Dravet syndrome is a rare and life-changing form of epilepsy. Dravet syndrome affects approximately 1 in 15,700 children, and most cases are caused by mutations in the SCN1A gene. This gene plays a critical role in the brain's ability to regulate activity through flash interneurons. The disease has long made scientists eager to develop more effective treatments due to severe seizures and developmental delays.
Researchers from the Allen Institute and Seattle Children's Research Institute collaborated to develop a new gene replacement therapy in a mouse model of Dravet syndrome. The treatment alleviated symptoms and led to long-term recovery without toxicity, side effects, and death. This is a groundbreaking development for families struggling to cope with the challenges of Dravet syndrome. The relevant research results were published in the journal Science Translational Medicine.
"People who take epilepsy medications often complain that these drugs are very effective, but they have a big impact on their brains," said Boaz Levi, PhD, associate investigator at the Allen Institute. "So our goal is to be so precise that we can deliver only the missing gene and really target the neural circuit. As a result, it can be safer, more effective, and have significantly fewer side effects."
The new therapy involves an innovative two-step strategy: (1) precise gene delivery: using specialized enhancers (short pieces of DNA that act like switches to control when and where specific genes are turned on) to target the specific cells that are defective in Dravet syndrome patients; and (2) overcoming the difficulty of gene size limitations: gene therapy is delivered via AAV vectors.
Figure 1. Observing cell class specificity using an independent marker for telencephalic GABAergic interneurons.
AAVs are harmless viruses that carry genes into cells. But the SCN1A gene is too large to fit into a traditional AAV vector. So they overcame this obstacle by using a protein fusion mechanism called split-intein, which splits the gene into two halves so that it can be carried into cells and reassembled inside them. Each half is delivered to the same cell by a separate AAV vector, where they fuse together to form the final gene. It's like having a large piece of furniture delivered to your home in two parts because it can't fit through the front door and then reassemble inside.
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In the study, treated mice showed dramatic improvements. Seizures were alleviated, recovery was long, and no adverse effects were observed. These results not only support the potential of AAV-mediated SCN1A gene replacement, but also highlight the critical role of cell-specific therapies in combating genetic diseases such as Dravet syndrome.
"These people's standard of living will be severely affected. We are excited about the huge impact we hope this gene therapy will have on families," Levi said.
Reference
- Mich J K, et al. Interneuron-specific dual-AAV SCN1A gene replacement corrects epileptic phenotypes in mouse models of Dravet syndrome. Science Translational Medicine, 2025, 17(790): eadn5603.