Base editing corrects genetic mutation responsible for severe form of hereditary epilepsy

Scientists at the University of Virginia School of Medicine have used next-generation gene editing to correct the underlying cause of a severe form of epilepsy in lab mice. Their promising results suggest that this approach could eventually be used to treat – or even cure – severe genetic epilepsy in people.

Researchers led by UVA’s Manoj Patel, PhD, used highly precise “base editing” to pinpoint the gene mutation responsible for a severe form of inherited epilepsy. SCN8A Developmental and epileptic encephalopathy (DEE). The condition causes seizures, learning disabilities, and problems with movement, and it can also lead to sudden death.

“Historically, treatments only addressed the downstream effects of the genetic mutation; today, we can correct the mutation itself by targeting the root cause of the disease,” said Patel, a member of UVA’s department of anesthesiology and the UVA Brain Institute. “Base editing opens the door to treatments not only for epilepsy, but for many genetic diseases, and has the potential to significantly improve patients’ quality of life.”

stopping epilepsy at the source

SCN8AIt is estimated that epilepsy-related epilepsy affects 1 in 56,000 births – about 1% of all epilepsies – although many experts believe the condition is underdiagnosed. a mutation in SCN8A The gene allows too much sodium to flow into neurons in the brain, causing nerve cells to become overexcited. It causes seizures that often resist treatment, as well as physical and mental developmental problems.

symptoms of SCN8A-related epilepsy typically appears in early infancy, but the severity of the condition can vary widely. Severe cases of epilepsy (SUDEP) carry a significant risk of sudden unexpected death.

The potential severity of the condition, coupled with the persistent drug-resistance of seizures, means that there is a great need for new and better treatment options. This helped Patel and his team target the underlying cause. They turned to base editing, which allows scientists to alter single nucleotides, the building blocks of genes.

The highly precise nature of base editing allows scientists to avoid unwanted side effects that come with gene editing. Patel and his team used the approach to correct the mutation in their lab mice and found that it either eliminated or dramatically reduced seizures and increased overall survival. It also improved the mice’s ability to move around and reduced anxiety-like behavior, which is used as a proxy for assessing cognitive benefits.

When the scientists examined the mice’s brains, they found concrete changes that showed their approach was having the desired effect: Sodium flow into neurons was reduced, and so was the harmful neuronal hyperexcitability that causes seizures.

This suggests that the devastating effects of the mutation are not permanent – ​​and can be reversed. We were able to effectively ‘fix’ mice carrying this specific gene mutation – a mutation that causes epilepsy in some children.

Kelly Rivers, lead researcher on this project

While much more research will need to be done before this approach can be used as a treatment in people, Patel is encouraged by her findings. He said this work paves the way for the treatment of not only SCN8A-related epilepsies but other inherited epilepsies. It also speaks to the great potential of base-editing technology to fight genetic diseases more generally.

“Our goal is to assess this gene therapy in children with this specific SCN8A variant,” Patel said. “Recent advances in gene therapy offer significant promise for patients with genetic diseases. Rather than simply addressing outcomes, these approaches enable the underlying cause – pathogenic genetic mutations – to be directly targeted with real potential for cure.”

Finding new ways to treat and cure the most complex diseases is the primary mission of UVA’s new Paul and Dianne Manning Institute of Biotechnology. The institute works closely with the UVA Brain Institute to advance our understanding of the brain and accelerate the development of new treatments and drugs for epilepsy, Alzheimer’s disease and other neurological disorders.

findings published

Patel and his team have published their findings Journal of Clinical Investigation. The article is open access, meaning it is free to read. Reaver, Alexis R. in the research team. Boccia, Tyler C.J. Deutsch, Mansi P. Patel, Raquel M. Miralles, Srinidhi Kittur, Eric J. Fleschel, Atom ML Buo, Matthew S. Yourek, Miriam H. Meisler, Charles R. Farber and Patel were involved.

The research was supported by the National Institutes of Health, grants NS103090, NS122834, NS120702, NS34509, GM24872, and F31 NS134264; UVA Brain Institute; and Ivy Biomedical Innovation Fund.