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Exp Neurol. 2018 Nov;309:79-90. doi: 10.1016/j.expneurol.2018.07.017. Epub 2018 Aug 1.

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

Author information

1
Dept. of Neurology, University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany.
2
Laboratory of Neurotherapies and NeuroModulation, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Pavillon 3, Avenue de Beaumont, 1011 Lausanne, Switzerland; Neuroscience Research Center, Lausanne University Hospital (CHUV), Pavillon 3, Avenue de Beaumont, 1011 Lausanne, Switzerland.
3
uniQure N.V., Paasheuvelweg 25a, 1105, BP, Amsterdam, The Netherlands.
4
Clinical Chemistry, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
5
Department of Genetics and Microbiology, Maria Curie-Sklodowska University, Akademicka 19, Lublin, Poland.
6
Laboratory of Neurotherapies and NeuroModulation, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Pavillon 3, Avenue de Beaumont, 1011 Lausanne, Switzerland.
7
Dept. of Neurology, University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany. Electronic address: sebastian.kuegler@med.uni-goettingen.de.

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:

AAV; GDNF; GeneSwitch; Huntington's disease; Mifepristone; Parkinson's disease; Regulated expression

PMID:
30076831
DOI:
10.1016/j.expneurol.2018.07.017
[Indexed for MEDLINE]

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