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3. Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT

Author

Schuetz, C., Gerke, J., Ege, M., Walter, J., Kusters, M., Worth, A., Kanakry, J. A., Dimitrova, D., Wolska-Kuśnierz, B., Chen, K., Unal, E., Karakukcu, M., Pashchenko, O., Leiding, J., Kawai, T., Amrolia, P. J., Berghuis, D., Buechner, J., Buchbinder, D., Cowan, M. J., Gennery, A. R., Güngör, T., Heimall, J., Miano, M., Meyts, I., Morris, E. C., Rivière, J., Sharapova, S. O., Shaw, P. J., Slatter, M., Honig, M., Veys, P., Fischer, A., Cavazzana, M., Moshous, D., Schulz, A., Albert, M. H., Puck, J. M., Lankester, A. C., Notarangelo, L. D., and Neven, B.

Published
2023
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4. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome

Author

Magnani, A., Semeraro, M., Adam, F., Booth, C., Dupré, L., Morris, E. C., Gabrion, A., Roudaut, C., Borgel, D., Toubert, A., Clave, E., Abdo, C., Gorochov, G., Petermann, R., Guiot, M., Miyara, M., Moshous, D., Magrin, E., Denis, A., Suarez, F., Lagresle, C., Roche, A. M., Everett, J., Trinquand, A., Guisset, M., Bayford, J. Xu, Hacein-Bey-Abina, S., Kauskot, A., Elfeky, R., Rivat, C., Abbas, S., Gaspar, H. B., Macintyre, E., Picard, C., Bushman, F. D., Galy, A., Fischer, A., Six, E., Thrasher, A. J., and Cavazzana, M.

Published
2022
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6. Author Correction: Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome

Author

Magnani, A., Semeraro, M., Adam, F., Booth, C., Dupré, L., Morris, E. C., Gabrion, A., Roudaut, C., Borgel, D., Toubert, A., Clave, E., Abdo, C., Gorochov, G., Petermann, R., Guiot, M., Miyara, M., Moshous, D., Magrin, E., Denis, A., Suarez, F., Lagresle, C., Roche, A. M., Everett, J., Trinquand, A., Guisset, M., Bayford, J. Xu, Hacein-Bey-Abina, S., Kauskot, A., Elfeky, R., Rivat, C., Abbas, S., Gaspar, H. B., Macintyre, E., Picard, C., Bushman, F. D., Galy, A., Fischer, A., Six, E., Thrasher, A. J., and Cavazzana, M.

Published
2022
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7. A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency

Author

Hacein-Bey-Abina, S., Pai, S.-Y., Gaspar, H.B., Armant, M., Berry, C.C., Blanche, S., Bleesing, J., Blondeau, J., de Boer, H., Buckland, K.F., Caccavelli, L., Cros, G., De Oliveira, S., Fernández, K.S., Guo, D., Harris, C.E., Hopkins, G., Lehmann, L.E., Lim, A., London, W.B., van der Loo, J.C.M., Malani, N., Male, F., Malik, P., Marinovic, M.A., McNicol, A.-M., Moshous, D., Neven, B., Oleastro, M., Picard, C., Ritz, J., Rivat, C., Schambach, A., Shaw, K.L., Sherman, E.A., Silberstein, L.E., Six, E., Touzot, F., Tsytsykova, A., Xu-Bayford, J., Baum, C., Bushman, F.D., Fischer, A., Kohn, D.B., Filipovich, A.H., Notarangelo, L.D., Cavazzana, M., Williams, D.A., and Thrasher, A.J.

Abstract

BACKGROUNDIn previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.METHODSWe enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).RESULTSAll patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients.CONCLUSIONSThis modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)

Published
2014

11. P1496: OPERATOR-INDEPENDENT, FLUORESCENCE-BASED QUANTIFICATION OF POCKED RED CELLS CORRELATES WITH SPLEEN SIZE AND FUNCTION IN SICKLE CELL DISEASE

Author

Sissoko, A., primary, Fricot, A., additional, Dumas, L., additional, Roussel, C., additional, Manceau, S., additional, Capito, C., additional, Allali, S., additional, Yekkache, N., additional, Dussiot, M., additional, NGUYEN, Y., additional, Lefort, A., additional, Aussilhou, B., additional, Tichit, M., additional, Hardy, D., additional, Maître, B., additional, Michel, A., additional, De Montalembert, M., additional, Cavazzana, M., additional, Joseph, L., additional, and Buffet, P., additional

Published
2022
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13. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome

Author

Albert, M.H., Slatter, M.A., Gennery, A.R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O.V., Balashov, D., Bernardo, M.E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C.A., Locatelli, F., Lum, S.H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M.G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T.C., Winiarski, J.H., Zecca, M., Neven, B., Veys, P., Lankester, A.C., EBMT, European Soc Immunodeficiencies ES, and Stem CELL Transplant Primary Immun

Subjects
Transplantation Conditioning, Immunology, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Cell Biology, Hematology, Biochemistry, Tissue Donors, Wiskott-Aldrich Syndrome, Treatment Outcome, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, immune system diseases, Child, Preschool, Humans, Busulfan, Retrospective Studies
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged

Published
2022

14. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis

Author

Albert, M. H., Slatter, M. A., Gennery, A. R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O. V., Balashov, D., Bernardo, M. E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C. A., Locatelli, Franco, Lum, S. H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M. G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T. C., Winiarski, J. H., Zecca, M., Neven, B., Veys, P., Lankester, A. C., Locatelli F. (ORCID:0000-0002-7976-3654), Albert, M. H., Slatter, M. A., Gennery, A. R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O. V., Balashov, D., Bernardo, M. E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C. A., Locatelli, Franco, Lum, S. H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M. G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T. C., Winiarski, J. H., Zecca, M., Neven, B., Veys, P., Lankester, A. C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.

