Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose.

Détails

ID Serval
serval:BIB_CBA61ACC8FAC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose.
Périodique
Gene Therapy
Auteur(s)
Touchard E., Heiduschka P., Berdugo M., Kowalczuk L., Bigey P., Chahory S., Gandolphe C., Jeanny J.C., Behar-Cohen F.
ISSN
1476-5462 (Electronic)
ISSN-L
0969-7128
Statut éditorial
Publié
Date de publication
2012
Peer-reviewed
Oui
Volume
19
Numéro
9
Pages
886-898
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 μg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.
Mots-clé
Animals, Ciliary Neurotrophic Factor/metabolism, Disease Models, Animal, Electroporation, Genetic Therapy/methods, Glial Cell Line-Derived Neurotrophic Factor/genetics, Glial Cell Line-Derived Neurotrophic Factor/metabolism, Photoreceptor Cells, Vertebrate/physiology, Plasmids, Rats, Retinal Degeneration/therapy, Retinitis Pigmentosa/therapy
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/08/2013 16:33
Dernière modification de la notice
09/05/2019 1:18
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