| Summary: | Cell replacement therapies have been thoroughly investigated in the hope of finding a long-term, continuous dopaminergic (DAergic) source to treat motor dysfunctions in Parkinson’s disease (PD). However, mixed clinical results, safety and logistical concerns, and ethical issues have led to the interruption of these therapies in the clinic. Human Retinal Pigment Epithelial (hRPE) cells from fetal or neonatal origin have been proposed as a tissue transplant alternative for PD. HRPE cells are of neuroectoderm origin and play an integral part in normal retinal survival and function by providing nutritive, trophic, and anti-inflammatory support. HRPE cells are a potential cell therapy source for PD because of their DAergic properties. In the RPE, dopa is an intermediate product in the melanin biosynthetic pathway, catalyzed by the tyrosine hydroxylase analog tyrosinase. Since tyrosinase-produced dopa can exit the cell through plasma membrane amino acid transporters, RPE implantation into the parkinsonian brain could provide a continuous source of dopa to striatal DA terminals.
Previous reports have shown that hRPE cells attached to biocompatible gelatin microcarriers (hRPE-GM) can successfully ameliorate parkinsonian symptoms in PD patients. However, these observations are empirical in nature; indeed, little is known about long-term hRPE-GM survival or its underlying mechanism of action. The present thesis addresses the hypotheses that 1) hRPE-GM implants ameliorate behavioural deficits, 2) hRPE-GM survive long-term in the host striatum, and 3) the mechanism of action of hRPE-GM implants is not solely due to the in situ production of dopa and may involve alternate mechanisms of action, with an emphasis on anti-inflammatory factors. Using the rodent 6-OHDA model for PD, we investigated the qualitative survival and behavioural effects of hRPE-GM implants combining post mortem immunohistochemistry and non drug-induced behavioural paradigms. Next, we assessed the hypothesized reduction in inflammatory reactions to hRPE-GM implants (in the absence of immunosuppression) by quantifying the inflammatory response using stereological methods. Finally, we described a quantitative timeline of in vivo hRPE-GM survival using our recently developed superparamagnetic labeling techniques and MRI. These studies will provide further support for using hRPE cells as a therapeutic option for PD.
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