Published
2022

19. KEYNOTE SPEAKER 6: UPDATE ON GENE THERAPY CLINICAL TRIALS FOR THE TREATMENT OF β-HEMOGLOBINOPATHIES: Sponsored by BlueBird Bio, Calimmune, Murdoch Childrens Research Institute and Thalassaemia Australia

Author

Leboulch, Philippe, Beuzard, Y., Cavazzana, M., Fucharoen, S., Abina, Hacein-Bay S., Ho, J., Hongeng, S., Kwiatkowski, J. L., Larsen, S., Macpherson, J., Negre, O., Payen, E., Petrusich, A., Rasko, J. E. J., Schiller, G., Soni, S., Thompson, A. A., von Kalle, C., and Walters, M.

Published
2015

20. Vascular access for optimal hematopoietic stem cell collection

Author

Couzin C, Manceau S, Diana JS, Joseph L, Alessandra Magnani, Magrin E, Amrane H, Dupont E, Raphalen JH, Sibon D, Marcais A, Suarez F, Cavazzana M, Lefrère F, and Delville M

Subjects
vascular access, hematopoietic stem cell collection
Abstract

BACKGROUND: Autologous and allogeneic hematopoietic stem cell transplantation of cytokine-mobilized peripheral blood stem cells (PBSCs) is increasingly used to treat patients with hematologic disorders. Different types of vascular access have been exploited for the apheresis procedure, including peripheral veins (PV) and central venous catheter (CVC). In some cases, PV access is unavailable. There are few published data on the efficiency and quality of harvesting with different types of vascular access. This study brings out complications and morbidity of this procedure linked to these different access. METHODS: We performed a comparative, retrospective, single-center study of hematopoietic stem cell collection using these two types of vascular access. We compared the efficiency and complication rate for 617 adults apheresis sessions in 401 patients and healthy donors, for PBSC collection via PV or CVC between 2010 and 2016. The quality of the HSC product was evaluated in terms of the total CD34 + count and neutrophil contamination. RESULTS: The PV and CVC groups did not differ significantly in terms of the quality of the apheresis product, mean ± SD CD34 + cells collected in PV group was 383.1 ± 402.7 × 10e6 and 298.8 ± 372.7 × 10e6 and the level of neutrophil contamination was 21.0 ± 17.8% in the PV group and 20.6 ± 18.4% in the CVC group. The complication rate did not differ between the two groups. CONCLUSION: The type of vascular access for apheresis hematopoietic stem cell harvesting must be determined by trained staff. Successful harvesting can be performed via PV then CVC is not needed or not available.

Published
2021

21. A DL-4-and TNF alpha-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors

Author

Moirangthem, R.D., Ma, K.Y., Lizot, S., Cordesse, A., Olivre, J., Chappedelaine, C. de, Joshi, A., Cieslak, A., Tchen, J., Cagnard, N., Asnafi, V., Rausell, A., Simons, L., Zuber, J., Taghon, T., Staal, F.J.T., Pflumio, F., Six, E., Cavazzana, M., Lagresle-Peyrou, C., Soheili, T., and Andre, I.

Subjects
EXPRESSION, RISK, Human T-lymphoid progenitor, Mobilized peripheral, ligand 4, Delta-like ligand 4, BLOOD, CELL TRANSPLANTATION, Tumor necrosis factor alpha, Hematopoietic stem and progenitor cells, HUMAN HEMATOPOIETIC STEM, PERIPHERAL-BLOOD, FAS, DELTA-LIKE 4, IMMUNE RECONSTITUTION, Mobilized peripheral blood, CORD, Medicine and Health Sciences, Delta-like, TUMOR-NECROSIS-FACTOR
Abstract

Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naive T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naive T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNF alpha) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).

Published
2021

24. Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy

Author

Alessandra Magnani, Pondarré C, Bouazza N, Magalon J, Miccio A, Six E, Roudaut C, Arnaud C, Kamdem A, Touzot F, Gabrion A, Magrin E, Couzin C, Fusaro M, André I, Vernant JP, Gluckman E, Bernaudin F, Bories D, and Cavazzana M

Abstract

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and =12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism 10 g/dL) and three with AS donors (hemoglobin

Published
2020

26. Hematopoietic stem cell transplantation for CD40 ligand deficiency : Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Author

