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Innovative Therapies Unit (Service des Thérapies Innovantes – STI)

Published on 4 July 2018
 

Innovative Therapies Unit (Service des Thérapies Innovantes – STI), directed by Stany Chrétien, is responsible for the development of new molecular and cellular approaches to the treatment of innate or acquired genetic diseases.

Our research is based around two approaches.

The first concerns the cell therapy  (expansion ex vivo of cell populations) and the gene therapy (gene transfer and correction). We participated in the first successful clinical trial of gene therapy for b-thalassemia.

The second approach involves studies of the molecular mechanisms controlling the proliferation and differentiation of somatic cells, physiopathogenic processes targeted by many cell therapy strategies. Our work involves the characterization of new connections between transcription factors, cell signaling and knowledge of the control of the balance between proliferation and differentiation in normal and pathological (cancer) cells.

​Research projects

The STI is composed of two laboratories. Specific scientific research projects were as follows:

1. To pursue basic research and clinical development towards a safe and effective gene therapy approach for the beta‐hemoglobinopathies (beta‐thalassemia and sickle cell disease), as a prototypical model of lentiviral hematopoietic gene therapy. In particular, P. Leboulch is the scientific director of the human clinical trial entitled "A Phase I/II Open Label Study With Anticipated Clinical Benefit Evaluating Genetic Therapy of the βHemoglobinopathies (Sickle Cell Anemia and βThalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Modified ExVivo with a Lentiviral βAT87QGlobin (LentiGlobinTM) Vector". This trial is ‐together with that for adrenoleukodystrophy ‐ the first worldwide clinical trial having received regulatory approval for the use of a lentiviral vector for the ex vivo gene therapy of inherited genetic disorders.

2. To contribute to other areas of hematopoietic gene therapy and cancer.

3. To investigate novel approaches for the controlled expansion of hematopoietic stem cells (HSCs).

4. To contribute to the elucidation of the molecular mechanisms that control the balance between cell proliferation and differentiation or cell quiescence and differentiation in normal and pathological (cancer) hematopoietic cells.

5. To set up a platform for autologous hematopoietic transplantation with gene transfer in non‐human primates.

6. To set up a platform for high‐throughput screening of small molecules capable of expanding HSC populations.

7. To set up an iPS platform in non‐human primates.


​​​​​FIRST SUCCESS IN A CLINICAL TRIAL OF GENE THERAPY FOR BETA-THALASSEMIA


Thalassemia and sickle-cell disease are the most frequent innate genetic diseases worldwide, and they represent immense public health problems in Africa and Asia. The STI was a key player in the first clinical trial of gene therapy for thalassemia, in which therapeutic efficacy (no further need for transfusion) was demonstrated in the first patient treated.

This department has played a key role in recent advances in the domain of hematopoietic gene therapy, demonstrating proof-of-principle for the clinical efficacy of lentiviral vectors in patients with adrenoleukodystrophy (Science, 2009) and thalassemia (Nature, 2010).



STUDY OF MOLECULAR MECHANISMS

 

The STI also studies the molecular mechanisms controlling the proliferation and differentiation of somatic cells, the balance between these two processes being at the heart of a large number of physiopathogenic processes and many cell therapy strategies. We were involved in the characterization of new connections between transcription factors, cell signaling and knowledge about control of the proliferation/differentiation balance (e.g. GATA-FOG-pRb and PPARgamma-STAT5; PLoS Biology 2009; JCI, 2008).


