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Title: Development of telomerase targeted gene therapy for treatment of cancer
Author: Arendt, Maja Louise
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2008
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Gene therapy is an area that is currently developing for treatment of various congenital and acquired diseases. The basic concept is that a transgene is expressed in a target cell resulting in alleviation of disease. In general there are certain obstacles limiting gene therapy regardless of the target disease. These include restriction of transgene expression to target cells, inadequate transgene expression and ineffective in vivo transgene delivery. Cancer is one of the leading diseases to cause death in the human and canine population. For this reason gene therapy has been studied as a potential novel treatment for cancer. Two step transcriptional amplification system is a system applied to gene therapy in order to improve efficacy. In this system a relatively weak tissue or disease specific promoter initiates the transcription of a transcriptional activator protein. This protein when expressed in target cells binds to binding sites upstream of a secondary promoter which then drives the transcription of the transgene of interest at a high level. By use of a two step amplification mechanism and a novel transcriptional activator fusion protein VP16E2, we increased transgene expression compared to the commonly used Gal4VP16 transcriptional activator fusion protein. By incorporating the human telomerase promoter hTERT as a primary promoter and the minimal 6xE23'BpTATA promoter as a secondary promoter, transgene expression is maintained in telomerase positive cells representing cancer cells, but is restricted in telomerase negative cell lines. By inserting the tumour necrosis factor apoptosis inducing ligand (TRAIL) gene as a transgene in this system we have shown that apoptosis is elicited in telomerase positive cells although not in telomerase negative cells. The similarities in incidence and nature of human and canine cancer forms and the need for a better translational model for human disease has put canines in focus for cancer studies and drug development. Conditionally replicative oncolytic viruses developed in humans are species specific and therefore can not be studied satisfactorily in rodent preclinical models. We have made a mutant adenovirus based on the canine adenovirus type 1. We have put the viral replication under control of our two step amplification mechanism making the viral replication dependent on telomerase activity of the infected cell. This virus is able to kill telomerase positive canine cells but not telomerase negative canine cells in vitro. This virus is a potential tool for studying a conditionally replicative oncolytic virus in vivo in naturally occurring canine cancer cases. This is a good translational model for human cancer treatment and thereby benefits both species.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral