Development of personalized stem cell-based therapies for Parkinson's disease patients
Development of personalised stem-cell based therapies for Parkinson´s disease patients
A central question in this project is to elucidate disease mechanisms and relate them to interventions that may help develop personalised therapies for Parkinson´s disease (PD) patients. We address this question by a combination of advanced crossdisciplinary principles and methodologies.
During the reporting period, we have developed a novel morphogenetic neuroengineering protocol, which enables us to efficiently generate dopaminergic (DA) neurons from commercially available, human induced pluripotent stem cells (iPSCs). These neurons are electrophysiologically active and spontaneously form hierarchical networks when interfaced with a multi electrode array (MEA) platform. Additionally, we study these neurons within custom-made microfluidics devices with embedded microarchitucture, facilitating studies of axonal connectivity. We thus now have a highly advanced, versatile experimental set up, which forms the basis for modelling PD in vitro. Thus, by electrochemical, molecular, as well as genetic modulation, we can mimic and/or influence PD associated mechanisms and dynamics, and also develop mathematical models that elucidate as well as predict neural network responses to damage and repair. Furthermore, we are in the process of developing reprogramming protocols for the generation of (DA) neurons from fibroblasts, which will subsequently enable us to proceed with the generation of donor-specific neural networks, recapitulating the genetic profile (when relevant) of the disease. Parallel to the above, we have available to us a range of tailored nanoparticles (NPs) that can be incorporated in the above studies. One such example, are NPs with dual properties, which enable simultaneous release of L-Dopa and a contrast agent compatible with live neuroimaging. We have recently published a relevant proof-of-principle paper (McDonagh et al. Small 2016). Furthermore, we have custom-designed NPs, which can achieve slow, controlled release of neurotrophic factors (such as GDNF) for more than four weeks in vitro. The next step is to test whether these NPs can achieve neuroprotection in vivo in an experimental model of PD.
L-DOPA-Coated Manganese Oxide Nanoparticles as Dual MRI Contrast Agents and Drug-Delivery Vehicles.
Small 2016 Jan 20;12(3):301-6. Epub 2015 nov 30