutations. 

Because exon skipping is available for certain mutations, it’s important to have genetic testing performed to determine if it’s right for someone with DMD. 

Duchenne Population Potentially Amenable to Exon Skipping

Duchenne Exon Skipping
Duchenne population theoretically amenable to exon skipping was determined through the following sources:    Fletcher, S., et. al. Dystrophin Isoform Induction In Vivo by Antisense-mediated Alternative Splicing. The American Society of Gene & Cell Therapy. 2010;18(6):1218-1223. Annemieke Aartsma-Rus, et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy. Hum Mutat. 2009 Mar;30 (3):293-9. 

To understand exon skipping, download
the Exon Map Explorer app (iOS only)

Approved Therapies

Several exon skipping drugs have been approved by the FDA. Discuss with your healthcare provider if these might be suitable for you:

**We recommend you discuss with your healthcare provider whether you or your child may be eligible for these treatments. Your care team can also help advocate for insurance coverage, if needed. 

Combination Therapies

Exon skipping therapy is usually combined with “standard of care” treatments such as steroid or cardiac medications.  As more drugs are approved for Duchenne, it will be increasingly possible for individuals to receive different combinations of therapies. It’s best to talk to your physician about the right approaches and treatment protocols for you or your child. 

Clinical Trials

In addition to the FDA-approved exon skipping therapies, there are many other experimental exon skipping therapies in clinical trials.  Goals of current therapies in clinical trials include:

1. Expand target exons

Researchers are working on targeting more exons in the DMD gene so the therapy will work for a larger number of individuals with Duchenne.

2. Improve targeting and delivery methods

 Researchers are exploring new delivery systems that could target more of the drug to all muscle groups—including the critical heart and diaphragm. 

3. Extend the time between dosing

The first FDA-approved exon skipping therapies are administered by a weekly infusion, but researchers are studying ways to extend the time between dosing to decrease the burden on families.

4. Confirm long-term safety and efficacy

Even after a therapy receives FDA approval, follow-up studies monitor the sustained effects and potential side effects of these treatments over time.

If you are interested in exploring a clinical trial for an exon skipping therapy, talk to your physician to review trial eligibility and site locations.  

To find the most up-to-date information on clinical trials for exon skipping therapies, you can visit ClinicalTrials.gov, drug sponsor company websites or our Clinical Trials page. You can also schedule a one-on-one session with a member of the CureDuchenne team. 

CureDuchenne Research Funding

CureDuchenne is a leader in accelerating research for treatments Duchenne. We invest in innovative and promising approaches, including exon skipping and other genetic and molecular strategies, through our venture philanthropy and investment arm, CureDuchenne Ventures. 

Get One on One support

Still have questions about exon skipping? Want to learn more about available treatments or clinical trials? Schedule a one-on-one session with CureDuchenne’s expert scientific team.

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