Why is this research needed?
Around 1 in 2,000 babies born in the UK have epilepsy due to a single error or variant, a bit like a spelling mistake, in their genetic code. These genetic epilepsies consist of seizures, but also difficulty with movement, mood disorders and learning disabilities. However, in most cases we simply do not understand how the genetic variant causes epilepsy and how we might most effectively intervene to help. It’s likely that the process starts before birth, making it extremely challenging to study in humans.
To try to understand how faulty genes might cause changes to the developing brain that could underlie epilepsy, I have developed a new way to study small pieces of developing human brain tissue in the laboratory. These samples have been donated to a special biobank called the Human Developmental Biology Resource. With ethical approval, I use the samples to study how genetic variants alter brain development to cause epilepsy in young children.
How will I carry out this research?
During my Epilepsy Research UK fellowship, I will utilise this new approach to modify specific genes associated with epilepsy and see how this affects developing brain cells. Initially I will focus on one of the most common single-gene epilepsies, called Syntaxin binding protein 1, or STXBP1. This gene is important for accurate communication between brain cells, like many other epilepsy risk genes, and is highly active during the earliest stages of brain development. Once I have identified the affect STXBP1 has on developing brain cells, I will assess the potential for this to be reversed or mitigated using gene therapy tools.
How can this research make a difference to people affected by epilepsy?
There is huge potential to translate the findings from the laboratory to directly benefit people affected by epilepsy. Initially, this project aims to inform families living with STXBP1–related epilepsy, their medical teams, and researchers, about how variants in the gene cause epilepsy. However, the major advantage of this new technique is how adaptable it can be to investigate any gene associated with epilepsy. Variants in over 400 genes can cause epilepsy and several more are discovered every year.
This approach highlights the effects of genetic variants in a developing human brain, and is an important step to bridge the gap from what can be learned in the lab to help test new treatments of people living with epilepsy. Once genes have been examined in this model, I will test a range of epilepsy drugs to determine which may be beneficial in treating genetic forms of epilepsy. This will be particularly helpful when developing gene therapies that target the faulty gene. I am really excited about the potential of this method to develop new knowledge that has the potential to transform the lives of people affected by epilepsy.