​STI publications
  
Induced pluripotent stem cell generation from a man carrying a complex chromosomal rearrangement as a genetic model for infertility studies
Mouka A, Izard V, Tachdjian G, Brisset S, Yates F, Mayeur A, Drevillon L, Jarray R, Leboulch P, Maouche-Chretien L, Tosca L
Gene Therapy in a Patient with Sickle Cell Disease
Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L, Neven B, Bourget P, El Nemer W, Bartolucci P, Weber L, Puy H, Meritet JF, Grevent D, Beuzard Y, Chretien S, Lefebvre T, Ross RW, Negre O, Veres G, Sandler L, Soni S, de Montalembert M, Blanche S, Leboulch P, Cavazzana M
N. Engl. J. Med., 2017
Gene Therapy in a Patient with Sickle Cell Disease REPLY
Leboulch P, Cavazzana M
N. Engl. J. Med., 2017
Gene Therapy of the beta-Hemoglobinopathies by Lentiviral Transfer of the beta(A(T87Q))-Globin Gene
Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S, Hongeng S, Hacein-Bey S, Cavazzana M, Leboulch P, Payen E
Hum. Gene Ther., 2016
High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells by AAV6 Vectors: Strategies for Overcoming Donor-Variation and Implications in Genome Editing
Ling C, Bhukhai K, Yin ZF, Tan MQ, Yoder MC, Leboulch P, Payen E, Srivastava A
Sci Rep, 2016
Preclinical Evaluation of Efficacy and Safety of an Improved Lentiviral Vector for the Treatment of beta-Thalassemia and Sickle Cell Disease
Negre O, Bartholomae C, Beuzard Y, Cavazzana M, Christiansen L, Courne C, Deichmann A, Denaro M, De Dreuzy E, Finer M, Fronza R, Gillet-Legrand B, Joubert C, Kutner R, Leboulch P, Maouche L, Paulard A, Pierciey FJ, Rothe M, Ryu B, Schmidt M, von Kalle C, Payen E, Veres G
Curr. Gene Ther., 2015
Erosion of the chronic myeloid leukaemia stem cell pool by PPAR gamma agonists
Prost S, Relouzat F, Spentchian M, Ouzegdouh Y, Saliba J, Massonnet G, Beressi JP, Verhoeyen E, Raggueneau V, Maneglier B, Castaigne S, Chomienne C, Chretien S, Rousselot P, Leboulch P
Nature, 2015
Transplantation of Macaca cynomolgus iPS-derived hematopoietic cells in NSG immunodeficient mice
Abed S, Tubsuwan A, Chaichompoo P, Park IH, Pailleret A, Benyoucef A, Tosca L, De Dreuzy E, Paulard A, Granger-Locatelli M, Relouzat F, Prost S, Tachdjian G, Fucharoen S, Daley GQ, Payen E, Chretien S, Leboulch P, Maouche-Chretien L
Haematologica, 2015
Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis
Kadri Z, Lefevre C, Goupille O, Penglong T, Granger-Locatelli M, Fucharoen S, Maouche-Chretien L, Leboulch P, Chretien S
Genes Dev., 2015
Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease
Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne G, Rea D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX
J. Clin. Oncol., 2014
An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia
Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, Grapton D, Paubelle E, Payen E, Beuzard Y, Leboulch P, Ribeil JA, Arlet JB, Cote F, Courtois G, Ginzburg YZ, Daniel TO, Chopra R, Sung V, Hermine O, Moura IC
Nat. Med., 2014
HSP70 sequestration by free alpha-globin promotes ineffective erythropoiesis in beta-thalassaemia
Arlet JB, Ribeil JA, Guillem F, Negre O, Hazoume A, Marcion G, Beuzard Y, Dussiot M, Moura IC, Demarest S, de Beauchene IC, Belaid-Choucair Z, Sevin M, Maciel TT, Auclair C, Leboulch P, Chretien S, Tchertanov L, Baudin-Creuza V, Seigneuric R, Fontenay M, Garrido C, Hermine O, Courtois G
Nature, 2014
C-Type Lectin-like Receptor LOX-1 Promotes Dendritic Cell-Mediated Class-Switched B Cell Responses
Joo H, Li DP, Dullaers M, Kim TW, Duluc D, Upchurch K, Xue YM, Zurawski S, Le Grand R, Liu YJ, Kuroda M, Zurawski G, Oh S
Immunity, 2014
Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Discontinuation of Imatinib: A Tyrosine Kinase Inhibitor Withdrawal Syndrome? Reply
Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne G, Rea D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX
J. Clin. Oncol., 2014
GENE THERAPY Primed for take-off
Leboulch P
Nature, 2013
Parallel Assessment of Globin Lentiviral Transfer in Induced Pluripotent Stem Cells and Adult Hematopoietic Stem Cells Derived from the Same Transplanted beta-Thalassemia Patient
Tubsuwan A, Abed S, Deichmann A, Kardel MD, Bartholoma C, Cheung A, Negre O, Kadri Z, Fucharoen S, von Kalle C, Payen E, Chretien S, Schmidt M, Eaves CJ, Leboulch P, Maouche-Chretien L
Stem Cells, 2013
Arrayed lentiviral barcoding for quantification analysis of hematopoietic dynamics
Grosselin J, Sii-Felice K, Payen E, Chretien S, Roux DT, Leboulch P
Stem Cells, 2013
LENTIVIRUS VECTORS IN beta-THALASSEMIA
Payen E, Colomb C, Negre O, Beuzard Y, Hehir K, Leboulch P
Methods Enzymol., 2012
Stem Cell Factor-Displaying Simian Immunodeficiency Viral Vectors Together with a Low Conditioning Regimen Allow for Long-Term Engraftment of Gene-Marked Autologous Hematopoietic Stem Cells in Macaques
Verhoeyen E, Relouzat F, Cambot M, Costa C, Negre D, Legrand F, Joubert C, Le Grand R, Cosset FL, Leboulch P, Dubart-Kupperschmitt A, Prost S
Hum. Gene Ther., 2012
BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7
Goupille O, Penglong T, Lefevre C, Granger M, Kadri Z, Fucharoen S, Maouche-Chretien L, Leboulch P, Chretien S
Biochem. Biophys. Res. Commun., 2012
Advances in stem cell transplantation and gene therapy in the beta-hemoglobinopathies
Payen E, Leboulch P
Hematol.-Am. Soc. Hematol. Educ. Program, 2012