Optimising delivery and survival of cell therapy in Huntington’s disease

Sharouf, Feras ORCID: https://orcid.org/0000-0002-3034-3392 2023. Optimising delivery and survival of cell therapy in Huntington’s disease. PhD Thesis, Cardiff University. Item availability restricted.

	PDF - Accepted Post-Print Version Restricted to Repository staff only Download (41MB)
	PDF (Cardiff University Electronic Publications Form) - Supplemental Material Restricted to Repository staff only Download (192kB)

Abstract

HD is a progressive, inherited neurological disorder characterised by a triad of motor, cognitive and psychiatric symptoms. It is an incurable, progressive condition that seriously erodes quality of life and has a high societal cost. Currently there are no disease-modifying therapies available that slow or halt the progression of the disease. It is the most common monogenetic neurodegenerative condition and is a powerful paradigm for understanding and treating neurodegeneration. There is a relatively focal loss of a specific neuronal cell type, striatal medium spiny neurons (MSNs), at least at the initial stages. This makes HD suitable for cell replacement therapy (CRT). However, a decade of research has shown that CRT encompasses many translational challenges, including the need to develop appropriate delivery devices, protocols, and graft survival. The hope is that the principles underlying effective CRT in HD will be applicable to other neurodegenerative conditions. We had two major aims; Investigate the immune response to surgical intervention in HD and Improve methods of cell delivery to prevent cell death during delivery, reduce cell reflux, and reduce sedimentation rates. Chapter 1 provides a general introduction. Chapter 2 and chapter 3 demonstrate that needle injury to the HD brain produced an exaggerated inflammatory response. In chapter 4 I developed an in vitro model to test cell delivery and tested multiple cell delivery paradigms with the aim to optimise cell delivery in terms of reducing reflux, optimizing initial cell survival, and maintaining accurate cell delivery. Chapter 5 includes a general discussion of the work presented in this thesis. The studies presented within this thesis demonstrate that simulation of the surgical aspects of cell replacement therapy through the introduction of a needle into HD brain produced an acute pro-inflammatory response consistent with a priming effect. The studies also demonstrate that agarose phantom is appropriate to study cell delivery in brain and that bioluminescence is a suitable paradigm to track delivery of small volume of live cells in real time.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	9 September 2024
Last Modified:	09 Sep 2024 15:54
URI:	https://orca.cardiff.ac.uk/id/eprint/171901

Actions (repository staff only)

Edit Item