کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6022082 1580659 2014 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی عصب شناسی
پیش نمایش صفحه اول مقاله
Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease
چکیده انگلیسی


- Tightly controllable expression of the neurotrophic factor GDNF for gene therapy
- Short-term induction of GDNF resulted in long-term neurorestoration.
- Discontinuous GDNF expression sufficient for therapeutic success
- Allows combining pharmacological control with efficacy of gene therapy
- May open novel venues for treatment of PD or other neurodegenerative disorders

Neurotrophic factors have raised hopes to be able to cure symptoms and to prevent progressive neurodegeneration in devastating neurological diseases. Gene therapy by means of viral vectors can overcome the hurdle of targeted delivery, but its current configuration is irreversible and thus much less controllable than that of classical pharmacotherapies. We thus aimed at developing a strategy allowing for both curative and controllable neurotrophic factor expression. Therefore, the short-term, intermittent and reversible expression of a neutrophic factor was evaluated for therapeutic efficacy in a slowly progressive animal model of Parkinson's disease (PD).We demonstrate that short-term induced expression of glial cell line derived neurotrophic factor (GDNF) is sufficient to provide i) substantial protection of nigral dopaminergic neurons from degeneration and ii) restoration of dopamine supply and motor behaviour in the partial striatal 6-OHDA model PD. These neurorestorative effects of GDNF lasted several weeks beyond the time of its expression. Later on, therapeutic efficacy ceased, but was restored by a second short induction of GDNF expression, demonstrating that monthly application of the inducing drug mifepristone was sufficient to maintain neuroprotective and neurorestorative GDNF levels.These findings suggest that forthcoming gene therapies for PD or other neurodegenerative disorders can be designed in a way that low frequency application of an approved drug can provide controllable and therapeutically efficient levels of GDNF or other neurotrophic factors. Neurotrophic factor expression can be withdrawn in case of off-target effects or sufficient clinical benefit, a feature that may eventually increase the acceptance of gene therapy for less advanced patients, which may profit better from such approaches.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 65, May 2014, Pages 35-42
نویسندگان
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