Our chromosomes are paired, and therefore we have two copies of almost every gene. The mutations that cause Dravet Syndrome affect only one copy of the Scn1a gene, which leads to production of only half the normal amount of Nav1.1 protein. New gene therapy approaches are starting to have success replacing mutated gene copies with native ones, using viruses to bring in the correct copy, but in the case of Dravet syndrome this approach is hampered by the large size of the Scn1a gene, which exceeds the delivery abilities of these virus particles.
An alternate approach could be to increase expression of the good copy. In this paper, the researchers use a CRISPR-Cas9 system to do just this. In short, the CRISPR-Cas9 technology is an exciting new and powerful method for genome editing. The authors were able to engineer robust, and highly specific, activation of the Scn1a gene, and thereby restore Nav1.1 protein levels, in neurons derived from a Dravet mouse. The functional result was restoration of excitability in these neurons.
Encouraged by these results, the authors utilized a viral system that allows efficient delivery to the brain, and injected Dravet mouse pups with their Scn1a-dCas9A treatment. They found a significant increase in Scn1a gene expression over controls. Further, these mice were found to have an increased threshold to hyperthermia-induced seizures.
In conclusion, this study confirmed the hypothesis that upregulation of Nav1.1 during development is protective against seizures. It also showed that a dCas9 activation system could be successfully packaged into a gene therapy approach for treating Dravet mice, raising optimism toward someday trying the same approach in humans.
