Genetic manipulation of the transplanted heart by adenoviral-mediated gene transfer

Yap, John Y. M (1998) Genetic manipulation of the transplanted heart by adenoviral-mediated gene transfer. MD thesis, University of Glasgow.

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Abstract

Heart transplantation is currently a viable option for the treatment of patients with end-stage cardiac disease. Although improved survival has been achieved over the last decade, transplant recipients remained vulnerable to the risks of rejection, infection, the effects of immunosuppression and accelerated transplant atherosclerosis. Recent advances in molecular biology and recombinant DNA technology have fostered the concept of gene transfer. Successful gene transfer is dependant on the properties of vectors used in delivering genes to the target cells. The vectors used to date include adenovirus, retrovirus, adeno-associated virus and plasmid-liposome. Replication defective adenoviral vectors are currently the agents of choice for in vivo cardiovascular gene transfer because of their relative efficiency and ability in transducing non-dividing cells. Disadvantages of adenoviral vectors include transient duration of transgene expression and potential cytotoxicity. Gene transfer to the transplanted heart may represent a novel approach to the study of transplantation biology and may have therapeutic potential in the management of human transplantation disease. The availability of the donor heart at the time of harvest and the period of cold preservation may allow for a prolonged viral vector dwell time which would not be possible in in vivo vascular wall gene transfer. This prolonged dwell time may lead to enhanced gene transfer in this setting. Also, the necessary use of immunosuppressive agents in transplant setting may modulate the potential cytotoxicity and duration of transgene expression of adenoviral-mediated gene transfer. In the cardiovascular system, nitric oxide (NO) derived from the vascular endothelium regulates vascular tone. Its other properties include inhibition of proliferation of smooth muscle cells, adhesion and activation of leukocytes and platelets. In addition, reduced bioactivity of nitric oxide is a feature of atherosclerosis and vascular injury. Therefore, overexpression of nitric oxide may be beneficial in modifying accelerated transplant atherosclerosis. The focus of this thesis was on adenoviral-mediated gene transfer in the heart transplant setting. It addressed the feasibility and favourable conditions to achieve efficient gene transfer in the donor heart during cold preservation. In particular, the effect of increased coronary distension during viral vector dwell and the potential role of warm ischaemia, during the transplant procedure, on efficiency of gene transfer were examined. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Christopher McGregor
Keywords: Genetics
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-71355
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71355

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