TY - JOUR
T1 - Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations
AU - Mora-Jimenez, Lucia
AU - Valencia, Miguel
AU - Sanchez-Carpintero, Rocio
AU - Tønnesen, Jan
AU - Fadila, Saja
AU - Rubinstein, Moran
AU - Gonzalez-Aparicio, Manuela
AU - Bunuales, Maria
AU - Fernandez-Pierola, Eva
AU - Nicolas, Maria Jesus
AU - Puerta, Elena
AU - Miguelez, Cristina
AU - Minguez, Paula Gimenez
AU - Lumbreras, Sara
AU - Gonzalez-Aseguinolaza, Gloria
AU - Ricobaraza, Ana
AU - Hernandez-Alcoceba, Ruben
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/9/3
Y1 - 2021/9/3
N2 - 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.
AB - 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.
KW - Dravet syndrome
KW - Nav1.1.
KW - SCN1A
KW - adenovirus
KW - encephalopathy
KW - epilepsy
KW - gene therapy
UR - http://www.scopus.com/inward/record.url?scp=85114684659&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2021.08.003
DO - 10.1016/j.omtn.2021.08.003
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C2 - 34589280
AN - SCOPUS:85114684659
SN - 2162-2531
VL - 25
SP - 585
EP - 602
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
ER -