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

University of Virginia School of Medicine scientists have used a next-generation form of gene editing to fix the underlying cause of a severe form of epilepsy in lab mice. Their promising results suggest the approach could eventually be used to treat – or cure – severe genetic epilepsies in people as well.

Researchers led by UVA's Manoj Patel, PhD, used highly precise "base editing" to correct the gene mutation responsible for a severe form of inherited epilepsy known as SCN8A developmental and epileptic encephalopathy (DEE). The condition causes seizures, learning disabilities and movement problems, and it can also trigger sudden death.

"Historically, treatments addressed only the downstream effects of genetic mutations; today, we can correct the mutations themselves, targeting the root cause of disease," said Patel, part of UVA's Department of Anesthesiology and the UVA Brain Institute. "Base editing opens the door to the treatment of numerous genetic diseases, not only those associated with epilepsy, and has the potential to significantly improve patients' quality of life."

Stopping epilepsy at the source

SCN8A-related epilepsy is estimated to affect 1 in 56,000 births – approximately 1% of all epilepsies – though many experts believe the condition is underdiagnosed. A mutation in the SCN8A gene allows too much sodium to flow into neurons in the brain, which causes the nerve cells to become hyperexcited. This leads to seizures which often resist treatment, as well as to physical and mental developmental problems.

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

The potential severity of the condition, coupled with the frequent medication-resistance of the seizures, means there is a great need for new and better treatment options. That led Patel and his team to 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 can 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 and reduced anxiety-like behaviors that are used as a proxy for assessing cognitive benefits.

When the scientists examined the mice's brains, they found concrete changes that suggested their approach had the desired effects: Sodium flow into neurons was reduced, and so was the harmful neuronal hyperexcitability that causes seizures.

This shows that the devastating impact of the mutation is not permanent – and can be reversed. We were able to effectively 'cure' mice carrying this specific gene mutation – a mutation that is known to cause epilepsy in some children."

Caeley Reever, the lead researcher on the project

While much more research will need to be done before the approach could be used as a treatment in people, Patel is encouraged by his findings. The work paves the way not just to treat SCN8A-related epilepsy but other inherited epilepsies, he notes. It also speaks to the great potential of the base-editing technology to battle 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. Instead of addressing only the consequences, these approaches enable direct targeting of the underlying cause – the pathogenic genetic mutation itself – with real potential for a cure."

Finding new ways to treat and cure the most complex diseases is a primary mission of UVA's new Paul and Diane Manning Institute of Biotechnology. The institute works hand-in-hand with the UVA Brain Institute to advance our understanding of the brain and accelerate the development of new treatments and medicines for epilepsy, Alzheimer's disease and other neurological disorders.

Findings published

Patel and his team have published their findings in the Journal of Clinical Investigation. The article is open access, meaning it is free to read. The research team consisted of Reever, Alexis R. Boscia, Tyler C.J. Deutsch, Mansi P. Patel, Raquel M. Miralles, Shrinidhi Kittur, Erik J. Fleischel, Atum M.L. Buo, Matthew S. Yorek, Miriam H. Meisler, Charles R. Farber and Patel.

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