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

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.

• Authors: Shi Cheng, Julia Tereshchenko, Virginie Zimmer, Gabriel Vachey, Catherine Pythoud, Maria Rey, Jolanda Liefhebber, Anupam Raina, Frank Streit, Andrzej Mazur, Mathias Bähr, Pavlina Konstantinova, Nicole Déglon, Sebastian Kügler
• Journal: Experimental neurology (Exp Neurol) Vol. 309 Pg. 79-90 (11 2018) ISSN: 1090-2430 [Electronic] United States
• PMID: 30076831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Adrenergic Agents
• Glial Cell Line-Derived Neurotrophic Factor
• HTT protein, human
• Hormone Antagonists
• Huntingtin Protein
• Synapsins
• Synucleins
• 3,4-Dihydroxyphenylacetic Acid
• Green Fluorescent Proteins
• Mifepristone
• Oxidopamine
• Homovanillic Acid

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Adrenergic Agents (toxicity)
• Animals
• Disease Models, Animal
• Gene Expression Regulation (drug effects, genetics)
• Glial Cell Line-Derived Neurotrophic Factor (genetics, metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• Homovanillic Acid (metabolism)
• Hormone Antagonists (therapeutic use)
• Huntingtin Protein (genetics, metabolism)
• Huntington Disease (genetics, metabolism, pathology, therapy)
• Mice
• Mice, Transgenic
• Mifepristone (therapeutic use)
• Oxidopamine (toxicity)
• Parkinson Disease (etiology, genetics, metabolism, therapy)
• Synapsins (genetics, metabolism)
• Synucleins (genetics, metabolism)
• Transduction, Genetic