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

Abdelwahed Chtarto, Marie Humbert-Claude, Olivier Bockstael, Atze T Das, Sébastien Boutry, Ludivine S Breger, Bep Klaver, Catherine Melas, Pedro Barroso-Chinea, Tomas Gonzalez-Hernandez, Robert N Muller, Olivier DeWitte, Marc Levivier, Cecilia Lundberg, Ben Berkhout, Liliane Tenenbaum
Molecular Therapy - Methods & Clinical Development. 2016-01-01; 3: 16027
DOI: 10.1038/mtm.2016.27

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1. Mol Ther Methods Clin Dev. 2016 Mar 30;5:16027. doi: 10.1038/mtm.2016.27.
eCollection 2016.

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

Chtarto A(1), Humbert-Claude M(2), Bockstael O(1), Das AT(3), Boutry S(4), Breger
LS(5), Klaver B(3), Melas C(1), Barroso-Chinea P(6), Gonzalez-Hernandez T(6),
Muller RN(7), DeWitte O(8), Levivier M(9), Lundberg C(5), Berkhout B(3),
Tenenbaum L(2).

Author information:
(1)Laboratory of Experimental Neurosurgery and Multidisciplinary Research
Institute (I.R.I.B.H.M.), Université Libre de Bruxelles (ULB) , Brussel, Belgium.
(2)Laboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience
Research, Dept of Clinical Neuroscience, Lausanne University Hospital , Lausanne,
(3)Laboratory of Experimental Virology, Department of Medical Microbiology,
Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center,
University of Amsterdam , Amsterdam, The Netherlands.
(4)Center for Microscopy and Molecular Imaging (CMMI) , Charleroi, Belgium.
(5)CNS Gene Therapy Unit, Department of Experimental Medical Sciences, Wallenberg
Neuroscience Center, Lund University , Lund, Sweden.
(6)Departamento de Ciencias Médicas Básicas (Anatomía), Facultad de Ciencias de
la Salud (Medicina), Instituto de Tecnologías Biomédicas (ITB, CIBICAN),
Universidad de La Laguna , Tenerife, Spain.
(7)Department of General, Organic and Biomedical Chemistry, NMR and Molecular
Imaging Laboratory, University of Mons , Mons, Belgium.
(8)Neurosurgery, Hôpital Erasme , Brussels, Belgium.
(9)Neurosurgery unit, Department of Clinical Neuroscience, Lausanne University
Hospital , Lausanne, Switzerland.

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.

DOI: 10.1038/mtm.2016.27
PMCID: PMC4813607
PMID: 27069954

Auteurs Bordeaux Neurocampus