Around 150,000 people in the UK have epilepsy that does not respond to medication, leaving them with no good treatment options. These patients face higher rates of illness, injury, and early death, and many cannot undergo surgery because the seizure-causing brain region overlaps with areas controlling speech, movement, or sensation. The researchers have developed a gene therapy called EKC that calms overactive neurons by boosting production of a normal human protein. In rats with drug-resistant epilepsy, a single injection into the seizure focus stopped seizures without causing inflammation or other side effects. This project will produce EKC to clinical-grade quality, run formal safety tests, and launch a first-in-human trial in a small group of epilepsy patients already scheduled for surgery. If the gene therapy works, those patients may avoid surgery entirely. If it does not, the treated tissue can be removed and studied. If this early trial succeeds, the next step would be testing EKC in people who are not candidates for surgery—patients for whom there is currently no treatment at all.
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Epilepsy is common, affecting up to 1% of the population. Approximately 25% of people with epilepsy (150,000 in the UK alone) do not respond well to available medication. Such patients have an increased mortality, an increased rate of medical, surgical and psychiatric disease, experience social exclusion, and suffer from the side effects of medication. Drug-resistant epilepsy is especially common when seizures arise from a region of the cortex (grey matter). This can occur as a consequence of numerous processes such as developmental abnormalities, head injury, stroke and brain infections. In rare cases it is possible to remove this region surgically, with a high expectation of a cure, but more commonly such surgery is precluded by unacceptable risk to neighbouring or overlapping areas responsible for language, sensation, movement and other normal brain functions. We recently showed that "calming down" neurons in an epilepsy focus was highly effective in a rat model of drug-resistant epilepsy. We achieved this by injecting a gene therapy treatment 'EKC' that leads to the overproduction of a normal human protein that regulates the excitability of neurons and their ability to talk to other neurons. The EKC treatment is safe and does not lead to inflammation, and we showed that the treatment was well tolerated and potentially amenable to clinical use in human epilepsy. This project will allow us to: (1) produce our EKC gene therapy treatment in a quality that is certified for use in humans, (2) to complete formal tests to show it is safe for use in the clinic, and (3) to carry out a first-in-human clinical trial of this gene therapy, to determine whether it is safe and well tolerated in a small group of patients with epilepsy. We will initially trial this approach in patients who are undergoing assessment for epilepsy surgery, and in whom it is possible to remove a region of the brain that is responsible for seizures. Injection of the gene therapy into the seizure focus may spare them the need for definitive surgery. If the treatment fails we can remove the tissue at operation and study it in the laboratory. In the longer term, if this first trial is successful, we will test the effectiveness of the treatment in people who are not candidates for surgery, and for whom there is currently no hope for treatment.
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