The worldwide prevalence of Parkinson’s disease is estimated to be 4.1 million cases and is expected to affect 8.7 million by 2030. In Switzerland, some 15’000 patients are affected with Parkinson’s disease, and up to 20% of newly diagnosed patients are under 60 years of age. Parkinson’s disease is defined by the loss of control of movements. It is due to the degeneration of the dopaminergic neurons in the pars compacta of the substantia nigra, which send its axons to the striatum (the nigro-striatal pathway). Patients affected by Parkinson’s disease show progressive bradykinesia (slow movements), rigidity and tremor. Current therapeutic modalities provide long-lasting control of motor symptoms. However, the two mainstays of Parkinson's disease (such as levodopa and deep brain stimulation) rely on the presence of a residual function of dopaminergic neurons and will not be effective anymore once neurodegeneration is too severe. Cell replacement therapy is a promising therapeutic option for neurodegenerative diseases such as Parkinson’s disease. Currently, the site of implantation for cell-based therapy for Parkinson’s disease is the striatum. Foetal mesencephalic stem cells-derived dopaminergic grafts have demonstrated the proof of principle for cell therapy in Parkinson’s disease patients. The transplantation of foetal mesencephalic stem cells allowed to improve the clinical outcomes (e.g. motor function evaluated by using the Unified Parkinson’s Disease Rating Scale, UPDRS), to restore dopamine release and axonal outgrowth. Although promising, foetal grafts are ethically questionable and suffer from a limited availability for clinical use. Pluripotent stem cell-derived dopaminergic neurons have been successfully transplanted into the striatum of animal models of Parkinson’s disease showing the same behavioural improvement (i.e. evaluation of motor function in animals by using amphetamine-induced rotation behaviour). The three major issues impairing cell-based therapies for Parkinson’s disease are:• The low survival rate (5-20%) of transplanted neurons• The decrease in the percentage of dopaminergic neurons after transplantation• The low integration rate of transplanted dopaminergic neurons Several factors may contribute to these major issues, including: trophic factor withdrawal, hypoxia, acute inflammation, immune rejection and anoikis (a type of apoptosis triggered by detachment from the extracellular matrix and cells). Recent protocols can yield a high quality of dopaminergic neurons by using stromal cells from mouse bone marrow (MS5) in vitro. However, according to the Good Manufacturing Practice (GMP), these cells are not of clinical use. Therefore, they cannot be used for the transplantation into human’s brain. Human mesenchymal stem cells (MSCs) from bone marrow have the potential to replace animal feeder cells during cell culture. In addition, MSCs are used as a therapeutic source for the secretion of neurotrophic factors (e.g. brain-derived neurotrophic factor/BDNF or glial cell line-derived neurotrophic factor/GDNF). These factors are essential for promoting the survival and neurite outgrowth of dopaminergic precursors in vitro and in vivo.To our knowledge, there is no available data regarding the impact of co-transplantation of mesenchymal stem cells (MSCs) and sustained release of neuroprotective factors with dopaminergic neurons. Thus, the current research project aims at filling this gap. We elaborate the following research hypotheses based on the previous observations:1. Survival and phenotypic stability of human dopaminergic precursor neurons can be optimized by neurotrophic support:a) In vitro co-culture of human dopaminergic precursor neurons with human MSCs can optimize invitro maturation towards a dopaminergic fate.b) In vivo striatal co-transplantation of human dopaminergic precursor neurons with human MSCscan improve dopaminergic neurons engraftment.c) In vivo striatal injection of a scaffold gradually releasing neurotrophic factors can improvedopaminergic neurons engraftment.2. Restoration of the nigro-striatal pathway by using a slow release system to guide axonal outgrowth of dopaminergic precursor neurons towards striatum.Accordingly, the two major aims of this research project are:1. To improve the survival, differentiation and maturation of human dopaminergic precursor neurons by cell co-culture and co-transplantation.2. To take advantage of an existing slow release system to deliver chemoattractants for axon outgrowth and guidance of human dopaminergic precursor neurons.
|Effective start/end date||1/09/15 → 31/08/17|
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung: $124,636.00