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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State: Public
Version: Author's accepted manuscript
License: Not specified
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
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
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 14:25
Last modification date
21/11/2022 9:19