Long-Term and Sustained Correction of the α-Galactosidase A Deficiency in Fabry Mice and Patient Cells Receiving Lentivirally Transduced Hematopoietic Stem/Progenitor Cells.
Notice bibliographique
Résumé
Abstract Fabry disease is a lysosomal storage disease caused by a defect in α-galactosidase A (α-gal A). Currently enzyme replacement therapy is available; however frequent infusions are required and long-term outcome in key organs remain to be established. Stable gene augmentation by virus-based delivery can correct cells and offers considerable potential as an effective, long-term therapeutic approach. Our goal is to engineer life-long correction of the disorder with a single treatment. Transplantation of genetically modified autologous hematopoietic stem/progenitor cells (HSPCs), which can self-renew and differentiate multiple cell types, is thus an attractive target in this context. Previously we have demonstrated long-term correction mediated by gene transfer into HSPCs by oncoretroviral vectors both with pre-selection of transduced cells prior to transplantation and without. In the interest of minimizing the effect on the graft by reducing ex vivo culture time and possibly reducing deleterious integration events, we are pursuing other integrative vector systems. It is well known that recombinant lentiviral vectors (LVs) can efficiently transduce not only dividing cells but also non-dividing or less-cycling cells like HSPCs. The aim of this study is to evaluate whether VSV-g pseudotyped LV-mediated gene modification of HSPCs can systemically treat affected organs in Fabry disease mouse model (Fabry mice). We first demonstrated sustained LV-mediated marking of peripheral blood (PB) cells by transducing bone marrow mononuclear cells (BMMNCs) with an LV which encodes enGFP cDNA at an MOI of 30 and transplanting into Fabry mice. Stable and robust enGFP expression (n=5, 65.8±5.8%) in PB cells was observed for >250 days. Next, we transplanted Fabry mice with BMMNCs transduced with an LV encoding the human α-gal A cDNA. Sustained expression of functional α-gal A in Fabry mice was observed over 24 weeks. Plasma α-gal A activity from treated Fabry mice (n=9) was two-fold higher than wild-type controls (n=8). Increased α-gal A activity, often above normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed including heart and kidney which are life-threatening in Fabry disease. To determine whether true HPSCs were transduced by LVs, secondary BM transplantations were performed. PB from secondary transplanted Fabry mice showed multilineage enGFP marking of PB, splenocytes, and BMMNCs, along with therapeutic levels of α-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34+ cells from a Fabry patient with corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease. These studies provide confirmation of the utility of this system for research and therapy for a variety of inherited disorders including Fabry disease.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».