A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses.

Détails

Ressource 1Télécharger: BIB_AB62686BE882.P001.pdf (3460.23 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_AB62686BE882
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses.
Périodique
Molecular Therapy. Methods and Clinical Development
Auteur(s)
Chtarto A., Humbert-Claude M., Bockstael O., Das A.T., Boutry S., Breger L.S., Klaver B., Melas C., Barroso-Chinea P., Gonzalez-Hernandez T., Muller R.N., DeWitte O., Levivier M., Lundberg C., Berkhout B., Tenenbaum L.
ISSN
2329-0501 (Electronic)
ISSN-L
2329-0501
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
5
Pages
16027
Langue
anglais
Résumé
Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging. To evaluate the dose range of GDNF biological activity, the inducible AAV vector (8.0 × 10(9) viral genomes) was injected in the rat striatum at four delivery sites and increasing doxycycline doses administered orally. ERK/Akt signaling activation as well as tyrosine hydroxylase downregulation, a consequence of long-term GDNF treatment, were induced at plasmatic doxycycline concentrations of 140 and 320 ng/ml respectively, which are known not to increase antibiotic-resistant microorganisms in patients. In these conditions, GDNF covered the majority of the striatum. No behavioral abnormalities or weight loss were observed. Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses.
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/04/2016 18:13
Dernière modification de la notice
20/08/2019 16:15
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