What is this study about?

Mitochondria are the energy factories of the cell. Due to an error in the DNA of the mitochondria, called a mutation, malfunctioning of the mitochondria can lead to mitochondrial disease. As a result, the parts of the body that need a lot of energy, such as the muscles and brain, are most affected. About half of all people who have the m.3243A>G mutation in the mitochondrial DNA suffer from muscle complaints and are easily fatigued during exercise. There is currently no treatment available for this.

In your muscles, there are stem cells located that can multiply and form new muscle fibres. In your body these are generally not very active, but they can be multiplied to huge amounts in a laboratory. Moreover, as the m.3243A>G mutation load varies between cell types, we have shown that these muscle stem cells contain only a very low level of the mutation in about half of the people with the m.3243A>G mutation. Introducing your own healthy muscle stem cells into a blood vessel could lead to the formation of new muscle cells with less mutation. Last year we conducted a study in which the muscle stem cells of the patients themselves were injected once into a blood vessel in the lower leg. This was proven to be safe. However, we believe that three administrations are needed to bring enough stem cells into the muscle, which is what this study is testing.

Who can take part? 

You may be eligible to participate in this trial if you:

• Are 18 to 65 years of age.
• Have a confirmed diagnosis of Primary Mitochondrial Disease caused by the 3243A>G mutation in mitochondrial DNA.

What is being tested?

In this study, we want to take a muscle biopsy to isolate and multiply the muscle stem cells and then inject these cells into a blood vessel in your upper arm three times over a period of 3-4 months. We will investigate whether introducing your own muscle stem cells into the body is safe and leads to the formation of new muscle cells, and whether the m.3243A>G error is less present in these new muscle cells. We will do this by taking measurements of the muscle and by examining pieces of muscle and counting the number of new muscle cells.

What’s involved in taking part?

Participation will include six study visits to the clinical trial site for 1 or 2 days over a period of 9 months. At visit one, a muscle biopsy of the left upper arm is collected to analyse the stem cells. If these stem cells fulfil the criteria, participants will come to Maastricht University Medical Centre in the Netherlands for five additional visits. If the stem cells do not fulfil the criteria, study participation ends after the first visit. At the second visit, a muscle biopsy of the left upper arm will be collected in order to culture the stem cells for administration. At visits three, four and five, exercise of the arms is performed and one day later, the participant’s own muscle stem cells will be administered in the left arm. To this end, a very thin tube (catheter) will be inserted into an artery in the upper leg and is moved to the left upper arm to administer the muscle stem cells. In order to assess the safety and effectiveness of the stem cell administration, strength tests of the arms (every study visit), blood sampling (every study visit), MRI (two times at visits two and six), and a muscle biopsy of the left upper arm (visit six) will be performed.

Will there be any costs associated with my participation in the study?

You will receive the study medication and all study-related care at no charge. You and a caregiver will be compensated for the time, travel and accommodation involved.

Where is the study taking place?

This study is being run at Maastricht University Medical Centre in the Netherlands. Participants will need to travel there six times to the study centre for 1 or 2 days over a period of 9 months.

Are there any risks?

Blood samples are collected during this study. Taking blood from your arm may lead to a bruise that heals on its own.

The movement exercises could lead to muscle pain in the upper arms, which will recover on its own in a few days.

Taking a muscle biopsy can be painful. There is a small chance that a bruise may occur, but if this happens it will heal by itself. If a skin branch of a sensory nerve is damaged, this can lead to a numb spot on the arm. There is also a very small chance of a bacterial infection, however if this happens you would be treated with antibiotics.

The administration of your own muscle stem cells can cause discomfort:

• An inflammatory reaction or clot may occur. As a precaution, all participants will be admitted to hospital for 8 hours after administration to monitor this and to treat it immediately if necessary.
• Discomfort may be experienced in the treated arm during the administration of the cells. Afterwards, the skin around the treated muscle may itch and/or show a red rash, which will disappear within a few days.
• Placing a very thin tube in your artery for administering the stem cells may result in leakage from the insertion site and/or groin bruising. You may not do any heavy lifting and/or exercise for a week.
• X-rays are used, which carry a small risk of radiation.
• If the stem cells do not meet all quality requirements, for example the number of cells is less, the doctor will discuss with you whether you agree that these cells are administered.
• Inserting the stem cells can also have side effects that we do not yet know.

Who will benefit?

There is no guarantee that you will receive any benefits. However, you will be helping others by contributing to medical research. You may feel that you are benefitting in the following ways:

• Your condition will be closely monitored for the duration of your participation in the study. However, all assessments carried out as part of the study should not be seen as a substitute for the careful evaluation, ongoing medical care, or follow up by your local and specialist clinical teams.
• The study drug may help to relieve your symptoms, though we cannot guarantee this and this is the reason we are carrying out this study.

How do I find out more?

If you think you might be eligible and are interested in taking part in this research, or would like any further information, please contact the study team directly:

Department of Toxicogenomics, Maastricht UMC, Maastricht, The Netherlands.

Contact study team: [email protected].

In addition, you can contact your specialist mitochondrial centre for information and advice.

We spoke to Bert Smeets, who is leading this study, to find out more about this research and what motivates him. You can read our interview with Bert here.