A5032143754- Parkinson's Disease Mechanisms and Treatments
- Nerve injury and regeneration
- Neurological disorders and treatments
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- Autism Spectrum Disorder Research
- RNA regulation and disease
- Pluripotent Stem Cells Research
- Genetic Neurodegenerative Diseases
- Botulinum Toxin and Related Neurological Disorders
- CRISPR and Genetic Engineering
- Mitochondrial Function and Pathology
- Electron Spin Resonance Studies
- Animal Genetics and Reproduction
- Neurogenesis and neuroplasticity mechanisms
- Electrospun Nanofibers in Biomedical Applications
- Biotin and Related Studies
- Neurotransmitter Receptor Influence on Behavior
- Cannabis and Cannabinoid Research
- Herpesvirus Infections and Treatments
- Neuroscience and Neural Engineering
- Paraquat toxicity studies and treatments
- Neuroscience and Neuropharmacology Research
- CAR-T cell therapy research
Université de Bordeaux
2018-2021
Centre National de la Recherche Scientifique
2018-2021
Lund University
2015-2020
Institut des Maladies Neurodégénératives
2018-2020
Cardiff University
2012-2016
Wallenberg Wood Science Center
2015
Significance Parkinson’s disease is the most common neurodegenerative movement disorder, but its faithful modeling in animals has been challenging. Animal models based on overexpression of disease-causing protein, α-synuclein (α-syn), are useful for studies pathogenesis rely unphysiologically high levels α-syn. Here, we present a model that combines preformed human α-syn fibrils and adenoassociated virus (AAV)-mediated α-syn, given doses that, by themselves, do not cause any acute...
Preclinical assessment of the therapeutic potential dopamine (DA) neuron replacement in Parkinson's disease (PD) has primarily been performed 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect pathological features or progressive nature disease. In study, we establish humanized transplantation PD that better recapitulates main features, obtained by coinjection preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV)...
Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark Parkinson's disease (PD). Here we investigate how chronic dopamine denervation and replacement with L-DOPA affect the morphology physiology direct pathway SPNs (dSPNS) in rat striatum. We used lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs rats 6-hydroxydopamine (6-OHDA) lesions. Changes were assessed through combination patch-clamp recordings two photon microscopy....
Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination genetic switch drug which, when administered at clinically-approved dose, reaches brain in sufficient amounts induce therapeutic effect. We describe highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for first time longitudinal...
Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson's disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories explain these negative outcomes that were done late-stage patients advanced nigrostriatal degeneration and may therefore not respond therapy. Based on this idea, we tested if stage important for GDNF-based therapies. Lentiviral vectors expressing regulated...
In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent (GFP) or GFP coupled HTT-Exon1 (19Q 103Q) the central nervous system adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing post-mortem analyses determine long-term consequences AAV injection. Both primates demonstrated changes at 2-3 weeks post-surgery. mice, these were absent...
Regulation of therapeutic transgene expression can increase the safety gene therapy interventions, especially when targeting critical organs such as brain. Although several systems have been described, none current has required profile for clinical applications. Our group previously adapted a system novel regulation based on destabilizing domain degron technology to successfully regulate glial cell-line derived neurotrophic factor in brain (GDNF-F-DD). In present study, we used GDNF-F-DD...
In recent years, substantial evidence has emerged to suggest that spreading of pathological proteins contributes disease pathology in numerous neurodegenerative disorders. Work from our laboratory and others have shown that, despite its strictly genetic nature, Huntington's (HD) may be another condition which this mechanism pathology. study, we set out determine if the mutant huntingtin protein (mHTT) present post-mortem brain tissue derived HD patients can induce mice and/or non-human...
Although intrastriatal transplantation of fetal cells for the treatment Parkinson's disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These highlighted need greater preclinical analysis parameters that may influence success cell therapy. While much this has focused on and location transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is...
Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) is thought to enhance transgene expression of target genes delivered by adeno-associated viral (AAV) vectors. This study assessed the protein α-synuclein, phosphorylated α-synuclein at Serine 129, extent nigrostriatal degeneration as well subsequent behavioral deficits induced unilateral intranigral stereotactic injection in male adult C57BL/6J mice an AAV2/9 expressing A53T human under control synapsin promoter...
In Parkinson's disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via vagus nerve, central system. Recent evidences collected in non-human primates challenge however hypothesis of a transmission α-synuclein (α-syn) pathology through nerve. Would whereby bloodstream acts as route for long-distance pathological α-syn hold true, an inter-individual could occur blood contact. Here, we used parabiosis approach join circulatory systems wild type and GFP transgenic...
Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat Parkinson's disease. The main challenge is finding a combination genetic switch drug which, when administered at clinically-approved dose, reaches brain in sufficient amounts induce therapeutic effect. We describe highly-sensitive doxycycline-inducible AAV vector (AAV-Dox-ON). This allowed for first time longitudinal...
Safety and tolerability of gene therapy mediated by adeno-associated viral vectors in the brain has been established several pioneer clinical trials.1 2 3 However, case genes coding for neurotrophic factors, prolonged uncontrolled exposure can lead to adverse effects.4 5 Given irreversibility administration method (viral DNA remains stable neurons), expression should be adjusted each patient's needs interrupted if necessary. Therefore, there is a crucial need clinically acceptable genetic...