Doris Doudet

Professor

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2021)
Human retinal pigment epithelial cell transplantation for the treatment of Parkinson's disease (2011)

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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Master's Student Supervision (2010 - 2020)
Validation of a novel progressive rat model of Parkinson's disease using in vivo positron emission tomography, behavioural assessments, and in vitro autoradiography (2019)

Parkinson’s disease (PD) is an incurable and progressive neurodegenerative disorder that primarily affects the motor system. PD patients also experience a wide range of non-motor symptoms. Despite many pharmacological treatments demonstrating neuroprotective properties in animal models, most fail to translate to successful clinical trial outcomes. This is partly due to the animal models that are being used to test the treatments. These models are either acute in nature or are able to reproduce primarily only the motor symptoms of PD. Time-limited consumption of β-sitosterol β-D-glucoside (BSSG), a component of the cycad seed, was shown to induce a progressive development of motor, non-motor, and histopathological features in rats that resemble to those observed in PD patients [1,2]. As part of a multi-center validation study, we employed behavioural assessments, in vivo positron emission tomography (PET), and in vitro autoradiography to further characterize the BSSG model. Rats were fed flour pellets or flour pellets containing 3mg of BSSG for 4 months. They were either sacrificed at the end of the BSSG feeding period or maintained for 6 additional months. Behavioural assessments including open field test, olfactory discrimination test, and cylinder test were conducted at baseline, 4 and 10 months following the initial BSSG exposure. No group differences were detected in any behavioural measures over time. PET images acquired using a radioactive tracer that labels dopamine terminals, [¹¹C]DTBZ, also demonstrated no group differences in the nigrostriatal system over time. Autoradiography using [³H]DTBZ, a tritiated analogue to the PET tracer, corroborated the PET findings. Additional autoradiographic experiments using a marker of neuroinflammation, [³H]PBR28, did not demonstrate group differences in the striatum and substantia nigra pars compacta at 4 and 10 months. There were also no group differences in gut microbiota composition during and following BSSG feeding. Our findings were replicated at two other laboratories receiving the pre-manufactured pellets from the same source. However, other independent investigators using the BSSG powder from the same source, but not the pre-made BSSG pellets, were able to replicate many of the original findings. The chemical composition of the BSSG pellets is being questioned and an investigation is under way.

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