Bright-Thomas, Rachel Marie; (2001) Corrective Gene Therapy In A Murine Model Of Familial Adenomatous Polyposis - A Study of The Efficacy of Gene Transfer and The Resultant Phenotypic Effects. Doctoral thesis (M.D), UCL (University College London).

Text Corrective_gene_therapy_in_a_m.pdf Download (14MB)

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.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item