Ferrua, F., Galimberti, S., Courteille, V., Slatter, M.A., Booth, C., Moshous, D., Neven, B., Blanche, S., Cavazzana, M., Laberko, A., Shcherbina, A., Balashov, D., Soncini, E., Porta, F., Al-Mousa, H., Al-Saud, B., Al-Dhekri, H., Arnaout, R., Formankova, R., Bertrand, Y., Lange, A., Smart, J., Wolska-Kusnierz, B., Aquino, V.M., Dvorak, C.C., Fasth, A., Fouyssac, F., Heilmann, C., Hoenig, M., Schuetz, C., Kelecic, J., Bredius, R.G.M., Lankester, A.C., Lindemans, C.A., Suarez, F., Sullivan, K.E., Albert, M.H., Kalwak, K., Barlogis, V., Bhatia, M., Bordon, V., Czogala, W., Alonso, L., Dogu, F., Gozdzik, J., Ikinciogullari, A., Krivan, G., Ljungman, P., Meyts, I., Mustillo, P., Smith, A.R., Speckmann, C., Sundin, M., Keogh, S.J., Shaw, P.J., Boelens, J.J., Schulz, A.S., Sedlacek, P., Veys, P., Mahlaoui, N., Janda, A., Davies, E.G., Fischer, A., Cowan, M.J., Gennery, A.R., SCETIDE, PIDTC, EBMT, ESID IEWP, Ferrua, F, Galimberti, S, Courteille, V, Slatter, M, Booth, C, Moshous, D, Neven, B, Blanche, S, Laberko, A, Shcherbina, A, Balashov, D, Soncini, E, Porta, F, Al-Mousa, H, Al-Saud, B, Al-Dhekri, H, Arnaout, R, Formankova, R, Bertrand, Y, Lange, A, Smart, J, Wolska-Kusnierz, B, Aquino, V, Dvorak, C, Fasth, A, Fouyssac, F, Heilmann, C, Hoenig, M, Schuetz, C, Kelečić, J, Bredius, R, Lankester, A, Lindemans, C, Suarez, F, Sullivan, K, Albert, M, Kałwak, K, Barlogis, V, Bhatia, M, Bordon, V, Czogala, W, Alonso, L, Dogu, F, Gozdzik, J, Ikinciogullari, A, Kriván, G, Ljungman, P, Meyts, I, Mustillo, P, Smith, A, Speckmann, C, Sundin, M, Keogh, S, Shaw, P, Boelens, J, Schulz, A, Sedlacek, P, Veys, P, Mahlaoui, N, Janda, A, Davies, E, Fischer, A, Cowan, M, and Gennery, A

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, primary immunodeficiency, Donor lymphocyte infusion, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, X-linked hyper-IgM syndrome, Humans, Medicine, Immunology and Allergy, Risk factor, Child, Prospective cohort study, business.industry, Infant, Newborn, Infant, medicine.disease, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Graft-versus-host disease, surgical procedures, operative, Supportive psychotherapy, Child, Preschool, hematopoietic stem cell transplantation, Primary immunodeficiency, Bone marrow, CD40 ligand, business, 030215 immunology
Abstract

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:143 issue:6 pages:2238-2253 ispartof: location:United States status: published

Published
2019

27. Ex vivo generated human T-lymphoid progenitors as a tool to accelerate immune reconstitution after partially HLA compatible hematopoietic stem cell transplantation or after gene therapy

Author

André I, Simons L, Ma K, Moirangthem RD, Diana JS, Magrin E, Couzin C, Alessandra Magnani, and Cavazzana M

Abstract

Prolonged T-cell immunodeficiency following HLA- incompatible hematopoietic stem cell transplantation (HSCT) represents a major obstacle hampering the more widespread use of this approach. Strategies to fasten T-cell reconstitution in this setting are highly warranted as opportunistic infections and an increased risk of relapse account for high rates of morbidity and mortality especially during early month following this type of HSCT. We have implemented a feeder free cell system based on the use of the notch ligand DL4 and cytokines allowing for the in vitro differentiation of human T-Lymphoid Progenitor cells (HTLPs) from various sources of CD34+ hematopoietic stem and precursor cells (HSPCs). Co- transplantion of human T-lymphoid progenitors (HTLPs) and non- manipulated HSPCs into immunodeficient mice successfully accelerated the reconstitution of a polyclonal T-cell repertoire. This review summarizes preclinical data on the use of T-cell progenitors for treatment of post- transplantation immunodeficiency and gives insights into the development of GMP based protocols for potential clinical applications including gene therapy approaches. Future clinical trials implementing this protocol will aim at the acceleration of immune reconstitution in different clinical settings such as SCID and leukemia patients undergoing allogeneic transplantation. Apart from pure cell-therapy approaches, the combination of DL-4 culture with gene transduction protocols will open new perspectives in terms of gene therapy applications for primary immunodeficiencies.

