Vision vers l’in vivo - Développement d'un ribozyme spécifique à l'ARNm de Tau pour contrer les

Chapitre 3 : Discussion

3. Vision vers l’in vivo

Il était aussi nécessaire d’élaborer une technique qui permettrait d’introduire le ribozyme in vivo. Étant donné que les neurones primaires sont très difficiles à transfecter, qu’il est impossible d’effectuer une transfection dans un cerveau humain, et que la barrière hémathoencéphalique demeure un enjeu important dans le cadre de l’élaboration de médicaments pour le cerveau : l’outil choisit pour un passage in vivo a été les virus.

Le choix du virus AAV (adénovirus associé) étant justifié par le fait que ce virus a une faible toxicité, une faible réponse immunitaire et est capable d’infecter un grand nombre de type cellulaire, y compris les cellules qui ne se divisent pas (Daya & Berns, 2008). En effet, notre cible principale se trouve dans le cerveau, le virus AAV permet ainsi l’infection des cellules neuronales avec une propagation efficace. Contrairement aux lentivirus, le virus AAV est non intégratif. Ce qui paraissait particulièrement important dans ces expériences, puisqu’il n’est pas nécessaire que la séquence du ribozyme soit intégrée au génome. En effet, pour des raisons éthiques et par manque de connaissances approfondies, cette thérapie devant être applicable à l’humain, ne doit pas modifier le génome.

La production virale a été réalisée dans les HEK-293AAV, et celle-ci permet la production de virus AAV de différents sérotypes. Ce mélange de sérotypes permet de cibler un plus grand type de cellules et d’augmenter l’efficacité d’infection. La purification des virus a été effectuée à partir du milieu des cellules et à partir des cellules (Guo et al., 2012). Ceci permettant de récolter plus de virus.

Comme vu précédemment, les cellules HEK-293 comportent très peu voire pas du tout de Tau endogène. L’infection dans les cellules SH-SY5Y a été testé. Néanmoins, moins de 5% des cellules étaient infectées. On peut émettre l’hypothèse que les SH-SY5Y ne possède pas le récepteur héparine nécessaire pour l’infection virale.

De ce fait, l’infection a été faite dans les cellules SK-N-MC. Cellules qui possèdent du Tau endogène et qui sont de type neuronal. L’infection a dû être réalisée à un passage très bas (P4), les cellules qui avaient un passage plus élevé (à partir de P6) ont été presque impossible à infecter. Malgré une infection plus efficace des cellules plus jeunes, la transduction n’a pas aussi bien fonctionné que la transfection. Les résultats observés par la suite ne démontraient aucun changement concernant l’ARNm de Tau en présence des virus contenant les ribozymes comparés au virus contenant le vecteur vide. Cette technique demande donc place à l’amélioration. Il est possible de faire un tri cellulaire (FACS), pour sélectionner uniquement les cellules infectées. Cependant, le tri cellulaire implique aussi de nombreux désavantages tels qu’une forte mortalité cellulaire. Les cellules SK-N-MC sont des cellules particulièrement fragiles qui nécessitent une attention particulière.

L’approche par virus est une approche intéressante mais il est aussi possible d’utiliser d’autres méthodes novatrices telle que les microbulles d’ultrasons (Hernot & Klibanov, 2008). Les modèles murins (P301L ou hTau) pourraient être utilisés pour étudier les effets du ribozyme sur le cerveau. Et des analyses génétiques, protéiques et comportementales pourraient être élaborées afin d’évaluer l’efficacité de cette approche thérapeutique. Aussi, il serait intéressant de développer des techniques efficaces susceptibles d’arrêter le ribozyme ou de contenir son expression dans le cerveau.

Conclusions et perspectives

Tout au long de ce mémoire, nous avons pu constater que les Tauopathies sont des maladies neurodégénératives assez fréquentes qui incluent un bon nombre de pathologies (Maladie d’Alzheimer, CBD, PiD etc.), avec des symptômes distincts selon les Tauopathies observées (perte de la mémoire, dépression, trouble moteur etc.). Bien qu’il existe plusieurs causes communes de ces pathologies déjà connues (mutation génétique, environnement etc.), ces maladies se caractérisent entres autre par l’hyperphosphorylation et l’accumulation de la protéine Tau dans le cerveau. Cependant, les mécanismes moléculaires liées à la toxicité et la propagation de cette protéine restent à approfondir afin de mieux comprendre ces pathologies et de développer des thérapies efficaces. En effet, aucun traitement à ce jour n’a été capable d’atteindre la phase clinique III et donc de vaincre les Tauopathies, malgré les différents essais semblant prometteurs en immunothérapie.

Ainsi ce projet c’est inscrit dans le prolongement des efforts entrepris par de nombreux scientifiques afin de trouver une approche thérapeutique efficace contre les Tauopathies.

Le SOFA-Delta-Ribozyme avait pour but ici de cliver l’ARNm de Tau, afin de diminuer les enchevêtrements neurofibrillaires et d’améliorer les fonctions cognitives. 2 des 5 ribozymes présélectionnés (350 et 395) ont démontré une tendance à la baisse pour l’ARNm de Tau en transfection transitoire. Il serait particulièrement intéressant de confirmer ces résultats en améliorant l’efficacité de ces ribozymes et enfin il serait possible d’envisager un passage à l’in vivo grâce à l’approche par virus.

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