Gene therapy for refractory epilepsy

Epilepsy is the commonest serious neurological disorder, affecting approximately 1% of the population. People with active epilepsy have seriously disrupted lives. They cannot drive, experience social exclusion, have a high rate of depression and suicide, and are at risk of injury and even death during a seizure. About one quarter of people with epilepsy have seizures which are not prevented by any available medicines. In many cases, epilepsy is so disruptive that affected individuals are willing to undergo surgery to remove parts of their brains that generate seizures. Even this option is only open to relatively few people where the seizure-generating region is far from brain centres that control movement, language, vision and other essential functions. Most people with drug-resistant epilepsy have no realistic treatment options. The main limitation to developing new medicines to treat epilepsy is that drugs taken as tablets affect nerve cells (neurons) throughout the brain, not just in the region responsible for triggering seizures. This results in side effects such as slowed thought processes, dizziness and altered mood, which prevent higher, potentially more effective, doses from being used. Moreover, most drugs used in epilepsy target similar mechanisms. There is an urgent need for new treatments that work in completely different ways. We believe that we have found such a treatment that could be effective in a substantial proportion of people in whom seizures arise from an identifiable brain region. Instead of using drugs, we are adding a gene to a small number of neurons that are involved in seizure generation to make them less excitable, so preventing seizures from occurring. Why should we undertake this work? We are a group of basic scientists and clinicians with in-depth knowledge of how neurons change as epilepsy develops, and how genes interact to make neurons more or less active. We have worked together for several years to develop a gene therapy that works in epilepsy. We identified an experimental model of epilepsy that is particularly difficult to treat, which resembles that seen in many people who are currently without effective treatment. We also worked with a collaborator in the USA to develop new ways of monitoring seizures automatically. Our results are very encouraging: not only does our treatment stop epilepsy from developing, but it also progressively stops seizures when epilepsy is already established. In essence, our treatment can 'cure' epilepsy, which has never been demonstrated previously. This is in spite of the fact that our treatment only targets a relatively small number of neurons. Gene therapy did not completely stop neurons from firing, and had no detectable side effects, and yet it completely prevented seizures. Although our work received considerable media interest, we are not yet ready to start clinical trials. We have only tried one experimental model of epilepsy, and only using two different genes. To maximise the prospects for success in clinical trials, we need to improve our understanding of how our treatment works, ensure that we are using the best gene therapy tools, and test them in different situations. We will compare several different ways of calming neurons, and different ways of delivering the gene therapy. We will also test ways of switching on and off the calming effect on the neurons by using gene therapy that makes a small number of neurons sensitive to a drug that is normally inactive in the brain, or that allows brief pulses of light shone into the brain to stop selected neurons firing. We will put our gene therapy through a series of increasingly stringent tests, and look closely for any possible side effects. By the end of our programme, complemented by safety studies, we aim to be ready to start clinical trials, raising hope for tens of thousands of people in the UK, and millions around the world, who currently suffer from uncontrolled seizures.