Published
2019

29. Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease

Author

Cappelli, B., Volt, F., Tozatto-Maio, K., Scigliuolo, G. M., Ferster, A., Dupont, S., Simoes, B. P., Al-Seraihy, A., Aljurf, M. D., Almohareb, F., Belendez, C., Matthes, S., Dhedin, N., Pondarre, C., Dalle, J. -H., Bertrand, Y., Vannier, J. P., Kuentz, M., Lutz, P., Michel, G., Rafii, H., Neven, B., Zecca, M., Bader, P., Cavazzana, M., Labopin, M., Locatelli, Franco, Magnani, A., Ruggeri, A., Rocha, V., Bernaudin, F., de la Fuente, J., Corbacioglu, S., Gluckman, E., Locatelli F. (ORCID:0000-0002-7976-3654), Cappelli, B., Volt, F., Tozatto-Maio, K., Scigliuolo, G. M., Ferster, A., Dupont, S., Simoes, B. P., Al-Seraihy, A., Aljurf, M. D., Almohareb, F., Belendez, C., Matthes, S., Dhedin, N., Pondarre, C., Dalle, J. -H., Bertrand, Y., Vannier, J. P., Kuentz, M., Lutz, P., Michel, G., Rafii, H., Neven, B., Zecca, M., Bader, P., Cavazzana, M., Labopin, M., Locatelli, Franco, Magnani, A., Ruggeri, A., Rocha, V., Bernaudin, F., de la Fuente, J., Corbacioglu, S., Gluckman, E., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2019

30. Sickle cell disease: An international survey of results of HLA-identical sibling hematopoietic stem cell transplantation

Author

Gluckman, E., Cappelli, B., Bernaudin, F., Labopin, M., Volt, F., Carreras, J., Simoes, B. P., Ferster, A., Dupont, S., De La Fuente, J., Dalle, J. -H., Zecca, M., Walters, M. C., Krishnamurti, L., Bhatia, M., Leung, K., Yanik, G., Kurtzberg, J., Dhedin, N., Kuentz, M., Michel, G., Apperley, J., Lutz, P., Neven, B., Bertrand, Y., Vannier, J. P., Ayas, M., Cavazzana, M., Matthes-Martin, S., Rocha, V., Elayoubi, H., Kenzey, C., Bader, P., Locatelli, Franco, Ruggeri, A., Eapen, M., Bordon, V., Labarque, V., Pereira, M., Bittencourt, H., Petersen, H., Deconninck, E., Jubert, C., Perrin, J., Cahn, J. Y., Bruno, B., Bordigoni, P., Mechinaud, F., Vernant, J. P., Stephan, J. L., Suttorp, M., Strahm, B., Da Cunha, C. B., Garwer, B., Rothmayer, M., Wendelin, K., Graphakos, S., Tbakhi, A., Naeimi, N., Zuckerman, T., Sharon, P. B., Yaniv, I., Amos, T., Prete, A., Lo Nigro, L., Lanino, E., Faraci, M., Ciceri, F., Marktel, S., De Simone, G., Messina, C., Bartolomeo, P. D. I., Santarone, S., Vallisa, D., Bertaina, A., Arcese, W., Foa, R., Berger, M., Maximova, N., Wallet, S., Bazuaye, G. N., Maschan, A., De Heredia, C. D., Bieler, C. B., Pato, J. R., Heras, I., Trevor, R., Abayomi, K., Thomson, J., Fasth, A., Frodin, U., Ljugman, P., Ansari, M., Gungor, T., Unal, E., Pehlivan, M., Anak, S., Ozturk, G., Unal, A., Lawson, S., Keshani, J., Drake, A., Wynn, R., Williams, J., Jagsia, M., Leung, W., Abraham, A., Sahdey, I., Margolis, D., Eames, G., Horwitz, E., Cowan, M., Kapoor, N., Rowley, S., Megason, G., Rogers, Z., Bolanos-Meade, J., Hudspeth, M., Rosenthal, J., Olson, T., Kassow, K., Selby, G., Haines, H., Chaudhury, S., Gluckman, E., Cappelli, B., Bernaudin, F., Labopin, M., Volt, F., Carreras, J., Simoes, B. P., Ferster, A., Dupont, S., De La Fuente, J., Dalle, J. -H., Zecca, M., Walters, M. C., Krishnamurti, L., Bhatia, M., Leung, K., Yanik, G., Kurtzberg, J., Dhedin, N., Kuentz, M., Michel, G., Apperley, J., Lutz, P., Neven, B., Bertrand, Y., Vannier, J. P., Ayas, M., Cavazzana, M., Matthes-Martin, S., Rocha, V., Elayoubi, H., Kenzey, C., Bader, P., Locatelli, F., Ruggeri, A., Eapen, M., Bordon, V., Labarque, V., Pereira, M., Bittencourt, H., Petersen, H., Deconninck, E., Jubert, C., Perrin, J., Cahn, J. Y., Bruno, B., Bordigoni, P., Mechinaud, F., Vernant, J. P., Stephan, J. L., Suttorp, M., Strahm, B., Da Cunha, C. B., Garwer, B., Rothmayer, M., Wendelin, K., Graphakos, S., Tbakhi, A., Naeimi, N., Zuckerman, T., Sharon, P. B., Yaniv, I., Amos, T., Prete, A., Lo Nigro, L., Lanino, E., Faraci, M., Ciceri, F., Marktel, S., De Simone, G., Messina, C., Bartolomeo, P. D. I., Santarone, S., Vallisa, D., Bertaina, A., Arcese, W., Foa, R., Berger, M., Maximova, N., Wallet, S., Bazuaye, G. N., Maschan, A., De Heredia, C. D., Bieler, C. B., Pato, J. R., Heras, I., Trevor, R., Abayomi, K., Thomson, J., Fasth, A., Frodin, U., Ljugman, P., Ansari, M., Gungor, T., Unal, E., Pehlivan, M., Anak, S., Ozturk, G., Unal, A., Lawson, S., Keshani, J., Drake, A., Wynn, R., Williams, J., Jagsia, M., Leung, W., Abraham, A., Sahdey, I., Margolis, D., Eames, G., Horwitz, E., Cowan, M., Kapoor, N., Rowley, S., Megason, G., Rogers, Z., Bolanos-Meade, J., Hudspeth, M., Rosenthal, J., Olson, T., Kassow, K., Selby, G., Haines, H., Chaudhury, S., France Monacord, Centre Scientifique de Monaco (CSM), CHI Créteil, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Eurocord, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Universitaire des Enfants - Reine Fabiola, Université Libre de Bruxelles, Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Duke University Medical Center, Service de Greffe de Moelle - Unité AJA, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Haematology, Hôpital Civil, Hopital Civil, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hemostase, Endothelium, Angiogenese (UMR_S_553), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Churchill Hospital [Breast Care Unit], Churchill Hospital Oxford Centre for Haematology, Santa Lucia Foundation, IRCSS, Rome, Medical College of Wisconsin, National Institute for Health Research, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique

