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dc.contributor.authorFarraha, Melad
dc.date.accessioned2019-08-12T07:24:25Z
dc.date.available2019-08-12T07:24:25Z
dc.date.issued2019-02-28
dc.identifier.urihttp://hdl.handle.net/2123/20886
dc.description.abstractRecombinant adeno-associated viral (rAAV) vectors, have been developed and are being clinically trialled for treatment of cardiovascular diseases. With an improved understanding of the molecular mechanisms involved in pacemaker dysfunction, gene therapy is being used to advance viable treatment options that can potentially replace the need for electronic devices. Currently, the only viable management option for pacemaker dysfunction is the insertion of an electronic pacemaker. We however proposed an alternative gene therapy approach using rAAV vectors to deliver the gene human T-box 18 (hTBX18), to advance the creation of a biological pacemaker. The work in this thesis aimed to address the limitations with current approaches to biological pacemaker development, to set up a relevant animal model to assess this gene transfer approach and to assess rAAV vector biosafety in this novel model. In the first phase of work, we successfully generated an original rAAV construct expressing hTBX18 and showed that rAAV6-hTBX18 gene transfer to ventricular cardiomyocytes resulted in molecular, physiological, morphological and functional changes, recapitulating the pacemaker phenotype in an in vitro setting. In the second body of work, we successfully developed, characterised and validated a large animal model of atrioventricular block that is stable and technically feasible in adult sheep. In the third body of work, we successfully performed rAAV cardiac infusions in sheep and analysed vector shedding in excreta samples from urine, nasal mucus, saliva and faeces. We concluded that rAAV-mediated gene transfer into sheep hearts results in low-grade shedding of non-functional vector particles following vector delivery. This thesis therefore lays the groundwork for the next phase of pre-clinical development of biological pacemakers using clinically relevant rAAV vectors in a previously non-existent sheep animal model.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherWestmead Clinical Schoolen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectAdeno-associated Virus, cardiology, , ,en_AU
dc.subjectpacemakeren_AU
dc.subjecthTBX18en_AU
dc.subjectgene therapyen_AU
dc.subjectcardiologyen_AU
dc.titleRecombinant Adeno-associated Viral Vector Mediated Gene Transfer of hTBX18: Advancing the Development of a Biological Pacemakeren_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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