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Title: Targeting chondroitin sulfate proteoglycans to promote repair and functional recovery following spinal cord injury
Author: Burnside, Emily Rachel
ISNI:       0000 0004 6347 9872
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Spinal cord injury results in debilitating permanent deficits in motor, sensory and autonomic function, for which there is no adequate treatment: there is a pressing need for the development of novel therapeutics. The adult central nervous system (CNS) has a poor capacity for neuronal repair following injury. The CNS extracellular matrix has a unique and specialised composition, rich in glycoproteins and proteoglycans. Chondroitin sulfate proteoglycans (CSPGs) are inhibitory to neuroplasticity and their presence within the matrix is increased within a scar at the site of injury. Thus, CSPGs are a key therapeutic target following spinal cord injury. This thesis extends a large body of work to target inhibitory CSPGs to promote functional recovery in a clinically-relevant contusion model of experimental spinal cord injury in the adult rat. Lentiviral-vector mediated ChABC gene therapy has emerged as an effective means by which to promote functional repair. In order to increase translational feasibility of ChABC gene therapy this thesis first considers the use of adeno-associated viral vector systems to deliver ChABC, in which promotor choice was found to be a crucial determinant of efficacy. Furthermore, for any gene therapy treatment for spinal cord injury it would be advantageous to achieve temporal control over gene expression. A doxycycline-inducible vector system with an immune-evasive transactivator was used in a novel approach to switch on ChABC expression and modulate the time for which it was delivered. This recapitulated the beneficial functional effects of the permanent system and revealed an additional functional benefit of long-term administration over that conferred in the short-term. Furthermore, there is evidence that a particular CSPG sulfation epitope, CS-E, is a potent mediator of inhibition. Here, two approaches are considered to target CS-E upregulated following spinal contusion injury: an anti-CS-E antibody and a small molecule inhibitor of its synthesis. Short-term intrathecal delivery of anti-CS-E did not promote functional recovery and alternative treatment paradigms will be explored. A small molecule inhibitor may reduce synthesis of CS-E on small proteoglycans or proteoglycan fragments following injury which may enable assessment as to the therapeutic efficacy of preventing CS-E biosynthesis. Approaches to promote neuroplasticity, such as those targeting CSPGs, aim to generate new functional connectivity. Use of functional probes would represent a novel method to gain insight into the functional status of new connections. Neural populations of interest were transduced to express such reporters and an ex-vivo spinal cord slice preparation was developed, which was stimulated electrophysiologically and changes in florescence were imaged in real time using 2- photon microscopy. Only a small number of cells underwent response to physiologically relevant stimuli which precluded the use of this ex vivo preparation from use in further experiments.
Supervisor: Bradbury, Elizabeth Jane ; Burrone, Juan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available