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MBPhD Programme

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KNIGHT, Sean Blandin

Entered:

2007-July

Current Position:

Qualified 2013

PhD title:

Insertional mutagenesis
 

Principal Supervisor:

Professor Mary Collins, Department of Immunology & Molecular Pathology
 

Funding Source:

Description of Project:

Gene therapy has developed considerably over the past years and has reached clinical application in the treatment of monogenetic disorders, as in this setting the possibility of ‘cure’ is realised, provided the defective gene can be replaced by a fully functional one. One such disease is X-linked Severe Combined Immune Deficiency disease (SCID), which although rare provides a convenient system to study the application of gene therapy. X-linked SCID is characterised by a mutation in the gene coding for the common gamma chain of the IL-2 receptor, causing a lack of development of T and NK cells and a functional defect in B cells, which thus results in a poorly constituted immune system. A clinical trial set up to test gamma retroviral vectors containing the functional gene was successful in reconstituting the immune system and inducing clinical improvement, however five out of nineteen children have subsequently developed T-cell leukaemias due to insertion of the retroviral vectors near the oncogene LM02 by insertional mutagenesis [1,2]. By using a cell line dependant on IL-3 we are studying the ability of different retroviral vectors to induce IL-3 independence by insertional mutagenesis, with a view towards establishing which parts of the vectors contribute to insertional mutagenesis and developing a safer vector to be used in the clinical setting.



1. Board of the European Society of Gene & Cell Therapy, Executive Committee of the Clinigene Network of Excellence and Executive of the Consert Integrated Project. Commentary: Case of Leukaemia Associated with SCID-X1 Gene Therapy Trial in London. Issued on 18 December 2007. 2. Baum, C. Insertional mutagenesis in gene therapy and stem cell biology. Current Opinion in Haematology. 2007; 14(4): 337-342

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