We hear from the researchers, clinicians who are working to translate neuroscience discoveries into ground-breaking new diagnostics and therapies for patients
Gene therapy approaches to treat refractory epilepsy
Associate Professor Gabriele Lignani talks us through the process.
When neurons participate in a seizure (green), the new gene therapy activates to tamp down their future activity. Benito Maffei / University College London
What’s the motivation behind your research?
Epilepsy affects approximately 50 million people worldwide, including 600,000 people in the UK and despite optimal treatment 30% of these continue to have seizures.
While the majority of these people are able to use medications to manage and prevent their seizures, around one-third don’t respond well to these treatments. In such cases, the only option available to bring seizures under control is to remove the part of the brain where seizures arise. But this procedure is extremely risky and possible in a small percentage of cases.
Since epileptic seizures are caused by excessive activity of a proportion of brain cells (neurons) in specific parts of the brain, being able to target these neurons and turn them off could very well prevent seizures from happening.
What did your research involve?
My group studies the basis of brain pathologies such as epilepsy and we use this knowledge to develop innovative therapies to overcome limitations in current treatments for patients without any therapeutic options.
We start from the understanding of the basic mechanisms to the development of genetic therapy tools and to testing them in different models both animal and humans. Using an innovative new gene therapy approach we have developed, we were able to show that it is possible to specifically target the neurons that cause epileptic seizures. This subsequently prevented them from becoming overactive and causing seizures in the future.
My group is formed by researchers with different and complementary expertise to cover all the preclinical process from the idea to the assessment of the efficacy of these new therapeutic tools.
What is gene therapy?
Gene therapy works by directly altering a person’s genes in order to treat a disease or condition. Our innovative new gene therapy tool has shown it’s possible to alter only the brain cells that cause seizures, while leaving nearby healthy neurons unaffected.
The 20,000 or so genes we have in our body each contain instructions to make different proteins and molecules. These genes are typically under the control of neighbouring stretches of DNA, called promoters. These determine whether and how much of a particular protein is made. Different cells express different proteins depending on which promoters are active or inactive.
There’s also a special type of promoter (called “activity-dependent” promoters) that will only switch on in response to biochemical signals made by neurons when they fire intensely – such as during a seizure. We took advantage of these activity-dependent promoters, creating a gene therapy that senses and turns down the excitability of neurons that cause seizures.
Research like this can take several years if it is a major breakthrough. Our latest research (Qiu et al. 2022) took six years from the ideation to the publication of the results, and it will probably need another five years to see the treatment applied to patients.
Many people were involved in this last publication. Most of the work has been done by a fabulous PhD student, Yichen Qiu, with the help of six postdocs, four PhD students and a technician. Furthermore, the collaboration with different Principal Investigators (PIs) at ION, and in particular Dimitri Kullmann, and at Institute of Child Health for the human model, have been fundamental for the success of this project.
What were the outcomes?
We initially tested the gene therapy tool in neurons grown in a dish, and then in mice that had drug-resistant epilepsy. We also tested this technique in lab-grown human “mini brains”. In each test, we were able to show this new gene therapy technique was effective in calming down the overactive neurons involved in seizures, while leaving healthy bystander cells unaffected.
Although it takes an hour or so to switch on – longer than the typical duration of a seizure – the new gene therapy is highly effective in preventing subsequent seizures. It does this by automatically selecting which neurons to treat and switching them off. It’s also able to return neurons to their original state when brain activity returns to normal. If seizures occur again, the promoter is ready to switch on. The treatment therefore only has to be given once, but has a lasting effect – possibly lifelong. Importantly, the treatment did not affect the performance of the mice in tests of memory and other normal behaviour (such as their anxiety levels, learning and mobility).
Our study was published in Science in Nov 2022 and was very well-received in the scientific community. We have now a licence with industry to move this therapy to the patients with several investors interested in financing this study.
What happens now?
This discovery not only has major implications for treating drug-resistant epilepsy, but there’s a chance it may also be used to treat other neurological conditions caused by overactive neurons, including Parkinson’s disease and migraines.
We are excited by the breakthrough, because it could in principle bring the prospect of gene therapy to a wide range of people with drug-resistant epilepsy. But before the therapy is ready to use with these patients, we will need to put it through a number of tests to verify that it can be scaled up to larger brains.
Living with epilepsy
Nicole Bateman – mum to her six-year-old son, who has temporal lobe epilepsy and her three year-old daughter, who has also experienced seizures, describes the impact that breakthrough treatments, such as gene therapies, could have her on her family.
The Bateman Family
In July 2020 our son experienced his first seizure. He was in the bath with his sister; suddenly he was quiet, colour drained from his face and he was staring, rigid and unresponsive. Seconds felt like minutes; minutes like hours; he was unresponsive for about three minutes, (three minutes may not sound like long, but for me it felt like a lifetime). Seeing your son like that and not being able to do anything about it is scary, you feel totally and utterly helpless.
Two-and-a-half years on, our son still lives with uncontrolled seizures. Over the years, we have trialled multiple medications and he’s experienced cognitive regression as well as emotional impacts from both the seizures and the side effects of medications. As a parent of a child with epilepsy, I find myself on constant high alert, waiting, watching, every moment of every day. Our daughter has also had multiple seizures in the last six months so genetic testing is being undertaken. Ground-breaking research, like Kullmann and Lignani’s work, gives hope to families like ours and will enable people, like my son, to live their lives uninterrupted by seizures and the side effects of current medications.
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