Subjects
Male, HYDROXYUREA, Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, CHILDREN, Hematopoietic stem cell transplantation, Biochemistry, THALASSEMIA, 0302 clinical medicine, HLA Antigens, Surveys and Questionnaires, 1114 Paediatrics And Reproductive Medicine, Child, ComputingMilieux_MISCELLANEOUS, CÉLULAS-TRONCO, Hazard ratio, Graft Survival, BONE-MARROW TRANSPLANT, Hematopoietic Stem Cell Transplantation, Hematology, Sickle cell anemia, 3. Good health, Survival Rate, medicine.anatomical_structure, Treatment Outcome, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, 030220 oncology & carcinogenesis, Child, Preschool, Histocompatibility, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Adolescent, Anemia, Immunology, Anemia, Sickle Cell, 1102 Cardiovascular Medicine And Haematology, Disease-Free Survival, 03 medical and health sciences, Internal medicine, MANAGEMENT, medicine, Humans, ANEMIA, Survival rate, Transplantation, Science & Technology, business.industry, Siblings, Sickle cell disease, Infant, 1103 Clinical Sciences, ADULTS, Cell Biology, medicine.disease, LIFE, EXPERT PANEL, Bone marrow, FOLLOW-UP, business, 030215 immunology
Abstract

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

Published
2017

31. International AIDS Society global scientific strategy: towards an HIV cure 2016

Author

Deeks, Sg, Lewin, Sr, Ross, Al, Ananworanich, J, Benkirane, M, Cannon, P, Chomont, N, Douek, D, Lifson, Jd, Lo, Yr, Kuritzkes, D, Margolis, D, Mellors, J, Persaud, D, Tucker, Jd, Barre-Sinoussi, F, International Aids Society Towards a Cure Working Group, International Aids Society Towards a Cure Working Group, Alter, G, Auerbach, J, Autran, B, Barouch, Dh, Behrens, G, Cavazzana, M, Chen, Z, Cohen, Ea, Corbelli, Gm, Eholié, S, Eyal, N, Fidier, S, Garcia, L, Grossman, C, Henderson, G, Henrich, Tj, Jefferys, R, Kiem, Hp, Mccune, J, Moodley, K, Newman, Pa, Nijhuis, M, Nsubuga, Ms, Ott, M, Palmer, S, Richman, D, Saez-Cirion, A, Sharp, M, Siliciano, J, Silvestri, G, Singh, J, Spire, B, Taylor, J, Tolstrup, M, Valente, S, van Lunzen, J, Walensky, R, Wilson, I, Zack, J, Department of Medicine [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), The Peter Doherty Institute for Infection and Immunity [Melbourne], University of Melbourne-The Royal Melbourne Hospital, Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia, International and Scientific Relations Office, ANRS, Paris, France, Walter Reed Army Institute of Research, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Southern California (USC), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), National Institutes of Health [Bethesda] (NIH), Frederick National Laboratory for Cancer Research (FNLCR), World Health Organization Regional Office for the Western Pacific, Manila, Philippines, Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Institut Pasteur [Paris] (IP), Ragon Institute of MGH, MIT and Harvard, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany, Département de Biothérapie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AIDS Institute, The University of Hong Kong, Pok Fu Lam, Hong Kong, Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), European AIDS Treatment Group, Italy, Programme PAC-CI, Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire, Harvard School of Public Health, Imperial College London, The B-Change Group, Manila, Philippines, Treatment Action Group (TAG), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Stellenbosch University, Factor-Inwentash Faculty of Social Work, University of Toronto, Toronto, Ontario, Canada, University Medical Center [Utrecht], Joint Clinical Research Centre, University of California (UC), The Westmead Institute for Medical Research, University of California [San Diego] (UC San Diego), Independent HIV Education and Advocacy Consultant, San Francisco, California, USA, Emory University [Atlanta, GA], Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CARE Collaboratory Community Advisory Board, Palm Springs, California, USA., Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark., The Scripps Research Institute [La Jolla, San Diego], ViiV Healthcare, London, United Kingdom., Massachusetts General Hospital [Boston], Brown University School of Public Health, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California [San Francisco] (UCSF), University of California-University of California, Institut Pasteur [Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Department of Medicine, Imperial College London, London, United Kingdom, University of California, Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Scripps Research Institute, Imperial College Healthcare NHS Trust- BRC Funding, American Foundation for AIDS Research, Medical Research Council (MRC), MRC DCS, British HIV Association (BHIVA), and Larose, Catherine

