The delivery of a codon-modified SCN1A open reading frame using a viral vector into the brain of a mouse model of Dravet syndrome improves comorbidities in juvenile and adolescent animals, reported a new study that appeared in the Journal of Clinical Investigation.
Moreover, the injection of the viral vector carrying the codon-modified SCN1A open reading frame into the hippocampus and/or the thalamus of the animals bilaterally increased survival and reduced epileptic spikes. It also provided protection from orrected background electrocorticography activity, behavioral deficits, and thermally-induced seizures, the researchers said. Finally, it restored hippocampal inhibition, which likely impacts the pathology of Dravet syndrome.
Read more about the symptoms of Dravet syndrome
“Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with [Dravet syndrome]-associated comorbidities,” wrote first author Saja Fadila, from Faculty of Medicine, Tel Aviv University in Israel and the co-authors of the study.
Dravet syndrome is a rare type of intractable childhood epilepsy with a high rate of death. Up to 85% of Dravet syndrome cases have a de novo mutation in the SCN1A gene, which codes for the alpha subunit 1 voltage-gated sodium channel protein (NaV1.1), which initiates action potentials in the neurons in the brain. The mutations reduce or completely abolish the function of the channel leading to frequent and repeated seizures that are often refractory to treatment, developmental delay or regression, and cognitive impairment. Other complications may include growth or nutritional problems, chronic infections, and orthopedic conditions.
Providing exogenous protein to the body using a viral vector could be one approach that could help treat the disease. Gene therapy using this approach has been used in other rare genetic diseases including spinal muscular atrophy.
Fadila S, Beucher B, Dopeso-Reyes IG, et al. Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome. J Clin Invest. 2023;16:e159316. doi:10.1172/JCI159316