Skip to Content
MilliporeSigma
  • Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations.

Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations.

Molecular therapy. Nucleic acids (2021-10-01)
Lucia Mora-Jimenez, Miguel Valencia, Rocio Sanchez-Carpintero, Jan Tønnesen, Saja Fadila, Moran Rubinstein, Manuela Gonzalez-Aparicio, Maria Bunuales, Eva Fernandez-Pierola, Maria Jesus Nicolas, Elena Puerta, Cristina Miguelez, Paula Gimenez Minguez, Sara Lumbreras, Gloria Gonzalez-Aseguinolaza, Ana Ricobaraza, Ruben Hernandez-Alcoceba
ABSTRACT

Dravet syndrome is a genetic encephalopathy characterized by severe epilepsy combined with motor, cognitive, and behavioral abnormalities. Current antiepileptic drugs achieve only partial control of seizures and provide little benefit on the patient's neurological development. In >80% of cases, the disease is caused by haploinsufficiency of the SCN1A gene, which encodes the alpha subunit of the Nav1.1 voltage-gated sodium channel. Novel therapies aim to restore SCN1A expression in order to address all disease manifestations. We provide evidence that a high-capacity adenoviral vector harboring the 6-kb SCN1A cDNA is feasible and able to express functional Nav1.1 in neurons. In vivo, the best biodistribution was observed after intracerebral injection in basal ganglia, cerebellum, and prefrontal cortex. SCN1A A1783V knockin mice received the vector at 5 weeks of age, when most neurological alterations were present. Animals were protected from sudden death, and the epileptic phenotype was attenuated. Improvement of motor performance and interaction with the environment was observed. In contrast, hyperactivity persisted, and the impact on cognitive tests was variable (success in novel object recognition and failure in Morris water maze tests). These results provide proof of concept for gene supplementation in Dravet syndrome and indicate new directions for improvement.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-NeuN Antibody, clone A60, clone A60, Chemicon®, from mouse
Sigma-Aldrich
Monoclonal Anti-VGLUT1 antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL2754, purified immunoglobulin, buffered aqueous glycerol solution