Duchenne UK is often asked about what gene therapy means for people living with Duchenne muscular dystrophy, and what the future of this therapy looks like. We have put together the following list of frequently asked questions to help you understand this potential treatment, which is currently being tested in clinical trials.
Visit out research glossary for an explanation of the terms used in DMD research.
Gene therapy is a new type of medicine used to treat conditions caused by faulty genes, like Duchenne muscular dystrophy.
In DMD, the faulty gene is the dystrophin gene. This gene is responsible for producing dystrophin, a protein which protects the muscles.
DMD gene therapy aims to deliver a working version of the dystrophin gene, so that the body can produce functioning dystrophin.
Researchers are currently testing two different approaches to treating DMD using gene therapy:
The questions and answers on this page refer to the ‘gene transfer’ type of gene therapy. Gene transfer is currently being tested in DMD clinical trials in the UK and abroad.
The potential benefits of gene therapy include protecting the muscles and preventing the progression of the disease. As all muscles in the body are affected by the lack of dystrophin, researchers expect that it could have muscle, heart, and breathing benefits.
However, gene therapy may not benefit people with advanced DMD. That’s because gene therapy will not be able to get into damaged muscle cells, that have been replaced by fat or fibrotic tissue (scar tissue).
Several gene therapies are currently being tested in clinical trials to assess whether they are effective and safe, and to understand benefits and risks. No gene therapies for DMD have yet been approved as treatments by regulatory authorities across the world.
Each gene therapy is designed differently and will have unique risks and side effects. We don’t know yet the full risk of using gene therapy.
Some studies in DMD have shown that an adverse reaction to gene therapy is possible.
In severe cases, a person’s immune system can have a strong reaction to gene therapy. This can cause the liver and kidneys to stop working, or a sudden inflammation of the muscle and/or the heart. These severe adverse reactions require hospitalisation, specialised treatment to reduce the immune-response against the gene therapy and temporary interventions such as dialysis (a procedure to remove waste products and excess fluid from the blood) or plasmapheresis (a method to remove antibodies from the blood).
In current trials, gene therapy is given to patients using an infusion into their bloodstream (intravenous). This is usually done by inserting a cannula (a thin tube inserted into a vein to administer medication) in one of the patient’s arms or hands and slowly injecting the gene therapy into the bloodstream.
The viral vector carrying the working copy of the dystrophin gene then travels through the patient’s bloodstream to deliver the genetic material to cells. The viral vector also carries a “promoter”, which is required to ensure that the working copy of the dystrophin gene reaches the right tissues (the muscle and heart for gene therapy in DMD).
The biggest challenges in DMD gene therapy are to do with the delivery of the dystrophin gene.
In current trials, gene therapy is delivered using a safe virus called adeno-associated virus (AAV).
Some patients may have already been exposed to this virus naturally. This means that they will have developed antibodies that destroy the virus and the gene within it before it gets to the muscle cells. As a result, the gene therapy won’t be delivered effectively.
Whilst AAVs are generally safe, they can cause side effects, including effects on the immune system, and the liver. This is because to deliver the gene therapy effectively to muscles, large quantities of AAV are needed.
Additionally, the dystrophin gene is very large and cannot fit into AAVs. For this reason, only a mini version of the gene is delivered (mini-dystrophin or micro-dystrophin), which will produce a shortened dystrophin protein. These smaller proteins have shown benefits in DMD animal studies in preserving muscle function, but their effects in humans are still being evaluated.
The video below explains these challenges (content accurate as of January 2020)
There are multiple types of AAV. Some of these are being used to deliver gene therapies for DMD (for example, AAV9), as they can better target the muscle cells and the heart.
If a patient has antibodies against one AAV, they may still be eligible for another gene therapy that uses another type of AAV that they have not been exposed to.
Because of this, patients will be screened for AAV antibodies before being enrolled on a gene therapy clinical trial.
