It is generally accepted that gene therapy holds great promise for the treatment
of certain genetic disorders but that a number of important problems remain. Dr.
Philippe Leboulch has been at the forefront in the design of gene therapy
vectors for many years. His group has published the first long-term correction
of a genetic disease (erythropoietic protoporphyria) by gene therapy in an
animal model in the absence of spontaneous selection for transduced cells (Pawliuk et al., Nat Med 1999). A
major current undertaking of his laboratory is the design of safe and effective
lentiviral vectors capable of achieving long-term correction of sickle cell
disease and beta-thalassemia, the most prevalent genetic diseases worldwide.
This model also serves as one of the most interesting paradigms in the field of
gene therapy because of the complexity of the genetic structures to be
transferred into hematopoietic stem cells (HSCs) to achieve high, regulated
beta-globin gene expression restricted to the red blood cell lineage. After
having reported the long-term correction of these diseases in mouse models (Pawliuk et al., Science 2001; Imren et
al., PNAS 2002), he has now tackled the prevention of potential adverse
events in human HSCs that include oncogenesis by insertional mutagenesis (Hacein-Bey-Abina et al., Science
2003).
Dr. Leboulch's work on the beta-hemoglobinopathies has recently led
to the first worldwide approval of a Phase I/II human clinical trial utilizing a
lentiviral vector for the gene therapy of a genetic disease. Novel gene transfer
approaches to HSCs are also investigated (e.g., integrases and transposases).
Another present interest of the laboratory is the control of somatic cell
expansion by "reversible immortalization" mediated by site-specific
recombination (Kobayashi et al.,
Science 2000; Narushima et al., Nat Biotechnol 2005). Finally, our gene
transfer vectors can effectively contribute to the identification of
gene-phenotype correlations in functional genomics, as Dr. Leboulch recently
published in the field of angiogenesis (Eriksson et al., Cancer Cell 2002;
Cao et al., Nat Med 2003).
