期刊
EXPERIMENTAL NEUROLOGY
卷 309, 期 -, 页码 79-90出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2018.07.017
关键词
GeneSwitch; Regulated expression; GDNF; Parkinson's disease; Huntington's disease; AAV; Mifepristone
资金
- German Research Council
- European Community [E!7900: ESTAR13113/19/NCBR/2014]
- Oversea Study program of the Guangzhou Elite project
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, back-ground-free, fully reversible and therapeutically active GDNF expression can be achieved under tight pharmacological control by this novel AAV - Gene Switch vector.
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