CELL REPLACEMENT THERAPY FOR PARKINSON’S DISEASE: The importance of neuronal subtype, cell source and connectivity for functional recovery
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor deficits such as slowness in movement, difficulty in initiating movement and tremor at rest. The cause of these motor symptoms is the selective loss of mesencephalic dopaminergic (mesDA) neurons, located in the substantia nigra (SN). These neurons project axons to the striatum where they release dopamine, a neurotransmitter that controls voluntary movement. Current drug treatments restore the lost dopamine, while initially efficacious, the beneficial effects wear off resulting in severe side effects. Thus, there is a clear requirement for alternative therapeutic options. One such idea is cell replacement therapy (CRT). CRT aims to replace neurons that have degenerated in PD, with donor cells that have the potential to functionally re-integrate into the host circuitry. This involves transplantation of developing midbrain cells from aborted fetuses, (the part that form mesDA neurons), into the striatum of a PD patient. Clinical trials have demonstrated that CRT can provide long-lasting, significant clinical benefit. Although some patients do not respond as favourably. We still do not know what specific factors contribute to the success in transplantation i.e. what cells are responsible for motor recovery? Can the transplants reform damaged neuronal circuitry? Use of human fetal tissue raises several ethical issues, but are there alternative cell sources that can substitute effectively? The aim of this thesis was to understand how particular factors such as neuronal content, placement and cell source, affect functional outcome after transplantation into the rodent brain. In paper ?1, I detail the neurodegenerative and behavioural outcomes in a mouse lesion model of PD, which can be used as a platform for the development of novel therapeutic strategies. I also describe the development of a novel behavioural task that is predictive of mesDA neuron cell loss in mice. Previously, it was thought that transplanted neurons could not extend axons over long distances rendering transplantation into the SN a non-viable approach. In paper ?2, I describe how mesDA neurons transplanted in the adult SN of a PD mouse model, extended axons across millimetres into the striatum, functionally reforming the nigrostriatal pathway. In paper ?3, I also identify the specific mesDA population (A9) that is critical for functional recovery, with transplants that lack A9 neurons failing to improve motor recovery. A potentially pre-clinical aspect of this thesis is detailed in paper ?4 where I describe a robust protocol for the generation of functional mesDA neurons from human embryonic stem cells that are functional in a rat model of PD. No evidence of tumour formation was observed in the transplanted animals, a major concern when utilising a pluripotent cell source. Through understanding functional recovery in terms of neuronal subtype and connectivity, the work presented in this thesis aims to bring the prospect of CRT closer to the clinic, I also describe the generation of a very promising alternative cell source that could rival fetal tissue. Together this work contributes to making CRT a reality for the treatment of PD.
CLICK HERE TO DOWNLOAD THE WHOLE DISSERTATION. (in PDF format)