Subjects
CD4(+) T-CELLS, 0301 basic medicine, International Cooperation, [SDV]Life Sciences [q-bio], VIRAL RESERVOIR, Human immunodeficiency virus (HIV), Stakeholder engagement, HIV Infections, [SDV.GEN] Life Sciences [q-bio]/Genetics, Research & Experimental Medicine, medicine.disease_cause, Medicine, Societies, Medical, IN-VIVO, ComputingMilieux_MISCELLANEOUS, HIGHLY PATHOGENIC SIV, virus diseases, LATENT HIV-1, 11 Medical And Health Sciences, General Medicine, TREATMENT INTERRUPTION, 3. Good health, [SDV] Life Sciences [q-bio], International AIDS Society Towards a Cure Working Group, Medicine, Research & Experimental, Goals, Life Sciences & Biomedicine, BROADLY NEUTRALIZING ANTIBODIES, Biochemistry & Molecular Biology, medicine.medical_specialty, RALTEGRAVIR INTENSIFICATION, Immunology, education, Article, General Biochemistry, Genetics and Molecular Biology, HISTONE DEACETYLASE INHIBITOR, 03 medical and health sciences, Global population, Acquired immunodeficiency syndrome (AIDS), SUPPRESSIVE ANTIRETROVIRAL THERAPY, Journal Article, Humans, Organizational Objectives, Acquired Immunodeficiency Syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, business.industry, Research, Cell Biology, medicine.disease, Antiretroviral therapy, 030104 developmental biology, Treatment interruption, Family medicine, business
Abstract

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.

Published
2016

32. Disease evolution and response to rapamycin in Activated Phosphoinositide 3-Kinase delta syndrome: the european society for immunodeficiencies-Activated Phosphoinositide 3-Kinase d syndrome registry

Author

Maccari, M.E., Abolhassani, H., Aghamohammadi, A., Aiuti, A., Aleinikova, O., Bangs, C., Baris, S., Barzaghi, F., Baxendale, H., Buckland, M., Burns, S.O., Cancrini, C., Cant, A., Cathebras, P., Cavazzana, M., Chandra, A., Conti, F., Coulter, T., Devlin, L.A., Edgar, J.D.M., Faust, S., Fischer, A., Prat, M.G., Hammarstrom, L., Heeg, M., Jolles, S., Karakoc-Aydiner, E., Kindle, G., Kiykim, A., Kumararatne, D., Grimbacher, B., Longhurst, H., Mahlaoui, N., Milota, T., Moreira, F., Moshous, D., Mukhina, A., Neth, O., Neven, B., Nieters, A., Olbrich, P., Ozen, A., Schmid, J.P., Picard, C., Prader, S., Rae, W., Reichenbach, J., Rusch, S., Savic, S., Scarselli, A., Scheible, R., Sediva, A., Sharapova, S.O., Shcherbina, A., Slatter, M., Soler-Palacin, P., Stanislas, A., Suarez, F., Tucci, F., Uhlmann, A., van Montfrans, J., Warnatz, K., Williams, A.P., Wood, P., Kracker, S., Condliffe, A.M., and Ehl, S.

Abstract

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal\ud dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary\ud immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical\ud and immunological manifestations, questions about long-term disease evolution and\ud response to therapy remain. The prospective European Society for Immunodeficiencies\ud (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors,\ud and evaluate treatment responses. So far, 77 patients have been recruited (51\ud APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early\ud occurrence of recurrent respiratory infections followed by chronic lymphoproliferation,\ud gastrointestinal manifestations, and cytopenias. Although most manifestations occur by\ud age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was\ud observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2\ud patients. By age 20, half of the patients had received at least one immunosuppressant,\ud but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response\ud to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9,\ud and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial,\ud 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and\ud cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative\ud manifestations should be a key target for novel therapies. This report from\ud the ESID-APDS registry provides comprehensive baseline documentation for a growing\ud cohort that will be followed prospectively to establish prognostic factors and identify\ud patients for treatment studies.

Published
2018

33. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT

Published
2018

35. Gene Therapy in Patients with Transfusion-Dependent ß-Thalassemia

Author

Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Alessandra Magnani, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarré C, Beuzard Y, Chrétien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, and Cavazzana M

Abstract

BACKGROUND: Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent ß-thalassemia. After previously establishing that lentiviral transfer of a marked ß-globin (ß(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with ß-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent ß-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent ß-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number. RESULTS: At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-ß(0)/ß(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a ß(0)/ß(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS: Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe ß-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).