Different trials use different AAV screening tests. Therefore, an independent AAV antibody test, taken outside of the trial, will not necessarily show whether a patient is eligible for specific trials. We advise families interested in screening for AAV antibodies to speak to their doctor before paying for independent tests.
We don’t yet know how long gene therapy will be effective for. This is being explored through clinical trials and long-term monitoring of patients.
The evidence so far suggests that gene therapy has the potential to increase or restore dystrophin function over a long period of time (8-10 years). However, this has not been proven, because gene therapies for DMD have only been in clinical trials for 3-4 years. This belief is based on studies in animals.
It is currently unknown whether repeat doses will be needed, but this is likely.
Researchers are working on approaches that may allow gene therapy to be given more than once, but we don’t currently know if this is possible.
All gene therapies currently in clinical development for DMD use AAV vectors. Once a patient has received AAV gene therapy, they will have been exposed to the AAV vector and developed antibodies against it. This means that they will not be able to receive a second dose using the same AAV.
If you take part in a gene therapy trial, it is likely that you will not meet the eligibility criteria for taking part in future trials (for other gene therapies or any other treatments). This is because the gene therapy could stay in the body for a long time. As a result, it would be difficult to test whether the new treatment being trialled is effective or not.
You will still be eligible to take approved treatments, as recommended by your doctor.
Many researchers and companies are looking into alternate delivery systems that could transfer the dystrophin gene to the body without using AAVs. Studies are currently being carried out in animal models, so we don’t know how or when these new delivery systems will be available to humans.
Before clinical trials began, researchers thought that AAV-based gene therapy could be available to patients with any genetic mutation. However, recent findings from clinical trial have shown that patients with some genetic mutations may be at risk of developing immune reaction to the gene therapy, which could cause severe side effects. Therefore, some trials are now excluding patients based on their mutations.
Whether you are eligible for a particular gene therapy trial is based on several criteria. Patients may be ineligible if they have pre-existing antibodies against the AAV used, or have previously received gene therapy and developed these antibodies.
Different trials may also include criteria such as age and whether the patient is ambulant (able to walk) or not, or the type of genetic mutation they have. This is because the trial is testing whether these criteria affect whether gene therapy is effective and safe for these patients.
Gene therapy aims to slow the progression of DMD, but current research suggests that it will not be able to repair existing muscle damage that occurred before treatment. For this reason, in older patients with advanced disease, muscle damage and the build-up of scar tissue (fibrosis) may limit the effectiveness of gene therapy.
We don’t know yet if gene therapy could replace the need for steroids, as this depends on the evidence from trials. At this stage, all patients who have had gene therapy should continue steroid treatment.
Currently, it is difficult to predict how long it will take for the first DMD gene therapy to become widely available.
Firstly, clinical trials need to demonstrate whether the gene therapies are effective and safe, so we can understand the extent of the benefits and risks.
Some gene therapies are in Phase 3 clinical trials, and companies are preparing to engage with regulatory agencies (such as the MHRA and NICE in the UK) to get approval to make them available to patients.
Eventually, we hope that gene therapy will become available to all patients regardless of where they live. However, this will take time as there are many different companies, healthcare systems and regulatory agencies involved.
We don’t know how much gene therapy will cost, but, if approved by the National Institute of Health and Care Excellence (NICE), we expect that it should be available on the NHS.
Visit the DMD Hub’s clinical trial finder to find out about every clinical trial for DMD taking place in the UK, including gene therapy. You can also sign up to the Central Recruitment Pilot Project to enable trial sites to contact you directly if you are potentially eligible.
Please note that the eligibility criteria for trials varies. Duchenne UK and the DMD Hub are not responsible for the direct recruitment of patients to trials, as this decision is made by the trial sites.
We cannot advise on trials recruiting outside of the UK. If you are based outside of the UK, use the Antidote clinical trial finder to find out whether there are any DMD trials near you.