686. Exploring Different Formulations as a Strategy To Enhance Adenoviral Gene Delivery to the Lung
Notice bibliographique
Résumé
Adenoviral vectors are currently being investigated for lung gene therapy, particularly for cystic fibrosis. However, one of the challenges is the low efficiency of viral transduction due to the presence of mucous in the airway, localization of CAR receptor on the basolateral surface, sweeping action of ciliated epithelial cells, apical membrane glycoconjugates and the host immune response. Helper dependent adenoviral vectors (HD-Ad) show reduced adaptive immune response compared to first generation adenoviral vectors. However innate immunity is a consistent challenge with the use of these vectors. Therefore, there is a need to identify formulations that can enhance the transduction efficiency and decrease immune response against the adenoviral vectors. LPC has previously been shown to enhance adenoviral delivery to the lung epithelium, which can be due to its mucolytic properties along with reduction of cilial motility. DEAE-Dextran has also been shown to enhance adenoviral delivery to the lung, presumably by complexing with the virus and facilitating virus binding to cells through charge interaction. NAC and its derivative NAL have been shown to possess mucolytic and anti-oxidant properties. However, they have not been evaluated in enhancing viral gene delivery to the lung. Inflammatory cells produce reactive oxygen species which may affect adenoviral particles and decrease efficacy of viral transduction. Therefore, the mucolytic and antioxidant properties of NAC and NAL may enhance viral transduction. NAC and NAL have also been shown to decrease NFkB which could be of further significance in enhancing viral transduction. In this study we chose to study the efficacy of LPC, DEAE- Dextran, NAC and NAL in enhancing adenoviral transduction to the lung. C57BL/6 mice were intranasally instilled with viral formulations in 0.1% LPC, 10 μg/ml DEAE-Dextran, 20mM NAL combined with 10 μg/ml DEAE-Dextan or instilled first with 20mM NAC or NAL followed by viral formulation in 10 μg/ml DEAE-Dextran. Nasal instillations were carried out in a volume of 20 μl with a titer of 1010 viral particles (HD-Ad encoding LacZ). Mice were sacrificed after 3 days and lungs were isolated to quantify the amount of viral transduction by assaying for beta-galactosidase activity. Results indicate no statistically significant difference between the transduction efficiency of DEAE-Dextran and LPC. However, pre-treatment of mice with NAC or NAL, resulted in enhancement of viral transduction. The highest increase in viral transduction efficiency was seen with NAL pre-treatment. However, simultaneous instillation of NAL with virus did not result in statistically significant increase, indicating that perhaps NAL primes the epithelium for enhanced viral transduction. The results suggest that NAL may be a very useful reagent in enhancing adenoviral gene delivery to the lung. The immune responses associated with the use of various formulations are currently being examined in detail and the findings will be presented at the meeting.
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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 | 0,001 |
| 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 ».