Adenovirus-Mediated Expression of NaV1.1 Ameliorates Dravet Syndrome Epilepsy in Mice
Abstract number :
1.046
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1825827
Source :
www.aesnet.org
Presentation date :
12/9/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Saja Fadila, MSc. - Tel Aviv University; Bertrand Beucher, PhD – Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France.; Iria gonzalez-dopeso-reyes, PhD – Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France.; Anat Mavashov – Human molecular genetics and biochemistry – Tel Aviv University; Marina Bruzel, MSc – Tel Aviv University; Karen Anderson – Human molecular genetics and biochemistry – Tel Aviv University; Eric Kremer, PhD – Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France.; Moran Rubinstein, PhD – Tel Aviv University
Rationale: Dravet syndrome (DS) is a severe childhood-onset encephalopathy, characterized by febrile and spontaneous intractable seizures, global developmental delay and high incidence of sudden unexpected death in epilepsy (SUDEP). Over 80% of DS cases are caused by loss of function mutations in the SCN1A gene, encoding for the voltage-gated sodium channel, NaV1.1. Restoring NaV1.1 activity, via vector-mediated gene transfer, offers unique chances for global, long-term, improvement in DS-associated comorbidities. Adenovirus vectors have the capacity to transfer large expression cassettes containing complex transcriptional regulatory elements.
Methods: We explored the use of adenovirus-mediated expression of SCN1A to modify DS-associated comorbidities at different stages of DS: the onset of spontaneous seizures (postnatal day 21) and later in life (postnatal day 35).
Results: We found that the therapeutic vector was protective in DS mice (Scn1aA1783V/WT) at both stages of DS. Specifically, it reduced the frequency of spontaneous seizures and interictal spikes, and increased the threshold temperature for thermally induced seizures, consistent with the amelioration of epileptic phenotypes. Moreover, our approach led to a reduction in the occurrence of premature mortality.
Conclusions: Adenovirus-mediated deliver of SCN1A in the brain of DS mice improves DS-associated comorbidities when administered following the onset of severe epilepsy. Thus, providing proof of concept for the effectiveness of increased NaV1.1 activity at multiple stages of DS.
Funding: Please list any funding that was received in support of this abstract.: ERA-NET E-Rare, Dravet Syndrome Foundation.
Basic Mechanisms