Philippe Leboulch

Atomic Energy and Alternative Energies Commission, Fontenay, Île-de-France, France

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Publications (110)904.96 Total impact

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    EBMT 2015 - 41st Annual Meeting of the European Society for Blood and Marrow Transplantation, Istanbul (Turkey); 03/2015
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    ABSTRACT: Background: In paƟents with β-thalassemia major, hematopoieƟc stem cell (HSC) gene therapy has the potenƟal to induce
    American Society of Hematology (ASH) 56th Annual Meeting, San Francisco (CA); 12/2014
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    ABSTRACT: A previously published clinical trial demonstrated the benefit of autologous CD34+ cells transduced with a self-inactivating lentiviral vector (HPV569) containing an engineered β-globin gene (βA-T87Q globin) in a subject with β-thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy (2 to 3 fold). An in vivo study in which 58 β-thalassemic mice were transplanted with vector- or mock-transduced syngenic bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the USA in patients with β-thalassemia major and sickle cell disease.
    Current Gene Therapy 11/2014; 15(1). DOI:10.2174/1566523214666141127095336 · 4.91 Impact Factor
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    ABSTRACT: β-Thalassaemia major (β-TM) is an inherited haemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of haemoglobin, leading to the accumulation of free α-globin chains that form toxic aggregates. Despite extensive knowledge of the molecular defects causing β-TM, little is known of the mechanisms responsible for the ineffective erythropoiesis observed in the condition, which is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation. Although erythroid transcription factor GATA-1, the master transcriptional factor of erythropoiesis, is a caspase-3 target, it is not cleaved during erythroid differentiation. We have shown that, in human erythroblasts, the chaperone heat shock protein70 (HSP70) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA-1 from caspase-3 cleavage. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation. Here we show in vitro that during the maturation of human β-TM erythroblasts, HSP70 interacts directly with free α-globin chains. As a consequence, HSP70 is sequestrated in the cytoplasm and GATA-1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA-1 mutant restores terminal maturation of β-TM erythroblasts, which may provide a rationale for new targeted therapies of β-TM.
    Nature 08/2014; 514(7521). DOI:10.1038/nature13614 · 42.35 Impact Factor
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    ABSTRACT: Gene therapy, cellular immunotherapy and vaccination ABSSUB-3287 (abstract Number S742) OUTCOMES OF GENE THERAPY FOR BETA-THALASSEMIA MAJOR VIA TRANSPLANTATION OF AUTOLOGOUS HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH A LENTIVIRAL BETA GLOBIN VECTOR. Marina Cavazzana* 1, Jean-Antoine Ribeil^1, Emmanuel Payen^2, 3, Felipe Suarez4, Olivier Negre5, Yves Beuzard2, 3, Fabien Touzot1, Resy Cavallesco6, François Lefrere1, Stany Chretien2, 3, Philippe Bourget7, Fabrice Monpoux8, Corinne Pondarre9, Benedicte Neven10, Frederic D. Bushman11, Manfred Schmidt12, Christof von Kalle12, Laura Sandler13, Sandeep Soni13, Byoung Ryu13, Robert Kutner13, Gabor Veres13, Mitchell Finer13, Stéphane Blanche10, Olivier Hermine4, Salima Hacein-Bey-Abina1, Philippe Leboulch2, 3, 6 1Département de Biothérapie, Hôpital Universitaire Necker - Enfants Malades, Paris, 2CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), 3UMR 962 (Inserm-CEA-University of Paris-Sud), Fontenay-aux-Roses, 4Service d'hématologie Adulte, Hôpital Universitaire Necker - Enfants Malades, Paris, 5bluebird bio France, CEA-iMETI, Fontenay-aux-Roses, France, 6Harvard Medical School and Brigham & Women's Hospital, Boston, United States, 7Clinical Pharmacy Department, Hôpital Universitaire Necker - Enfants Malades, Paris, 8Unité d’Hemato-Oncologie