Scientists from the Allen Institute and Seattle Children’s Research Institute have announced a breakthrough in the development of gene replacement therapies for Dravet syndrome, a rare form of epilepsy. According to details published in aScience Translational Medicinepaper, mice treated with the new therapy survived and had alleviated symptoms and long-term recovery without toxicity and negative side effects. The paper is titled, “Interneuron-specific dual-AAV SCN1A gene replacement corrects epileptic phenotypes in mouse models of Dravet syndrome.”
Dravet syndrome is a severe and difficult to treat condition that is typically caused by a loss-of-function mutation in theSCN1A gene which encodes a sodium channel protein that is involved in brain cell signaling. This mutation leads to problems with interneurons, brain cells that help regulate brain activity. The disease, which is characterized by severe seizures and developmental delays, affects 1 in 15,700 children.
“People who take drugs for epilepsy often complain that the drugs are very impactful, they can slow down the seizures but it changes a lot about their brain,” said Boaz Levi, PhD, associate investigator at the Allen Institute and one of the lead scientists on the study. The goal of the new therapy was “to be very precise” and “just deliver the gene that’s missing.” The result is a treatment that is safer and more effective with significantly fewer side effects, he said.
To ensure that the genes were delivered to the precise location in the defective genes, the researchers used specialized enhancers, short stretches of DNA that act like switches to control when and where specific genes are turned on. They also had to solve the problem of delivering the gene. The conventional approach using adeno-associated viruses would not work for SCN1A because of the gene’s size. Their workaround was to split the gene into two parts and carry each half in separate AAVs. The halves are delivered to the same cells and fused together to make the final gene at their destination.
According to results reported in the paper, dual or single injections of the therapy, dubbed DLX2.0-SCN1A, into mice “did not result in increased mortality, weight loss, or gliosis as measured by immunohistochemistry.”
These results are promising for patients living with Dravet who would “have a severely impacted standard of living” without treatment, Levi said. “We are hopeful this sort of therapy could have a huge impact on families and that’s what’s exciting to me.”