Philippe Leboulch

Department of Medicine (Genetics Division)
Harvard Medical School and Brigham & Women's Hospital
New Research Building, 4th Floor, Room 0466C
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 253-5818
Fax: (617) 253-3459
Email: pleboulch@mit.edu (to be updated)

Our laboratory focuses on the development of novel strategies for the gene therapy of human diseases. Our overall approach is to gain understanding of the basic principles that govern the chromosomal integration and the transcriptional regulation of genetic structures after their transfer to somatic cells including stem cells. As an illustration, we have published the first long-term correction of a genetic disease by gene therapy in an animal model in the absence of spontaneous selection for transduced cells (Pawliuk et al. Nat Med 1999;5:768-73).

A major current undertaking of the laboratory is the design of lentiviral vectors capable of achieving long-term correction of sickle cell disease and beta-thalassemia, which are among the most prevalent genetic diseases worldwide. After having recently reported efficacy studies in mouse models (Pawliuk et al. Science 2001;294:2368-71; Imren et al. PNAS 2002;99:14380-5), we are now tackling the prevention of potential adverse events that include oncogenesis by insertional mutagenesis and contamination with replication-competent lentiviruses. To this aim, we are designing and making use of chromatin insulators and novel "super-split" packaging systems. Additional collaborative gene therapy projects include other genetic disorders of the hematopoietic system and degenerative diseases of the retina, liver and muscle.

Another interest of the laboratory is the development of novel approaches to achieve site-specific integration of therapeutic genes within non-hazardous areas of the human genome, by means of transposases and site-specific integrases. We are also interested in the control of cell expansion by "reversible immortalization" mediated by site-specific recombination (Kobayashi et al. Science 2000;287:1258-62). Finally, our gene transfer vectors can contribute to the identification of gene-phenotype correlation in functional Genomics, as we recently published in the field of angiogenesis (Eriksson et al. Cancer Cell 2002;1:99-108; Cao et al. Nat Med 2003;9:604-13).

Possible rotation projects:

• Design, construction and packaging of lentiviral vectors.
• Bone marrow transplantation in mice after lentiviral transfer to hematopoietic stem cells.
• Transcription and transposition assays.

References:

• Pawliuk R, Bachelot TJ, Wise RJ, Mathews-Roth MM, Leboulch P. Long-term cure of the photosensitivity of murine erythropoietic protoporphyria by preselective gene therapy. Nat Med 1999;5:768-73.
• Kobayashi N, Fujiwara T, Westerman KA, Inoue Y, Sakaguchi M, Noguchi H, Miyazaki M, Tanaka N, Fox IJ, Leboulch P. Prevention of Acute Liver Failure in Mice with Reversibly Immortalized Human Hepatocytes. Science 2000;287:1258-62.
• Pawliuk R, Westerman KA, Fabry ME, Payen E, Tighe R, Bouhassira EE, Acharya SA, Ellis J, London IM, Eaves CJ, Humphries RK, Beuzard Y, Nagel RL, Leboulch P. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 2001;294:2368-71.