infantile, Centre Hospitalier de Nice Sophia-Antipolis, Nice, 9Service de pédiatrie, Centre de référence de la Drépanocytose, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, 10Unité d'Immunologie-Hématologie Pédiatrique, Hôpital Universitaire Necker - Enfants Malades, Paris, France, 11Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States, 12Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany, 13bluebird bio, Cambridge, United States Background: In patients with β-thalassemia major, haematopoietic stem cell (HSC) gene therapy has the potential to induce production of β-globin, γ-globin or modified β-globin in the RBC lineage and reduce or stop the need for transfusions. A prior clinical trial (LG001) demonstrated benefit of autologous CD34+ cells transduced with a replication-defective, self-inactivating lentiviral vector (HPV569) containing an engineered β-globin gene (βA-T87Q). A further modified βA-T87Q vector (LentiGlobin BB305) has achieved greater transduction efficiency and a similar pre-clinical safety profile. LentiGlobin BB305 is now being evaluated in the HGB-205 clinical trial. Aims: To provide (i) long-term follow-up data on two subjects treated in LG001 and (ii) initial results from the HGB-205 study. Methods: After the provision of informed consent, subjects with β-thalassemia major underwent HSC collection via peripheral blood apheresis and CD34+ cells were selected. Estimation of the mean ex vivo vector copy number (VCN) was obtained by qPCR performed on pooled in vitro colony-forming progenitors. Subjects underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells. Subjects were monitored for haematological engraftment, βA-T87Q expression (by HPLC) and transfusion requirements. Integration site analysis (by LAM-PCR and high-throughput sequencing on nucleated cells) and replication-competent lentivirus assays were performed. Results: In LG001, two subjects (#1003 and #1004) with βE/β0 thalassemia major successfully engrafted following gene therapy with autologous HSCs transduced with HPV569. Neither subject experienced a cell infusion related adverse event. As reported previously (Nature 2010), #1003 became transfusion-independent one year post–transplant and remains so 5 years later, with the production of 2.5 - 3.5 g/dL βA-T87Q-globin (~30% of total haemoglobin). The most recent VCN in #1003's peripheral neutrophils is 0.23. Subject #1003 also demonstrated partial dominance of a clone with vector integration within the HMGA2 gene that peaked at 4 years post-treatment (22% of the nucleated cells) and has now fallen to 6.8% while maintaining transfusion independence. For #1004, the current VCN (2 years post-treatment) in neutrophils is 0.016 and βA-T87Q–globin accounts for ~5% of total haemoglobin. This subject remains transfusion dependent. Two subjects with βE/β0 thalassemia major (#1201 and #1202) have enrolled in the current HGB-205 trial and one has undergone transplantation. Transduction efficiency of the new BB305 vector compared to HPV569 is shown in Table 1. Data on the transplant outcomes and up to 6 months of follow-up in subjects treated in the HGB-205 trial will be presented at the meeting. Summary/Conclusion: Long-term transfusion independence is achievable with gene therapy for β thalassemia major. Use of the LentiGlobin BB305 vector has resulted in substantially higher VCN in CD34+ cells. It remains to be seen how the clinical outcomes will reflect this improvement. Table1. Comparison of gene transfer efficiencies and transplantation outcomes with HPV569 vs. BB305 βA‑T87Q‑LentiGlobin vectors ^these authors contributed equally Keywords: beta thalassemia, Gene therapy, Lentiviral vector, Transduction
    European Hematology Association - 19th Congress, Milano (Italy); 06/2014
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    ABSTRACT: The pathophysiology of ineffective erythropoiesis in β-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of β-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in β-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.
