A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses
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-approv...
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Elsevier
2016-01-01
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Series: | Molecular Therapy: Methods & Clinical Development |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116301693 |
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doaj-777931018d894258974b7053b2660708 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses Molecular Therapy: Methods & Clinical Development |
author_facet |
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 |
author_sort |
Abdelwahed Chtarto |
title |
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses |
title_short |
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses |
title_full |
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses |
title_fullStr |
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses |
title_full_unstemmed |
A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses |
title_sort |
regulatable aav vector mediating gdnf biological effects at clinically-approved sub-antimicrobial doxycycline doses |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2016-01-01 |
description |
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 × 109 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. |
url |
http://www.sciencedirect.com/science/article/pii/S2329050116301693 |
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doaj-777931018d894258974b7053b26607082020-11-24T22:57:03ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012016-01-013C10.1038/mtm.2016.27A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline dosesAbdelwahed Chtarto0Marie Humbert-Claude1Olivier Bockstael2Atze T Das3Sébastien Boutry4Ludivine S Breger5Bep Klaver6Catherine Melas7Pedro Barroso-Chinea8Tomas Gonzalez-Hernandez9Robert N Muller10Olivier DeWitte11Marc Levivier12Cecilia Lundberg13Ben Berkhout14Liliane Tenenbaum15Laboratory of Experimental Neurosurgery and Multidisciplinary Research Institute (I.R.I.B.H.M.), Université Libre de Bruxelles (ULB), Brussel, BelgiumLaboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Dept of Clinical Neuroscience, Lausanne University Hospital, Lausanne, SwitzerlandLaboratory of Experimental Neurosurgery and Multidisciplinary Research Institute (I.R.I.B.H.M.), Université Libre de Bruxelles (ULB), Brussel, BelgiumLaboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsCenter for Microscopy and Molecular Imaging (CMMI), Charleroi, BelgiumCNS Gene Therapy Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, SwedenLaboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Experimental Neurosurgery and Multidisciplinary Research Institute (I.R.I.B.H.M.), Université Libre de Bruxelles (ULB), Brussel, BelgiumDepartamento de Ciencias Médicas Básicas (Anatomía), Facultad de Ciencias de la Salud (Medicina), Instituto de Tecnologías Biomédicas (ITB, CIBICAN), Universidad de La Laguna, Tenerife, SpainDepartamento de Ciencias Médicas Básicas (Anatomía), Facultad de Ciencias de la Salud (Medicina), Instituto de Tecnologías Biomédicas (ITB, CIBICAN), Universidad de La Laguna, Tenerife, SpainDepartment of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, BelgiumNeurosurgery, Hôpital Erasme, Brussels, BelgiumNeurosurgery unit, Department of Clinical Neuroscience, Lausanne University Hospital, Lausanne, SwitzerlandCNS Gene Therapy Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, SwedenLaboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsLaboratory of Cellular and Molecular Neurotherapies, Center for Neuroscience Research, Dept of Clinical Neuroscience, Lausanne University Hospital, Lausanne, SwitzerlandPreclinical 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 × 109 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.http://www.sciencedirect.com/science/article/pii/S2329050116301693 |