What is gene therapy, and what could it mean for people with epilepsy?

Dr Gabriele Lignani
ERUK Emerging Leader Fellow
University College London

 

This week we caught up with ERUK Emerging Leader Fellow Dr Gabriele Lignani. Dr Lignani is based at the Queen Square Institute of Neurology, University College London. His ERUK-funded research focuses on the use of gene therapy to treat epilepsy. But what exactly is gene therapy?

Epilepsy is estimated to affect around 1% of the population and for one third of these patients there is still no available treatment. The causes of epilepsy are diverse and include infections, brain damage and stroke. However, a common cause can be found in our genetic code – our DNA – or our genes. Gene therapy is an exciting type of treatment that can change or modulate our genetic code to correct errors and to treat the causes of a disease rather than just its symptoms.

But, firstly, what is a gene?

Our body is formed of many different, very small bricks: the cells. Each cell type is specific for a different part of our body, such as the brain, heart, blood, skin and so on. If we consider that one of the most important, the brain cell – known as a neuron, is so small that we need more or less 100 billion of them to create an entire human brain, we can imagine just how complex our body is. All the cells in the same body have the same DNA but only some parts of it are active in the neurons, while other parts are active in blood cells, for example. These DNA parts are called genes. Different cells have different functions thanks to their genes. Human DNA has around 20,000 genes and it is what makes us different from one another.

But how does it work?

Like languages with alphabets, the language of DNA is formed using a simple “alphabet” of 4 molecules. By ordering the molecules one after the other we are able to create “words”, the genes. Each gene means something, just as words do in language. This something is defined by proteins. The proteins are the expression of the genes and are at the basis of everything that happens in our cells: they form them, shape them and make them functional. To understand the complexity just imagine that the DNA in each cell of our body is composed of around 6 billion letters, equal to 1000 times the entire collection of Harry Potter books.

Mistakes in this long code are known as ‘genetic mutations’ and can lead to the development of several disorders. For instance, when a neuronal gene and related protein are altered, this can lead to neurological disorders. But imagine if humans had a tool that allowed them to correct these mistakes as simply as a typo in Microsoft Word. Imagine if humans could treat or even reverse neurological disorders with this tool.

So what is gene therapy?

Gene therapy encompasses a range of treatment strategies that can be used not only to correct mutated genes, but also to modulate how many genes function together in a cell to control its properties. This is very important for epilepsy, because despite its possible multiple causes, the final outcome is always too much electrical activity, otherwise known as seizures. Therefore, with gene therapy we have the potential to modulate genes in a way that will stop seizures, no matter the cause.

A good analogy is that of a sound mixer. The sound you hear is the combined result of many different settings and the mixer tunes the individual settings to create the sound you like. The electrical activity of brain cells represents the sound and the different knobs on the mixer are the genes. Tuning the genes with gene therapy can change the abnormal activity of brain cells in epilepsy and stop seizures.

When did you start working on gene therapy and what is your work about?

Finding a new treatment for epilepsy using gene therapy has been my main focus since I started working at UCL 6 years ago, after previously studying the disease mechanisms of epilepsy. My main focus, which is also part of my Epilepsy Research UK Emerging Leader Fellowship Award, is to use innovative genetic tools to develop new gene therapy approaches and to broaden the portfolio of possible treatments for patients with hard to treat epilepsies. I have pioneered new ways to precisely treat brain cells in order to develop more effective gene therapies, taking advantage of recent technological innovations such as “CRISPR”.

CRISPR is a very powerful genetic tool that can be used to target specific genes. CRISPR has the ability to change the genetic code, for example to correct a mutation, or to increase the function of a gene in a cell (turn up its “sound”). CRISPR is relatively easy to design, cheap, fast to test and holds massive potential in treating brain diseases such as epilepsy. Theoretically, there is a possibility of using CRISPR to prevent genetic diseases directly in embryos, but this has raised ethical concerns, such as fears surrounding ‘designer babies’. We must first gain a complete understanding of all the pros and cons of this radical new technology before this technology can be used in the womb.

What is the future for gene therapy?

Finding new treatments, such as gene therapy, for genetic and non-genetic epilepsies is the way forward. I really hope that gene therapy will soon represent one of the possible treatment options for epilepsy patients for which current treatments are unable to control their seizures.

-Dr Gabriele Lignani

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