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Le Touquet – Paris-Plage, France

Cavazzana M.,Necker Childrens Hospital | Cavazzana M.,Groupe Hospitalier University Ouest | Cavazzana M.,University of Paris Pantheon Sorbonne | Cavazzana M.,French Institute of Health and Medical Research | And 9 more authors.
Current Opinion in Allergy and Clinical Immunology | Year: 2014

Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies - such as gene therapy - emerge as an interesting option for some PIDs. Copyright © Lippincott Williams & Wilkins. Source

Cartier N.,University of Paris Descartes | Hacein-Bey-Abina S.,Hopital Necker Enfants Malades | Hacein-Bey-Abina S.,University of Paris Descartes | Hacein-Bey-Abina S.,Groupe Hospitalier University Ouest | And 9 more authors.
Methods in Enzymology | Year: 2012

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34 + cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34 + cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14 of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16 months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC gene therapy in cerebral forms of X-ALD. © 2012 Elsevier Inc. All rights reserved. Source

Hauer J.,University of Paris Descartes | Hauer J.,Heinrich Heine University Dusseldorf | Mullighan C.,St Jude Childrens Research Hospital | Morillon E.,University of Paris Descartes | And 16 more authors.
Blood | Year: 2011

In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf-/-Rag1 -/- mouse model to confirm the previously published results concerning the contribution ofCDKN2A(p19ARF/INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-nitiating mechanism originating from a Sca1 +CD19+ precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34+CD19+ population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans. © 2011 by The American Society of Hematology. Source

Fischer A.,French Institute of Health and Medical Research | Fischer A.,University of Paris Descartes | Hacein-Bey-Abina S.,French Institute of Health and Medical Research | Hacein-Bey-Abina S.,University of Paris Descartes | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Gene therapy has become an option for the treatment of 2 forms of severe combined immunodeficiency (SCID): X-linked SCID and adenosine deaminase deficiency. The results of clinical trials initiated more than 10 years ago testify to sustained and reproducible correction of the underlying T-cell immunodeficiency. Successful treatment is based on the selective advantage conferred on T-cell precursors through their expression of the therapeutic transgene. However, "first-generation" retroviral vectors also caused leukemia in some patients with X-linked SCID because of the constructs' tendency to insert into active genes (eg, proto-oncogenes) in progenitor cells and transactivate an oncogene through a viral element in the long terminal repeat. These elements have been deleted from the vectors now in use. Together with the use of lentiviral vectors (which are more potent for transducing stem cells), these advances should provide a basis for the safe and effective extension of gene therapy's indications in the field of primary immunodeficiencies. Nevertheless, this extension will have to be proved by examining the results of the ongoing clinical trials. © 2011 American Academy of Allergy, Asthma & Immunology. Source

Van Der Loo J.C.M.,Cincinnati Childrens Hospital Medical Center | Swaney W.P.,Washington University in St. Louis | Grassman E.,Cincinnati Childrens Hospital Medical Center | Terwilliger A.,Cincinnati Childrens Hospital Medical Center | And 13 more authors.
Gene Therapy | Year: 2012

Patients with X-linked severe combined immunodeficiency (SCID-X1) were successfully cured following gene therapy with a gamma-retroviral vector (gRV) expressing the common gamma chain of the interleukin-2 receptor (IL2RG). However, 5 of 20 patients developed leukemia from activation of cellular proto-oncogenes by viral enhancers in the long-terminal repeats (LTR) of the integrated vector. These events prompted the design of a gRV vector with self-inactivating (SIN) LTRs to enhance vector safety. Herein we report on the production of a clinical-grade SIN IL2RG gRV pseudotyped with the Gibbon Ape Leukemia Virus envelope for a new gene therapy trial for SCID-X1, and highlight variables that were found to be critical for transfection-based large-scale SIN gRV production. Successful clinical production required careful selection of culture medium without pre-added glutamine, reduced exposure of packaging cells to cell-dissociation enzyme, and presence of cations in wash buffer. The clinical vector was high titer; transduced 68-70% normal human CD34 + cells, as determined by colony-forming unit assays and by xenotransplantation in immunodeficient NOD.CB17-Prkdc scid/J (nonobese diabetic/severe combined immunodeficiency (NOD/SCID)) and NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ (NOD/SCID gamma (NSG))) mice; and resulted in the production of T cells in vitro from human SCID-X1 CD34 +cells. The vector was certified and released for the treatment of SCID-X1 in a multi-center international phase I/II trial. © 2012 Macmillan Publishers Limited All rights reserved. Source

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