488. Development of a Robust Non-Viral Gene Delivery System for Gut Mucosal Cells
Notice bibliographique
Résumé
The gastrointestinal tract is the largest immune and endocrine organ in the body, and represents an attractive target organ for gene therapy. With a robust gene delivery system for mucosal cells, immune-modulatory proteins can be delivered locally to the gut, thus reducing the potential for systemic side effects. Furthermore, given the accessibility of the gut via the oral route, it is conceivable that a “gene pill” can be formulated to enable oral delivery of a wide range of therapeutic proteins. We report the development of a gene delivery system optimized for gut mucosal cells. The foundation of this gene delivery platform is a novel polymer, synthesized by conjugating arginine (R) and gluconic acid (GA) to low molecular weight poly-glucosamine. We demonstrated by cytotoxicity assay that this novel polymer (DDX) is biocompatible and non-toxic. Polyplex nanoparticles made from DDX containing plasmid DNA have a Z-avg diameter of ~100 nm and ζ of ~ +30 mV. In vitro transfections using DDX as a DNA carrier revealed unexpected synergistic effects, compared to mono-conjugated (R or GA) poly-glucosamine controls. In vivo intramuscular and intrarectal administration in mice also demonstrated superior gene transfection with DDX polyplex relative to R-conjugated and non-conjugated poly-glucosamine polyplexes. To demonstrate efficacy using DDX as a carrier to concentrate expression of the human IL-10 gene to the gut, we assessed the effectiveness of delivery by enema as a treatment for colitis in the dextran sulfate sodium-induced murine colitis model. Treated mice showed improved body weight recovery: (AUC: 19.3 for EG-12-treated vs 7.2 for control-treated, p=0.01). Additionally, the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-17α and TNF-α) in colon tissue of EG-12-treated mice were significantly lower than control-treated animals. Furthermore, localized delivery of IL-10 to the gut of NOD mice using the same gene delivery platform led to significant reduction in diabetes incidence, accompanied by increased regulatory T-cells and decreased activation of insulin-reactive T-cells in the mesenteric lymph nodes. Taken together, our results indicate that our novel gene transfer system can effectively deliver and concentrate immune-modulatory proteins to gut mucosal cells. We aim to formulate the polyplex for oral administration to achieve transient, but renewable, protein production in the gut. This platform may enable delivery of proteins into the circulation via the oral route. To this end, we have developed processes to convert the liquid formulation into dry powder by both spray drying or lyophilization, followed by compression into tablets or filled into capsules. Dissolution testing of these tablets and capsules in water revealed that the nanoparticles remain intact and biologically active. Preliminary studies in rats demonstrated detectable circulating IL-10 after oral administration of non-enteric coated capsules. With enteric coating, a platform capable of oral dosage of protein drugs may be made possible.
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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 | 0,000 |
| 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 ».