Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274918
Title: Corrective gene therapy in a murine model of familial adenomatous polyposis : a study of the efficacy of gene transfer and the resultant phenotypic effects
Author: Bright-Thomas, Rachel Marie
ISNI:       0000 0001 3480 0768
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Abstract:
The Adenomatous Polyposis Coli (APC) tumour suppressor gene is known to be mutated or deleted in the early stages of the majority of sporadic colorectal cancers, and is thought to initiate neoplasia when its mutation leads to uncontrolled intra-cellular levels of the oncogene β-catenin. Germline mutation of APC gives rise to Familial Adenomatous Polyposis (FAP), a pre-neoplastic syndrome characterised by the development of multiple intestinal polyps, one or more of which invariably becomes malignant. Extra-intestinal manifestations of this disease include potentially fatal fibromatoses (desmoids). The Min/+ mouse is a murine model of FAP with an homologous germline mutation of Ape. It also develops multiple small intestinal polyps and a smaller number of colorectal tumours. However, it does not develop desmoid tumours. Corrective gene therapy for cancer has now reached the stage of human clinical trials, most based on replacement of wild type (WT) p53 function in advanced cancers that show mutation or loss of this tumour suppressor. In the case of FAP, it has been postulated that local replacement of WT APC may decrease the incidence or rate of growth of intestinal polyps (and possibly desmoid tumours) by restoration of 'normal' β-catenin degradation. This project studied in vivo transfer of APC into the gut of Min/+ and WT mice. The safety of this treatment was demonstrated, and transgene expression was seen to correlate with a decrease in intestinal β-catenin levels. Intra-peritoneal transfer of APC into WT mice was also performed. This revealed high level transgene expression in tissues known to give rise to desmoid tumours in human disease. These promising preliminary results in model systems will have to be confirmed in humans, and advances which improve the efficiency of transfection incorporated, before Phase I human trials of APC gene therapy can be considered.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.274918  DOI: Not available
Keywords: Tumour suppressor gene
Share: