Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector.

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Version: Author's accepted manuscript
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Serval ID
serval:BIB_74113391BE61
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Therapeutic efficacy of regulable GDNF expression for Huntington's and Parkinson's disease by a high-induction, background-free "GeneSwitch" vector.
Journal
Experimental neurology
Author(s)
Cheng S., Tereshchenko J., Zimmer V., Vachey G., Pythoud C., Rey M., Liefhebber J., Raina A., Streit F., Mazur A., Bähr M., Konstantinova P., Déglon N., Kügler S.
ISSN
1090-2430 (Electronic)
ISSN-L
0014-4886
Publication state
Published
Issued date
11/2018
Peer-reviewed
Oui
Volume
309
Pages
79-90
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Gene therapy is currently an irreversible approach, without possibilities to fine-tune or halt the expression of a therapeutic gene product. Especially when expressing neurotrophic factors to treat neurodegenerative disorders, options to regulate transgene expression levels might be beneficial. We thus developed an advanced single-genome inducible AAV vector for expression of GDNF, under control of the approved small molecule drug mifepristone. In the rat brain, GDNF expression can be induced over a wide range up to three hundred-fold over endogenous background, and completely returns to baseline within 3-4 weeks. When applied with appropriate serotype and titre, the vector is absolutely free of any non-induced background expression. In the BACHD model of Huntington's disease we demonstrate that the vector can be kept in a continuous ON-state for extended periods of time. In a model of Parkinson's disease we demonstrate that repeated short-term expression of GDNF restores motor capabilities in 6-OHDA-lesioned rats. We also report on sex-dependent pharmacodynamics of mifepristone in the rodent brain. Taken together, we show that wide-range and high-level induction, background-free, fully reversible and therapeutically active GDNF expression can be achieved under tight pharmacological control by this novel AAV - "Gene Switch" vector.
Keywords
3,4-Dihydroxyphenylacetic Acid/metabolism, Adrenergic Agents/toxicity, Animals, Disease Models, Animal, Gene Expression Regulation/drug effects, Gene Expression Regulation/genetics, Glial Cell Line-Derived Neurotrophic Factor/genetics, Glial Cell Line-Derived Neurotrophic Factor/metabolism, Green Fluorescent Proteins/genetics, Green Fluorescent Proteins/metabolism, Homovanillic Acid/metabolism, Hormone Antagonists/therapeutic use, Huntingtin Protein/genetics, Huntingtin Protein/metabolism, Huntington Disease/genetics, Huntington Disease/metabolism, Huntington Disease/pathology, Huntington Disease/therapy, Mice, Mice, Transgenic, Mifepristone/therapeutic use, Oxidopamine/toxicity, Parkinson Disease/etiology, Parkinson Disease/genetics, Parkinson Disease/metabolism, Parkinson Disease/therapy, Synapsins/genetics, Synapsins/metabolism, Synucleins/genetics, Synucleins/metabolism, Transduction, Genetic, AAV, GDNF, GeneSwitch, Huntington's disease, Mifepristone, Parkinson's disease, Regulated expression
Pubmed
Web of science
Create date
13/08/2018 13:25
Last modification date
20/08/2019 14:31
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