Published
2018

36. S141 CLINICAL OUTCOMES OF LENTIGLOBIN GENE THERAPY FOR TRANSFUSION-DEPENDENT β-THALASSAEMIA (TDT) FOLLOWING COMPLETION OF THE NORTHSTAR (HGB-204) STUDY

Author

Walters, M.C., primary, Kwiatkowski, J.L., additional, Rasko, J.E.J., additional, Hongeng, S., additional, Schiller, G.J., additional, Anurathapan, U., additional, Cavazzana, M., additional, Ho, P.J., additional, Schmidt, M., additional, Kletzel, M., additional, Leboulch, P., additional, Vichinsky, E., additional, Deary, B., additional, Chen, Y., additional, Petrusich, A., additional, and Thompson, A.A., additional

Published
2019
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37. PF441 RED BLOOD CELLS PROPERTIES IN PATIENTS WITH SICKLE CELL DISEASE TREATED WITH LENTIGLOBIN GENE THERAPY IN THE HGB-205 TRIAL

Author

Magrin, E., primary, Semeraro, M., additional, Hebert, N., additional, Kiger, L., additional, Nguyen-Peyre, K.-A., additional, Joseph, L., additional, Miccio, A., additional, Chalumeau, A., additional, Magnani, A., additional, Couzin, C., additional, Marouene, J., additional, Gabrion, A., additional, Roudaut, C., additional, El Nemer, W., additional, Pirenne, F., additional, Negre, O., additional, Ribeil, J.-A., additional, Brousse, V., additional, De Montalembert, M., additional, Asmal, M., additional, Bartolucci, P., additional, and Cavazzana, M., additional

Published
2019
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39. Gene Therapy Approaches to Hemoglobinopathies

Author

Ferrari, G., Cavazzana, M., and Mavilio, F.

Subjects
Gene transfer, Globin gene regulation, Hematopoiesis, Lentiviral vectors, Retroviral vectors, Sickle cell disease, Stem cell transplantation, Thalassemia, Anemia, Sickle Cell, Animals, Clinical Trials as Topic, Drug Evaluation, Preclinical, Gene Expression, Gene Transfer Techniques, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Hemoglobinopathies, Hemoglobins, Humans, Transduction, Genetic, beta-Thalassemia, Genetic Therapy
Published
2017

40. Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency

Author

Ginn, SL, Hallwirth, CV, Liao, SHY, Teber, ET, Arthur, JW, Wu, J, Lee, HC, Tay, SS, Hu, M, Reddel, RR, McCormack, MP, Thrasher, AJ, Cavazzana, M, Alexander, SI, Alexander, IE, Ginn, SL, Hallwirth, CV, Liao, SHY, Teber, ET, Arthur, JW, Wu, J, Lee, HC, Tay, SS, Hu, M, Reddel, RR, McCormack, MP, Thrasher, AJ, Cavazzana, M, Alexander, SI, and Alexander, IE

Abstract

© 2016 The Author(s) In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy. To test this hypothesis, in the absence of transduction, SCID-X1 mice were reconstituted with serially fewer wild-type hematopoietic progenitors. A robust inverse correlation between hematopoietic progenitor cell dose and T-lymphoid malignancy was observed, with earlier disease onset at lower cell doses. Malignancies were of donor origin and carried activating Notch1 mutations. These findings align with emerging evidence that thymocyte self-renewal induced by progenitor deprivation carries an oncogenic risk that is modulated by intra-thymic competition from differentiation-committed cells. Although insertional proto-oncogene activation is required for the development of malignancy in humans, failure of γc-deficient thymocytes to effectively compete with this at-risk cell population may have also contributed to oncogenesis observed in early SCID-X1 trials.

Published
2017

42. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

Author

Elkaim, E, Neven, B, Bruneau, J, Mitsui-Sekinaka, K, Stanislas, A, Heurtier, L, Lucas, CL, Matthews, H, Deau, MC, Sharapova, S, Curtis, J, Reichenbach, J, Glastre, C, Parry, DA, Arumugakani, G, McDermott, E, Kilic, SS, Yamashita, M, Moshous, D, Lamrini, H, Otremba, B, Gennery, A, Coulter, T, Quinti, I, Stephan, JL, Lougaris, V, Brodszki, N, Barlogis, V, Asano, T, Galicier, L, Boutboul, D, Nonoyama, S, Cant, A, Imai, K, Picard, C, Nejentsev, S, Molina, TJ, Lenardo, M, Savic, S, Cavazzana, M, Fischer, A, Durandy, A, and Kracker, S

Subjects
Adult, Male, Adolescent, Genotype, p110δ, Class I Phosphatidylinositol 3-Kinases, activated phosphoinositide 3-kinase δ syndrome, Biopsy, Immunology, CD8-Positive T-Lymphocytes, primary immunodeficiency, APDS2, combined immune deficiency, Cohort Studies, Young Adult, Gene Frequency, T-Lymphocyte Subsets, lymphadenopathy, P110δ-activating mutations causing senescent T cells, Immunology and Allergy, Humans, hyper-IgM, Child, Alleles, and immunodeficiency, Primary immunodeficiency, phosphoinositide 3-kinase, Immunologic Deficiency Syndromes, p85α, adenopathy, Middle Aged, antibody deficiency, Phenotype, Activated phosphoinositide 3-kinase δ syndrome, Adenopathy, And immunodeficiency, Antibody deficiency, Hyper-IgM, Immunodeficiency, Lymphadenopathy, P110δ, P85α, Phosphoinositide 3-kinase, Child, Preschool, Mutation, p110δ-activating mutations causing senescent T cells, Female, RNA Splice Sites, immunodeficiency
Abstract

Background Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]–R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. Objectives We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.

