Development of HIV-based lentiviral vectors for clinical gene therapy.

Primary supervisor: Dr Yasu Takeuchi
Secondary Supervisor: Prof Mary Collins
Clinical Supervisor Dr Adrian Thrasher

Lentiviral vectors based on human immunodeficiency virus type 1 (HIV-1) have reached clinical application in the treatment of adrenoleukodystrophy (1), HIV/AIDS (2) and  thalassaemia (3), with clinical trials planned for several other diseases. These vectors are currently produced by transient co-transfection of 293T cells with the vector genome and vector packaging functions. Stable production of lentiviral vectors would be preferred for clinical applications, as this enables more consistent safety characteristics between batches and an easily scalable means of producing large batches for clinical use. Previously our laboratory developed a lentiviral packaging cell line that was able to achieve stable titers of over 107 infectious units/ml (4), which demonstrated proof of principle. However further improvement in vector safety and mass production is necessary to enable usage of lentiviral vectors in a wide range of disease treatment.

This student project, as a part of long standing collaboration between Takeuchi/Collins Group in Division of Infection and Immunity and Thrasher Group at Institute of Child Health, will tackle the above issues and aims for establishment of stable HIV vector producers for clinical use and development of systems for vector manufacturing and processing. HIV vector packaging cell lines with improved/safer constructs will be established in the clinical-grade, clean condition and used for clinical vector production. Methods for concentration and purification of vector particles produced by these stable vector producers will be assessed for efficiency and feasibility for mass production.

This project will require student’s development in their laboratory skills in molecular biology, molecular virology and cell culture and knowledge of HIV virology, cell biology and clinical gene therapy. The clinical, translational side of the project is significant: the clinical supervisor’s group runs several gene therapy clinical trials and the student will be exposed to such clinical environment through his/her interaction with Thrasher lab and our joint lab meetings.

References

1. Cartier, N et al. 2009. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818-823.

2. Levine, B et al. 2006. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A 103:17372-17377.

3. Cavazzana-Calvo, M et al. 2010. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467:318-322

4. Ikeda Y., Y. Takeuchi, F. Martin, F. L. Cosset, K. Mitrophanous, and M. Collins. 2003. Continuous high-titer HIV-1 vector production. Nat Biotechnol 21:569-72

TO APPLY please go to
http://www.ucl.ac.uk/infection-immunity/study/phd/bench_bedside
CLOSING DATE: 14 DECEMBER 2012