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- W2617963546 abstract "Safety and tolerability of gene therapy mediated by adeno-associated viral vectors in the brain has been established in several pioneer clinical trials.1 2 3 However, in the case of genes coding for neurotrophic factors, prolonged uncontrolled exposure can lead to adverse effects.4 5 Given the irreversibility of the administration method (viral DNA remains stable in neurons), gene expression should be adjusted to each patient's needs and interrupted if necessary. Therefore, there is a crucial need for a clinically acceptable genetic system, which allows modulation of the level of neurotrophic factor released into the brain. The main challenge is to obtain a genetic switch responding to a clinically approved inducer, at a dose which does not elicit adverse effects. The BrainVectors consortium (http://www.brainvectors.org) has developed a highly sensitive inducible AAV vector whose activity depends on the administration of the antibiotic doxycycline (AAV-DoxON). We have evaluated the potential of this new vector for a safe pharmacologically controlled glial cell line–derived neurotrophic factor (GDNF) gene therapy in a rat model of Parkinson disease. Briefly, animals received intrastriatal stereotaxic injection of the AAV-DoxON-GDNF vector, followed by oral administration of Dox. Using three vector doses and five Dox doses, we demonstrated that GDNF had biological effects that were dependent on the Dox dose. Importantly, the minimal Dox dose inducing GDNF receptor signaling was lower than that commonly prescribed for long-term treatment of inflammatory diseases of the skin (rosacea) and of the teeth surrounding tissue (periodontitis), demonstrated to be safe for both the patient and the environment.6 We furthermore observed that a previously described adverse effect of GDNF on the motor behavior only started to appear at a 13-fold higher Dox dose combined with a 2.5-fold higher vector dose, whereas reduced weight gain, another well-known undesirable effect of GDNF, was not observed even at the highest vector and Dox doses. These data demonstrate that the window of pharmacological parameters for a safe neuroprotective gene therapy using AAV-DoxON-V16-GDNF is wide." @default.
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- W2617963546 date "2015-09-07" @default.
- W2617963546 modified "2023-10-16" @default.
- W2617963546 title "Toward the Pharmacological Control of Gene Transfer-Mediated Intracerebral Neurotrophic Factor Administration" @default.
- W2617963546 doi "https://doi.org/10.1055/s-0035-1564510" @default.
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