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One of the most promising treatments for DMD is gene therapy. This involves delivering new genetic material to cells to overcome errors (or mutations) on the dystrophin gene.

DMD is an inherited, genetic disease. A gene is a very large molecule, and the gene for dystrophin is the longest known human gene. 

To treat DMD, we need to repair or deliver a new copy of this gene to every cell in the body where it is needed. 

In the last few years, huge progress has been made in gene therapy to treat DMD.

How does gene therapy work? 

Gene therapy is the delivery of working copies of a gene to the cells that need it.

Our cells have evolved ways of preventing intrusion from foreign molecules. To overcome this, researchers use vectors to carry the new gene into the cell. Currently, the most promising approach is based on the use of a relatively harmless virus called Adeno-associated virus (AAV) as the vector, as viruses have evolved to be able to get inside our cells.

Once inside the cell, viruses deliver their genetic material, and force the cell to make many copies of the virus. With most viruses, like colds or flu, this makes us feel unwell. However, if scientists remove the unwanted, disease-causing viral genes and replace them with genes that the body needs, like the dystrophin gene, it could help the body to produce the proteins it needs.

Researchers have created a shortened version of the dystrophin gene called microdystrophin so that it can fit into the AAV vector. In animal studies, microdystrophin has resulted in improved muscle function.

What are the challenges of gene therapy? 

Gene therapy for DMD poses some big technical challenges. This includes the body developing an immune response to the AAV, which prevents it from reaching cells. As the dystrophin gene is the longest in the body, it is also a challenge to find a delivery system which is large enough to carry it. 

Watch our video below to understand more about the challenges in gene therapy:

What gene therapy research is Duchenne UK funding?

Duchenne UK is funding research to overcome the challenges of gene therapy in DMD, with projects looking at:

• Progressing gene therapy into clinical trials
• Preventing the immune responses that can prevent AAVs from entering the body and delivering microdystrophin
• Exploring alternative delivery vectors for gene therapy that could carry a larger dystrophin gene

Gene editing, or genome editing, is a technology that enables the editing of parts of the genome (your body’s set of genetic instructions) by removing, adding or altering the DNA sequence.

This is an exciting new area of research that has the potential to make precise, targeted changes to correct the mutations that cause diseases like DMD.

How does gene editing work?

Researchers have developed techniques that use enzymes (called endonucleases) that work like a pair of molecular scissors to cut the DNA at a specific location. A guide RNA (gRNA) ensures that the enzyme cuts the DNA in the right place.

Once the DNA has been cut, the body tries to repair it. This removes the deletion that means dystrophin cannot be produced, and allows for the genetic sequence to be read.

This has not yet been tested in humans and has been mainly tested in animal models. As with gene therapy, there are several challenges to delivering it as a treatment. It also uses adeno-associated viruses (AAVs) to deliver the genetic material to the cell, and there is still work to be done to ensure that the gRNA only targets the area it is supposed to.

Although there are still many hurdles to overcome, this is a very promising area for DMD.

What gene editing projects are Duchenne UK funding? 

We are funding research into making gene editing a possibility for DMD, including:

• Early stage research looking at the use of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a genome-editing technology, to repair deletions in the dystrophin gene. (the majority of DMD cases are caused by deletion)
• Early stage research looking at the use of CRISPR to repair duplications on the dystrophin gene (approximately 10 – 15% of DMD cases are caused by duplication)
• Testing CRISPR techniques in-vivo (in a mouse model)

The active part of the dystrophin gene is made up of 79 pieces called exons. These exons link together to form a code that is read in the cells so that the protein dystrophin can be made.

In DMD, some of the exons are not readable. The result is that very little or no dystrophin is made.

How does exon skipping work?

Exon skipping drugs hide or ‘patch’ the missing piece so that the exons fit together again and can be read. This means that a functional, although shorter, dystrophin protein can be produced by the body. 

Exon skipping has been shown to work in animal models of DMD.  

As the exon skipping drug is designed to skip over a particular exon, different versions need to be made depending on which exons needs to be skipped. This is because people with DMD have different genetic mutations that cause the disease. The most common mutation is around exon 51 and accounts for approximately 13% of cases of Duchenne. 

EXONDYS 51 (previously known as eteplirsen) is an approved treatment in the USA that targets the 51 mutation. Existing treatments are administered by injection.  

Ataluren (sold under the brand name Translarna) is an approved treatment in the UK which treats DMD resulting from a nonsense mutation.

What exon skipping research is Duchenne UK funding?

We are funding research into more effective exon skipping treatments that target different mutations. This includes:

• Developing more effective and safer exon skipping treatments
• Investigating whether exon skipping can help to restore dystrophin in the brain

By improving the ways in which we collect and analyse data from DMD patients, we have a much better chance of proving whether treatments are effective or not. This not only speeds up the drug development process, but is essential to getting treatments approved so that patients can access them.

What is Duchenne UK funding in this area? 

We are funding studies that will help us to better understand the progression of DMD and better measure the difference that treatments make. This includes:

• Developing a set of Patient Reported Outcomes so that patients can record the day-to-day differences a treatment makes during clinical trials. This will provide a more patient and caregiver-focused evaluation, so that treatments are better assessed in trials and when being considered for approval by regulatory agencies.
• Increasing our understanding of how DMD progresses by analysing data from a six-year clinical trial of corticosteroid treatments. This data analysis will help us reduce the use of placebos in future trials, improve the way we measure outcomes, as well as better understand which corticosteroid treatments are safest.
• Monitoring the hearts of DMD patients to understand the prevalence of arrhythmias (heart rhythm problems) and cardiac scarring (when muscle is replaced with scar tissue). This is so that heart problems can be better detected and sudden deaths from heart failure can be prevented.
• Developing minimally-invasive biomarkers (measurable indicators of the severity of a disease) to measure muscle health. Current methods, which require the use of MRI scans and muscle biopsies, are invasive, expensive and time consuming. Researchers are looking at ways of measuring muscle health using blood and urine samples instead, so that diagnosing and monitoring DMD is easier and it is quicker and easier to evaluate treatments.

Before a potential treatment can be tested on humans in a clinical trial, researchers use animal models of the disease to understand the effectiveness of a treatment and its potential side effects.

The most commonly used animal model in DMD is called the mdx mouse. These are mice that have a mutation in the dystrophin gene, like humans with DMD. However, they show milder symptoms than humans, so we cannot guarantee that treatments that are effective in mdx mice will be equally effective in clinical trials. This means that research is held back by the lack of small animal models that are comparative to humans with DMD.

What research is Duchenne UK funding in this area?

We are funding research to increase the chance of potential treatments being effective in humans following animal studies. This includes:

• Improving understanding of how the disease progresses in a new mouse model, the D2-mdx mouse, vs. the classic mdx model
• Identifying best practice in the use of the mouse models of DMD when evaluating potential new treatments