Déméthylation ciblée du gène de la sous-unité bêta-1 du récepteur gamma-aminobutyrique type A à l’aide de CRISPR–dCas9–TET pour restaurer la fonction du récepteur gamma-aminobutyrique type A dans l’épilepsie
DOI :
https://doi.org/10.18192/osurj.v5i2.7937Résumé
L’épilepsie est un trouble neurodéveloppemental caractérisé par des crises récurrentes non provoquées dues à des déséquilibres anormaux entre la neurotransmission excitatrice et inhibitrice (1). Touchant près d’un Canadien sur 100 (2), l’épilepsie réduit significativement la qualité de vie par des risques physiques, des troubles cognitifs et une anxiété et dépression cliniquement significatives (3). Le récepteur gamma-aminobutyrique de type A (GABAAR) est un récepteur ionotrope qui médiatise la neurotransmission inhibitrice en se liant au neurotransmetteur GABA (4). La méthylation du gène de la sous-unité GABAAR Bêta-1 (GABRB1) a démontré réduire la fonction du GABAAR chez les personnes épileptiques, contribuant ainsi à l’hyperexcitabilité neuronale et mettant en lumière une cible épigénétique potentielle pour une intervention thérapeutique visant à restaurer la signalisation inhibitrice (5). Cette étude propose d’administrer CRISPR-dCas9-TET pour déméthyler sélectivement les cytosines dans les régions promoteurs GABRB1 chez la souris en utilisant la séquence d’ARNg GABRB1 (5′ à 3′) CACCg GCCGCGGGGCTTCGGGTGT et sa séquence complémentaire 3' à 5' afin de réactiver l’expression de GABRB1 (6). Des modèles murins FVB/N avec épilepsie induite par l’acide kainique sont utilisés en raison de leur sensibilité neurologique et de similitudes avec l’homo sapiens (7). L’imagerie des ions calcium d’indicateurs fluorescents codés génétiquement à l’aide d’une microscopie à deux photons via une fenêtre crânienne implantée chirurgicalement sera réalisée parallèlement à une analyse qualitative de la fréquence des crises afin de déterminer les effets du traitement sur l’inhibition neuronale. Les limites de cette approche incluent un traumatisme cérébral potentiel dû à un fenêtrement crânien ou à l’administration de CRISPR-dCas9-TET, pouvant entraîner une diminution systématique de la signalisation inhibitrice (8). Cette approche épigénétique proposée est importante en raison de son potentiel en tant qu’alternative aux médicaments antiépileptiques (ASM). Notamment, les ASM nécessitent des doses fréquentes et sont souvent inefficaces pour traiter les patients atteints d’épilepsie pharmaco-résistante (DRE) (9). Le traitement proposé pourrait réduire la susceptibilité aux crises, offrant un traitement à long terme à intervention unique pour les patients épileptiques et DRE. Dans l’ensemble, cette étude apportera un éclairage sur l’efficacité de la déméthylation ciblée pour restaurer la neurotransmission inhibitrice.
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