Scientists reverse epilepsy in lab mice to find cure

Scientists at the University of Virginia School of Medicine have used a next-generation gene-editing technique to correct the cause of a severe form of epilepsy in lab mice. Their promising results suggest that the method could eventually be used to treat – or cure – severe epilepsy in humans as well.

Researchers led by Manoj Patel, PhD of UVA, used highly precise “search editing” to correct the genetic mutation responsible for a severe form of epilepsy known as. SCN8A developmental encephalopathy and epilepsy (DEE). The condition causes seizures, learning disabilities and movement problems, and can lead to sudden death.

Patel, who is part of the UVA Faculty of Medicine and the UVA Brain Center, said: “Traditionally, treatments have dealt with the negative effects of gene mutations; “Base editing opens up the possibility of treating many genetic diseases, not only those related to epilepsy, and has the potential to significantly improve the quality of life of patients.”

Stopping Epilepsy at the Source

SCN8AIt is estimated that epilepsy is related to 1 in 56,000 – about 1% of epilepsy – although many experts believe that this condition is not properly diagnosed. Change to SCN8A the gene allows more sodium to flow into the neurons in the brain, causing the nerve cells to become overexcited. This leads to trauma that often resists treatment, as well as problems with physical and mental development.

Symptoms a SCN8A-Related epilepsy usually begins in childhood, but the severity of the condition can vary greatly. Severe cases have a high risk of sudden unexpected death in epilepsy (SUDEP).

The potential pain of this condition, as well as the frequent rejection of medication when a person falls, means that there is a great need for new treatments. That led Patel and his team to face the root cause. They turned to “base editing”, which allows scientists to change single nucleotides, the building blocks of genes.

The highly precise method of genetic modification allows scientists to avoid the unwanted side effects that can come from genetic modification. Patel and his team used this method to correct the mutation in laboratory mice and found that it eliminated or reduced seizures and increased overall survival. It also improved the mice’s ability to move and reduced anxiety-like behavior used as a proxy for cognitive benefits.

When the scientists examined the brains of the mice, they found concrete changes that show that their approach has the desired results: The flow of sodium in the neurons was reduced, and so was the neuronal hyperexcitability that causes epilepsy.

“This shows that the destructive effect of change is permanent – and can be reversed” said Caeley Reever, the main researcher of the project. “We were able to effectively ‘treat’ mice with this genetic mutation – a mutation known to cause epilepsy in some children,”

Although more research will need to be done before this method can be used as a treatment in humans, Patel is encouraged by his findings. The work paves the way not only for SCN8A-related epilepsy but also for other genetic diseases, he says. It also speaks to the great potential of technology to transform the foundation to fight genetic diseases in general.

“Our plan is to test this gene therapy in children with this specific variant of SCN8A,” Patel said. “Recent advances in gene therapy offer great promise for patients with genetic diseases.” Instead of dealing only with the results, these methods help to direct attention to the cause of the cause – the genetic change itself – which has a real possibility of treatment.

Finding new ways to treat and cure the most complex diseases is the primary mission of UVA’s new Paul and Diane Manning Institute of Biotechnology. The center collaborates 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 diseases.

Findings Published

Patel and his team published their findings in Journal of Clinical Investigation. The article is open access, which means it can be read for free. The research team consisted of Reever, Alexis R. Boscia, Tyler CJ Deutsch, Mansi P. Patel, Raquel M. Miralles, Shrinidhi Kittur, Erik J. Fleischel, Atum ML Buo, Matthew S. Yorek, Miriam H. Meisler, Charles R. Farber and Patel.

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

To keep up with the latest medical research news from UVA and the Manning Center, check out the Making of Medicine blog at https://makingofmedicine.virginia.edu.