    Nature medicine 03/2014; DOI:10.1038/nm.3468 · 28.05 Impact Factor
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    ABSTRACT: Our understanding of system dynamics of mixed cell populations in whole organisms has benefited from the advent of individual cell marking by non-arrayed DNA barcodes subsequently analyzed by high-throughput DNA sequencing. However, key limitations include statistical biases compromising quantification and the lack of applicability to deconvolute individual cell fate in vivo after pooling single cells differentially exposed to different conditions ex vivo. Here, we have derived an arrayed lentiviral library of DNA barcodes and obtained a proof-of-concept of its resolving capacity by quantifying hematopoietic regeneration after engraftment of mice with genetically modified autologous cells. This method has helped clarify and bridge the seemingly opposed clonal-succession and continuous-recruitment models of hematopoietic stem cell behavior and revealed that myeloid-lymphoid biases are common occurrences in steady-state hematopoiesis. Arrayed lentiviral barcoding should prove a versatile and powerful approach to deconvolute cell dynamics in vivo with applications in hematology, embryology and cancer biology.
    Stem Cells 10/2013; 31(10). DOI:10.1002/stem.1383 · 7.70 Impact Factor
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    ABSTRACT: A patient with β(β) /β(0) -thalassemia major was converted to transfusion-independence 4.5 years ago by lentiviral gene transfer in hematopoietic stem cells while showing a myeloid-biased cell clone. Induced Pluripotent Stem Cells (iPSCs) are a potential alternative source of hematopoietic stem cells. If fetal to adult globin class switching does not occur in vivo in iPSC-derived erythroid cells, β-globin gene transfer would be unnecessary. To investigate both vector integration skewing and the potential use of iPSCs for the treatment of thalassemia, we derived iPSCs from the thalassemia gene therapy patient and compared iPSC-derived hematopoietic cells to their natural isogenic somatic counterparts. In NSG mice, embryonic to fetal and a partial fetal to adult globin class switching were observed, indicating that gene transfer is likely necessary for iPSC-based therapy of the β-hemoglobinopathies. Lentivector integration occurred in regions of low and high genotoxicity. Surprisingly, common integration sites (CIS) were identified across those iPSCs and cells retrieved from isogenic and non-isogenic gene therapy patients with β-thalassemia and adrenoleukodystrophy, respectively. This suggests that CIS observed in the absence of overt tumorigenesis result from non-random lentiviral integration rather than oncogenic in vivo selection. These findings bring the use of iPSCs closer to practicality and further clarify our interpretation of genome-wide lentivector integration.
    Stem Cells 09/2013; 31(9). DOI:10.1002/stem.1436 · 7.70 Impact Factor
  • Philippe Leboulch
    Nature 08/2013; 500(7462):280-2. DOI:10.1038/500280a · 42.35 Impact Factor
  • Emmanuel Payen, Philippe Leboulch
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    ABSTRACT: High-level production of β-globin, γ-globin, or therapeutic mutant globins in the RBC lineage by hematopoietic stem cell gene therapy ameliorates or cures the hemoglobinopathies sickle cell disease and beta thalassemia, which are major causes of morbidity and mortality worldwide. Considerable efforts have been made in the last 2 decades in devising suitable gene-transfer vectors and protocols to achieve this goal. Five years ago, the first β(E)/β(0)-thalassemia major (transfusion-dependent) patient was treated by globin lentiviral gene therapy without injection of backup cells. This patient has become completely transfusion independent for the past 4 years and has global amelioration of the thalassemic phenotype. Partial clonal dominance for an intragenic site (HMGA2) of chromosomal integration of the vector was observed in this patient without a loss of hematopoietic homeostasis. Other patients are now receiving transplantations while researchers are carefully weighing the benefit/risk ratio and continuing the development of further modified vectors and protocols to improve outcomes further with respect to safety and efficacy.
    Hematology 12/2012; 2012:276-83. DOI:10.1182/asheducation-2012.1.276 · 2.86 Impact Factor
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    ABSTRACT: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell line able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We shown that only two days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.
