498. Optimization of rAAV Targets ON Bipolar Cells and Rescues the nobnyx Mouse Model of X-Linked Congenital Stationary Night Blindness
Notice bibliographique
Résumé
Within the retina, Adeno associated virus (AAV) has been effectively used to target photoreceptors, retinal pigment epithelial cells, muller glia and retinal ganglion cells. However, transduction of cells in the middle of non-degenerate retina has proven more difficult. Transduction of bipolar cells is particularly attractive both for treating forms of Congenital Stationary Night Blindness (CSNB), in which the ON-type bipolar cells are unable to receive electrochemical input from photoreceptors, as well as for use in optogenetics. Even more attractive is the ability to target this cell type via a non-invasive intravitreal injection. The purpose of our study was to establish methodology to robustly and exclusively express transgene in ON bipolar cells utilizing AAV vectors, and to use these tools to restore retinal function to an animal model of the X-linked form of complete CSNB. Like patients, the nobnyx mouse carries a mutation in NYX, which encodes nyctalopin, a protein essential for proper localization of the TRPM1 cation channel in ON BCs. This disease is characterized by an absence of the electroretinogram (ERG) b-wave in addition to a high incidence of myopia, nystagmus, strabismus, and low visual acuity. A construct containing an ON BC specific promoter, Ple155, driving either hGFP or YFP_Nyx was packaged into rationally designed AAV2(quadY-F+T-V). nobnyx mice were intravitreally injected with 6.5×1012 VG/ml. GFP expression and localization were confirmed using immunohistochemistry before proceeding with Nyx replacement. ERG was performed 4 weeks post injection on mice injected with the YFP_Nyx vector, and then retinas were harvested for single cell recordings, and immunohistochemistry. Mice intravitreally injected with Ple155-hGFP had robust and exclusive GFP expression in their ON bipolar cells. Additionally, Ple155-YFP_Nyx- injected mice exhibited NYX (YFP) expression exclusively in ON BCs, as well as restoration of the glutamate cascade, as evidenced by wild-type responses to capsaicin, an agonist of the disrupted TRPM1 cation channel, in a YFP+ cell. Both scotopic and photopic ERG b-waves were restored to P2-treated mice. This is the first demonstration of therapy following gene replacement in a model of ONBC-mediated disease and provides proof of concept for an AAV-based strategy to treat Congenital Stationary Night Blindness and effectively target ON BCs. Efforts are currently underway to further modify the AAV capsid and genome in order to enhance transduction and increase window of therapy.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».