The potential of neurotrophin-secreting mesenchymal stem cells for the treatment of Parkinson's disease
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The most effective experimental neuroprotectant for Parkinson's disease that has been identified from extensive preclinical studies is the neurotrophin, glial cell line-derived neurotrophic factor (GDNF). However, the efficacy of GDNF in clinical trials has been hampered by issues related to its delivery. A possible alternative approach for delivery of this neurotrophin is through ex vivo gene therapy, in which suitable cells, such as bone marrow-derived mesenchymal stem cells (MSCs), are genetically engineered to overexpress GDNF prior to transplantation. Thus, the overarching aim of this project was to develop and preclinically validate an ex vivo gene therapy approach using MSCs for delivery of GDNF to the Parkinsonian brain. We first assessed the ability of GDNF-transduced MSCs to enhance the survival of primary dopaminergic neurons (obtained from ventral mesencephalon (VM) dissection) when co-transplanted in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. Following this, we then assessed the neuroprotective potential of GDNF-MSCs in the inflammation-driven lipopolysaccharide (LPS) model of Parkinson's disease. Based on the results of these studies, we then investigated various strategies to improve the survival of MSCs in the rat brain including encapsulation of the cells in a collagen hydrogel prior to transplantation. In brief, we found that GDNF-MSCs did not improve the survival of primary dopaminergic neurons when co-transplanted into the 6-hydroxydopamine-lesioned rat striatum. However, when these cells were grafted into the striatum in advance of an intra-nigral LPS lesion, these cells were capable of providing localised protection against inflammation-driven neurodegeneration to the dopaminergic terminals surrounding the graft site. However, due to issues with the poor survival of these bone marrow-derived cells in the ectopic environment of the brain, this neuroprotection did not extend beyond the immediate vicinity of the graft site. We attempted a number of strategies to improve MSC survival in the rat brain. Of these, encapsulation in a type 1 collagen hydrogel proved the most promising approach, as the hydrogel was not detrimental to cell survival, did not impede the striatal diffusion of GDNF secreted by the transplanted cells, and significantly reduced the host immune response to the graft. Furthermore, the GDNF released from the collagen encapsulated MSCs was also capable of providing local neuroprotection at the site of transplant in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. To conclude, GDNF-transduced MSCs are capable of inducing local dopaminergic neuroprotection in both inflammatory and a neurotoxic models of Parkinson's disease when transplanted alone or encapsulated in a collagen hydrogel. Therefore, while we believe the optimisation of this therapeutic approach warrants further study, until the issue of poor survival of these cells in the brain can be addressed, the progression and potential clinical translation of this ex vivo gene therapy remains limited.
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