Long-term doxycycline-regulated secretion of erythropoietin by encapsulated myoblasts.

Détails

ID Serval
serval:BIB_832819DC9427
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Long-term doxycycline-regulated secretion of erythropoietin by encapsulated myoblasts.
Périodique
Molecular Therapy
Auteur(s)
Sommer B., Rinsch C., Payen E., Dalle B., Schneider B., Déglon N., Henri A., Beuzard Y., Aebischer P.
ISSN
1525-0016 (Print)
ISSN-L
1525-0016
Statut éditorial
Publié
Date de publication
2002
Volume
6
Numéro
2
Pages
155-161
Langue
anglais
Notes
Publication types: In Vitro ; Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
We developed an ex vivo gene therapy approach for the regulated delivery of therapeutic proteins based on the implantation of encapsulated, genetically engineered C(2)C(12) myoblasts. We investigated doxycycline-based regulation of gene expression to modulate the secretion of erythropoietin (EPO) from encapsulated myoblasts in a mouse model. An autoregulatory tet-off system provided high induction levels with low basal expression in the noninduced state. Stable C(2)C(12) clones constitutively secreted between 25 and 50 IU mouse EPO/10(6)cells/24 hours in the on-state. The clone C15, selected for its in vivo survival characteristics, displayed a desirable secretion profile when encapsulated. Devices released 5 IU EPO per capsule in the on-state, with EPO levels being undetectable upon the addition of doxycycline (dox). Capsules subcutaneously implanted in DBA/2J mice demonstrated a tightly regulated secretion of EPO through up to four on-off cycles during a period lasting 40 weeks. Hematocrits could be modulated between basal levels (40-50%) and elevated levels (70-90%) through the presence or absence of dox in the drinking water. Hematocrit returned to normal levels, paralleling the kinetics observed following capsule explantation, 6 to 8 weeks following dox administration to polycythemic mice. The results of this study suggest that encapsulation and implantation of a tet-off regulated C(2)C(12) cell clone represents a safe method for the controlled long-term delivery of proteins in vivo.
Mots-clé
Animals, Cell Survival, Clone Cells, Doxycycline/pharmacology, Erythropoietin, Recombinant/genetics, Erythropoietin, Recombinant/secretion, Female, Gene Therapy/methods, Genetic Engineering, Hematocrit, Kinetics, Mice, Mice, Inbred DBA, Muscle, Skeletal/cytology, Muscle, Skeletal/drug effects
Pubmed
Web of science
Création de la notice
13/12/2011 17:36
Dernière modification de la notice
03/03/2018 18:52
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