DNA Editing Targets Root Cause of Dravet in Preclinical Study

Rare Daily Staff

A preclinical study in mice suggests that precision gene editing could one day correct the root cause of Dravet syndrome, a severe and often fatal form of childhood epilepsy, raising the possibility of a one-time, curative treatment.

Researchers from The Jackson Laboratory, the Broad Institute, and Children’s Hospital of Philadelphia reported in Science Translational Medicine that they successfully repaired a disease-causing mutation using adenine base editing, a next-generation gene editing approach. Treated mice experienced far fewer seizures and lived significantly longer.

Dravet syndrome is most often caused by mutations in the SCN1A gene, which produces a sodium channel essential for normal brain activity. The mutation targeted in this study, known as R613X, disrupts protein production, leading to overactive brain signaling and severe seizures that begin in infancy.

Using a single injection directly into the brain, researchers delivered a base editor designed to fix the mutation at the DNA level. The treatment corrected the mutation in nearly 60 percent of affected brain cells. Even with partial correction, gene function was largely restored, because cells naturally break down faulty genetic messages from uncorrected DNA.

The results showed treated mice showed more normal brain activity, a sharp reduction in seizures, and improved survival. Notably, the therapy was effective even when given after symptoms had already begun—an important finding, since early intervention is often considered critical in neurological disorders.

“Once you correct the gene, the cell’s own regulatory systems take over again,” said Matthew Simon of JAX’s Rare Disease Translational Center. “You’re not managing a disease—you’re restoring the underlying biology.”

The study also highlights the challenges of gene editing in the brain, where target cells are widespread and difficult to reach. Encouragingly, researchers observed low levels of unintended DNA changes, supporting the potential safety of this approach.

The work builds on ongoing collaborations between JAX, the Broad Institute, and clinical partners, including previous efforts to apply gene editing to other rare pediatric disorders such as Zellweger spectrum disorder and alternating hemiplegia of childhood.

Looking ahead, one major challenge will be adapting the approach to the many different SCN1A mutations seen in patients. Rather than developing entirely new therapies for each mutation, researchers aim to create a modular platform in which the core technology remains the same and only the targeting component is customized.

“The long-term vision is a platform that makes correcting new mutations a matter of precision and speed, rather than starting from scratch,” said Cathleen Lutz of JAX.

Photo: Matthew Simon, senior study director at JAX Rare Disease Translational Center