    Biochemical and Biophysical Research Communications 11/2012; 429(1-2). DOI:10.1016/j.bbrc.2012.10.112 · 2.28 Impact Factor
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    ABSTRACT: Although clinical benefits have been reported in several human hematopoietic gene therapy trials, a remaining important goal is the transition to nonmyeloablative pretransplantation conditioning to decrease toxicity. Previous attempts at reduced intensity conditioning in nonhuman primates have resulted in only temporary vector marking of autologous blood cells or their persistence at low levels, well below the thresholds for clinical efficacy. In addition, we reasoned that lentiviral vector particles displaying cytokines at their surface have the potential to preserve stem cell fitness better than current ex vivo transduction protocols, which involve exposure to cytokine overstimulation. Here we show that the classically nonmyeloablative agent fludarabine (30 mg/m(2)/day for 3 days) together with low-level total body irradiation (2 Gy) and the use of a stem cell factor-displaying simian immunodeficiency virus-based vector, resulted in sustained, single-copy vector marking of autologous blood cells in two macaques over 3 years posttransplantation at levels averaging 1% of all lineages. This percentage is within the range of anticipated efficacy levels for hemophilia and related diseases and forms a basis for further improvement.
    Human gene therapy 03/2012; 23(7):754-68. DOI:10.1089/hum.2012.020 · 3.62 Impact Factor
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    Advances in Hematopoietic Stem Cell Research, 01/2012; , ISBN: 978-953-307-930-1
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    ABSTRACT: Integration of retroviral DNA into host cell DNA is a defining feature of retroviral replication. The integration system is important as a new a drug target, as a model for function of molecular machines that change genomes, and as a tool for use in human gene therapy. The lecture will cover the mechanisms underlying integration and the consequences for the host cell. One line of work to be discussed centers on the mechanisms by which retroviruses select integration target sites in chromosomes. HIV integration is known to be favored in active transcription units, which promotes efficient transcription of the viral genes. A host cell factor, PSIP1/LEDGF/p75 acts as a tethering factor to direct local integration, accounting for part of the effect. In addition, the methods devised for basic studies of retroviral integration targeting are useful for analyzing integration sites generated during human gene therapy. Selected results from such studies will also be discussed.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2012; 59:55. DOI:10.1097/01.qai.0000413753.07879.71 · 4.39 Impact Factor
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    ABSTRACT: Patients with β-thalassemia major require lifelong transfusions and iron chelation, regardless of the type of causative mutations (e.g., β⁰, β(E)/β⁰). The only available curative therapy is allogeneic hematopoietic transplantation, although most patients do not have an HLA-matched, geno-identical donor, and those who do still risk graft-versus-host disease. Hence, gene therapy by ex vivo transfer of a functional β-globin gene is an attractive novel therapeutic modality. In β-thalassemia, transfer of a therapeutic globin gene does not confer a selective advantage to transduced stem cells, and complex DNA regulatory sequences have to be present within the transfer vector for proper expression. This is why lentiviral vectors have proven especially suited for this application, and the first Phase I/II human clinical trial was initiated. Here, we report on the first gene therapy patient with severe β(E)/β⁰-thalassemia, who has become transfusion-independent, and provide methods and protocols used in the context of this clinical trial.
    Methods in enzymology 01/2012; 507:109-24. DOI:10.1016/B978-0-12-386509-0.00006-5 · 2.19 Impact Factor
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    ABSTRACT: Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis.
    The American Journal of Human Genetics 06/2011; 89(1):44-55. DOI:10.1016/j.ajhg.2011.05.023 · 10.99 Impact Factor
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    ABSTRACT: A challenge for gene therapy of genetic diseases is to maintain corrected cell populations in subjects undergoing transplantation in cases in which the corrected cells do not have intrinsic selective advantage over nontransduced cells. For inherited hematopoietic disorders, limitations include inefficient transduction of stem cell pools, the requirement for toxic myelosuppression, and a lack of optimal methods for cell selection after transduction. Here, we have designed a lentiviral vector that encodes human β-globin and a truncated erythropoietin receptor, both under erythroid-specific transcriptional control. This truncated receptor confers enhanced sensitivity to erythropoietin and a benign course in human carriers. Transplantation of marrow transduced with the vector into syngenic thalassemic mice, which have elevated plasma erythropoietin levels, resulted in long-term correction of the disease even at low ratios of transduced/untransduced cells. Amplification of the red over the white blood cell lineages was self-controlled and averaged ∼ 100-fold instead of ∼ 5-fold for β-globin expression alone. There was no detectable amplification of white blood cells or alteration of hematopoietic homeostasis. Notwithstanding legitimate safety concerns in the context of randomly integrating vectors, this approach may prove especially valuable in combination with targeted integration or in situ homologous recombination/repair and may lower the required level of pretransplantation myelosuppression.
