Multiple Reduced-intensity Conditioning Regimens Facilitate Correction of Fabry Mice After Transplantation of Transduced Cells
Notice bibliographique
Résumé
Hematopoietic cell transplantation can impact lysosomal storage disorders (LSDs) and will be enhanced by gene therapy. Transduced cells in LSDs often secrete the therapeutic hydrolase, which can be used by bystander cells. However, toxicity associated with myeloablative transplant preparative regimens limits many applications of this approach in gene therapy. We hypothesized that reduced-intensity (RI) conditioning regimens would allow stable engraftment of therapeutically transduced cells and allow correction of Fabry disease. We transplanted transduced cells into Fabry mice receiving eight different clinically relevant chemotherapy- and/or radiotherapy-based RI conditioning regimens generating modest and transient lymphoid/myeloid cell depletion. Two comprehensive transplantation Protocols were performed. Firstly, transplantation of 0.38 × 106 gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stable α-galactosidase A (α-gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 × 106 cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasma α-gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses against α-gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context. Hematopoietic cell transplantation can impact lysosomal storage disorders (LSDs) and will be enhanced by gene therapy. Transduced cells in LSDs often secrete the therapeutic hydrolase, which can be used by bystander cells. However, toxicity associated with myeloablative transplant preparative regimens limits many applications of this approach in gene therapy. We hypothesized that reduced-intensity (RI) conditioning regimens would allow stable engraftment of therapeutically transduced cells and allow correction of Fabry disease. We transplanted transduced cells into Fabry mice receiving eight different clinically relevant chemotherapy- and/or radiotherapy-based RI conditioning regimens generating modest and transient lymphoid/myeloid cell depletion. Two comprehensive transplantation Protocols were performed. Firstly, transplantation of 0.38 × 106 gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stable α-galactosidase A (α-gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 × 106 cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasma α-gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses against α-gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context.
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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 ».