POLG disease is one of the most severe forms of mitochondrial disease, affecting babies, children and adults. Researchers around the world are working to better understand the condition and develop new treatments, including at the LifeArc Centre for Rare Mitochondrial Diseases.

The POLG gene is a nuclear gene, meaning it’s found in the main DNA inside our cells rather than in the mitochondria themselves. However, it plays a vital role in maintaining mitochondrial DNA, a smaller set of genetic material found inside mitochondria, which helps them produce energy. When the POLG gene is not working properly, mitochondrial DNA can become damaged, leading to problems with energy production and a wide range of symptoms.

We have two copies of the POLG gene, one inherited from our mother and one from our father. In many cases, problems arise when both copies of the gene are faulty. This often leads to severe disease in babies and young children, sometimes affecting the liver and causing epilepsy.

In some cases, a change in just one copy of the POLG gene can also cause disease. These forms are usually milder, develop later in life and may include symptoms such as vision problems, hearing loss and fatigue.

You can read more about how these inheritance patterns work in our Research Zone.

Why is POLG disease so difficult to treat?

There are currently no medicines approved to treat POLG disease.  Therapies need to work across many different parts of the body that can be affected, which can include our nervous system, and that’s hard for medicines to reach. We also don’t have good ‘models’ of POLG disease. Models are miniature versions of disease (often made from cells donated by patients and relatives, or non-human animals) which present similar features of the disease. Models are extremely useful because we can try new medicines on them, to check to see if they work, or have unexpected side-effects, before testing them in humans.

Building better models to study the disease

Mouse models can sometimes be made which develop similar symptoms to humans. These mouse models allow scientists to study how the disease progresses and to test potential therapies.

However, this isn’t straightforward. For reasons we don’t fully understand, mice are more tolerant of mutations that cause mitochondrial disease in humans, and so don’t always go on to develop the same symptoms.

To address this, researchers across the UK and in Italy are working together to develop better mouse models of mitochondrial disease. By improving how these models are created and studied, they hope to give researchers more reliable tools for testing new therapies.

Exploring new gene therapy approaches

Alongside this work, researchers are also exploring whether gene therapies could be used to treat POLG disease.

Gene therapies aim to correct or replace faulty genes. In POLG disease, this is particularly complex, and researchers are testing several different approaches.

One approach is to deliver a new, healthy copy of the POLG gene into cells. Because the gene is very large, researchers are working on ways to deliver it in smaller pieces that can be assembled once inside the cell.

Another approach aims to repair the faulty gene inside patients. This involves using specially designed molecules to correct the faulty copy of POLG and restore its function.

Researchers are also exploring ways to treat forms of POLG disease caused by a single faulty gene. In these cases, the goal is to encourage cells to use the healthy copy of the gene instead of the faulty one.

What does this mean for patients?

This research is still at an early stage. Scientists first need to test these approaches in cells and in laboratory models, and understand whether they’re safe.

It’s not yet known whether any of these strategies will lead to treatments for patients. However, this work is an important step forward. POLG mutations are one of the most common causes of mitochondrial disease, and their effects can be severe.

By developing better models and exploring new ways to target the POLG gene, researchers hope to lay the foundations for future treatments.

Watch out for our POLG webinar taking place later this year – keep an eye on our socials to find out more.