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Parameters impacting the outcome of cell replacement therapy for Parkinson’s disease: A preclinical study

Breger, Ludivine 2013. Parameters impacting the outcome of cell replacement therapy for Parkinson’s disease: A preclinical study. PhD Thesis, Cardiff University.
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Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, currently affecting 6.3 million people worldwide. Although it is associated, in the longterm, with severe complications (dyskinesias), L-DOPA remains the gold standardtreatment. An alternative approach to the treatment of PD is the replacement of the lost striatal dopaminergic innervation by transplantation of foetal ventral mesencephalon (VM) dopaminergic precursor cells. Opened trials have provided the proof of concept that intrastriatal VM transplant can survive, integrate and in some cases, restore motor functions. Nevertheless, later double blind studies reported inconsistent benefit of the therapy and the development of dyskinesias remaining after withdrawal of L-DOPA medication. The failure of the animal models in predicting these problems raises concern about their reliability. Therefore, the global aim of this PhD work was to identify some of the critical factors that can influence the functional outcome of cell therapy for PD, and on the basis of this, to develop an improved 6-OHDA unilaterally lesioned rat model for transplantation. The first step was to determine the most reliable method to assess dyskinesias in rats. The second part of this thesis was set out to determine the effect that chronic L-DOPA treatment, administered at different time could had on the survival and function of immunologically incompatible foetal VM transplant. The results demonstrated that L-DOPA administered chronically post-grafting increases the host immune response around the xenogeneic transplant. Therefore, the last set of experiments were designed to create a model of mixed donors graft to better reproduce the patient situation, where each transplant required up to 8 donors from unknown immunological background. All of these experiments come together to help to develop a rat model that more accurately represents all aspects of patients undergoing transplantation for PD.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Parkinsons Disease; Cell Replacement; Preclinical studies; dyskinesias; L-DOPA;
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/49925

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