    Blood 03/2011; 117(20):5321-31. DOI:10.1182/blood-2010-01-263582 · 9.78 Impact Factor
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    ABSTRACT: Human genetic diseases have been successfully corrected by integration of functional copies of the defective genes into human cells, but in some cases integration of therapeutic vectors has activated proto-oncogenes and contributed to leukemia. For this reason, extensive efforts have focused on analyzing integration site populations from patient samples, but the most commonly used methods for recovering newly integrated DNA suffer from severe recovery biases. Here, we show that a new method based on phage Mu transposition in vitro allows convenient and consistent recovery of integration site sequences in a form that can be analyzed directly using DNA barcoding and pyrosequencing. The method also allows simple estimation of the relative abundance of gene-modified cells from human gene therapy subjects, which has previously been lacking but is crucial for detecting expansion of cell clones that may be a prelude to adverse events.
    Nucleic Acids Research 03/2011; 39(11):e72. DOI:10.1093/nar/gkr140 · 8.81 Impact Factor
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    ABSTRACT: A lentiviral vector encoding β-globin flanked by insulator elements has been used to treat β-thalassemia (β-Thal) successfully in one human subject. However, a clonal expansion was observed after integration in the HMGA2 locus, raising the question of how commonly lentiviral integration would be associated with possible insertional activation. Here, we report correcting β-Thal in a murine model using the same vector and a busulfan-conditioning regimen, allowing us to investigate efficacy and clonal evolution at 9.2 months after transplantation of bone marrow cells. The five gene-corrected recipient mice showed near normal levels of hemoglobin, reduced accumulation of reticulocytes, and normalization of spleen weights. Mapping of integration sites pretransplantation showed the expected favored integration in transcription units. The numbers of gene-corrected long-term repopulating cells deduced from the numbers of unique integrants indicated oligoclonal reconstitution. Clonal abundance was quantified using a Mu transposon-mediated method, indicating that clones with integration sites near growth-control genes were not enriched during growth. No integration sites involving HMGA2 were detected. Cells containing integration sites in genes became less common after prolonged growth, suggesting negative selection. Thus, β-Thal gene correction in mice can be achieved without expansion of cells harboring vectors integrated near genes involved in growth control.
    Molecular Therapy 03/2011; 19(7):1273-86. DOI:10.1038/mt.2011.20 · 6.43 Impact Factor

Publication Stats

6k Citations
904.96 Total Impact Points


  • 2013
    • Atomic Energy and Alternative Energies Commission
      • Institute of Emerging Diseases and Innovative Therapy (IMETI)
      Fontenay, Île-de-France, France
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 1995–2013
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2004–2012
    • Harvard Medical School
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
    • The University of Calgary
      • Faculty of Medicine
      Calgary, Alberta, Canada
  • 2011
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2005–2007
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
    • Institut Universitaire de France
      Lutetia Parisorum, Île-de-France, France
  • 2001–2005
    • Idenix Pharmaceuticals, Inc.
      Cambridge, Massachusetts, United States
  • 1997–2005
    • Massachusetts Institute of Technology
      • Division of Health Sciences and Technology
      Cambridge, MA, United States
    • Albert Einstein College of Medicine
      • Department of Medicine
      New York City, NY, United States
  • 2003–2004
    • Kawasaki Medical University
      • Department of General Internal Medicine 2
      Kurasiki, Okayama, Japan
  • 2000–2004
    • Okayama University
      • Department of Cell Biology
      Okayama, Okayama, Japan
  • 2002
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France