In a world first, a research team at the University of Zurich has successfully treated mice carrying an inherited form of epilepsy. The scientists used gene editing to fix faulty DNA directly in the brain cells of mice, which reduced fever-induced seizures and markedly improved survival rates in an animal model. This approach paves the way for future treatment of inherited epilepsy rather than just managing its symptoms.
Epilepsy can have many causes. Where the cause is genetic, the culprit can be a mutation in a gene called SCN1A, which carries the blueprint for a sodium channel in nerve cells and plays a key role in transmitting electrical signals. These neurons normally act as the brain's brakes, and when that braking system fails, neural networks can become hyperactive and trigger epileptic seizures.
Certain mutations in the SCN1A gene cause an inherited form of epilepsy known as GEFS+. People with GEFS+ suffer from febrile seizures, often beginning in early childhood. Until now, inherited epileptic disorders have been treated with epileptic drugs that reduce the frequency of seizures but often come with side effects. What's more, not all patients respond well to current treatments.
Correcting mutations directly in the brain
Using a mouse model of GEFS+, a research team led by professors Gerald Schwank and Hanns Ulrich Zeilhofer at the UZH Institute of Pharmacology and Toxicology has now shown for the first time that gene editing can correct such a disease-causing mutation directly in the brain. "The treatment improved communication between nerve cells, significantly reduced the frequency of febrile seizures and increased the survival of the animals," says Lucas Kissling, a postdoctoral researcher and co-first author of the study.
Gene editing on a molecular level
The researchers took a new approach. "Rather than treating the consequences of the mutation, we wanted to correct the error directly in the gene sequence," Kissling explains. To achieve this, the team applied a precise gene editing method called prime editing. This technique builds on the gene editing tool CRISPR/Cas and allows isolated genomic errors to be corrected with extreme accuracy, without the need to sever the DNA completely. "That's crucial for nerve cells, which hardly divide and are therefore difficult to access with many conventional gene editing methods," says Francesca Pietrafesa, a postdoctoral researcher and co-first author of the study.
The researchers worked with mice carrying the same SCN1A mutation found in patients with GEFS+. Like their human counterparts, the animals also developed fever-induced epileptic seizures. After the mice were treated with prime editing, the results were clear: the scientists had successfully corrected the disease-causing mutation in most of the nerve cells in a key region of the brain. The therapy also markedly improved the altered signaling between nerve cells in the brain while sharply decreasing the frequency of febrile seizures. "In the control group, around 80 percent of the animals developed seizures," says Pietrafesa. "But after undergoing the highly effective prime editing treatment, that figure dropped to around 15 percent."
Striking at the root cause of disease
This approach is highly promising due to its preservation of the body's natural gene regulation mechanisms. Rather than delivering an extra copy of the gene, as in conventional gene therapies, it corrects the faulty sequence right at the source. "Even though these are still preclinical findings from a mouse model, the results open up new perspectives – not only for treating SCN1A-linked epilepsy, but potentially also for other neurological diseases caused by a single genetic mutation," says Kissling.