Published
2015

43. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1

Author

Touzot F, Moshous D, Creidy R, Neven B, Frange P, Cros G, Caccavelli L, Blondeau J, Alessandra Magnani, Luby JM, Ternaux B, Picard C, Blanche S, Fischer A, Hacein-Bey-Abina S, and Cavazzana M

Abstract

During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT.

Published
2015

44. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages

Author

Six, E, Lagresle-Peyrou, C, Susini, S, De Chappedelaine, C, Sigrist, N, Sadek, H, Chouteau, M, Cagnard, N, Fontenay, M, Hermine, Olivier, Chomienne, C, Reynier, Pascal, Fischer, Alain, André-Schmutz, I, Gueguen, Naïg, Cavazzana, M, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))

Subjects
Neutrophils, Adenine Nucleotides, Gene Expression Profiling, Stem Cells, Primary Cell Culture, HL-60 Cells, Cell Differentiation, Leukopenia, Oxidative Phosphorylation, adenylate kinase, mitochondria, Gene Expression Regulation, Gene Knockdown Techniques, Mutation, Humans, Severe Combined Immunodeficiency, CD34, Lymphocytes, Antigens, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. Our present results demonstrate that AK2-knocked-down progenitor cells have poor proliferative and survival capacities and are blocked in their differentiation toward lymphoid and granulocyte lineages. We also observed that AK2 deficiency impaired mitochondrial function in general and oxidative phosphorylation in particular - showing that AK2 is critical in the control of energy metabolism. Loss of AK2 disrupts this regulation and leads to a profound block in lymphoid and myeloid cell differentiation.

Published
2015

45. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

Author

Angelucci, E., Matthes-Martin, S., Baronciani, D., Bernaudin, F., Bonanomi, S., Cappellini, M.D., Dalle, J.H., Bartolomeo, P. di, Heredia, C.D. de, Dickerhoff, R., Giardini, C., Gluckman, E., Hussein, A.A., Kamani, N., Minkov, M., Locatelli, F., Rocha, V., Sedlacek, P., Smiers, F., Thuret, I., Yaniv, I., Cavazzana, M., Peters, C., and EBMT Inborn Error EBMT Paediat Wor

Subjects
medicine.medical_specialty, Anemia, Thalassemia, medicine.medical_treatment, Cell, Anemia, Sickle Cell, Disease, Hematopoietic stem cell transplantation, Guideline Article, medicine, Humans, Child, Intensive care medicine, business.industry, Marrow transplantation, beta-Thalassemia, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, Surgery, surgical procedures, operative, medicine.anatomical_structure, N/A, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Savior sibling, business
Abstract

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.

Published
2014

46. Pre-transplant donor CD4− invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease

Author

Rubio, M-T, primary, Bouillié, M, additional, Bouazza, N, additional, Coman, T, additional, Trebeden-Nègre, H, additional, Gomez, A, additional, Suarez, F, additional, Sibon, D, additional, Brignier, A, additional, Paubelle, E, additional, Nguyen-Khoc, S, additional, Cavazzana, M, additional, Lantz, O, additional, Mohty, M, additional, Urien, S, additional, and Hermine, O, additional

Published
2016
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47. Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

Author

Fernandes, Jf, Rocha, V, Labopin, M, Neven, B, Moshous, D, Gennery, Ar, Friedrich, W, Porta, F, Diaz de Heredia, C, Wall, D, Bertrand, Y, Veys, P, Slatter, M, Schulz, A, Chan, Kw, Grimley, M, Ayas, M, Gungor, T, Ebell, W, Bonfim, C, Kalwak, K, Taupin, P, Blanche, S, Gaspar, Hb, Landais, P, Fischer, A, Gluckman, E, Cavazzana Calvo, M, Eurocord, Inborn Errors Working Party of European Group for Blood, Marrow Transplantation: Ahmed, A, Auiti, A, Biffi, A, Cant, A, Fasth, A, Gennery, A, Hassan, A, Lankester, A, O'Mera, A, Plabani, A, Rovelli, A, Salmon, A, Scarselli, A, Thrasher, A, Van Royen, A, Villa, A, Wawer, A, Wahadneh, A, Worth, A, Belohradsky, B, Wolska, B, Gaspar, B, Bonfirm, C, Booth, C, Klein, C, Messina, C, Peters, C, Steward, C, Lindemans, C, Schuetz, C, de Heredia Rubio CD, Bensoussan, D, Gleadow, D, Lilic, D, Gambineri, Eleonora, Smith, E, Aerts, F, Caracseghi, F, Roberts, G, Davies, G, Al Mousa, H, Jossanc, H, Ozsahim, H, Hirsch, I, Meyts, I, Tezcan, I, Mueller, I, Andresc, I, Boelens, J, Fernandes, J, Folloni, J, Keuhl, J, Reichenbach, J, Stary, J, Wachowiak, J, Xu Bayford, J, Cunha, Jm, Ehlert, J, Rao, K, Sykora, K, Andais, L, Brown, L, Dal Cortivo, L, Griffith, L, Notarangelo, L, Abinun, M, Albert, M, Bierings, M, Bouchet, M, Cavazzana, M, Hirschfield, M, Cowan, M, Hoenig, M, Loubser, M, Roncarolo, M, Sauer, M, Schneider, M, Verstegen, M, Schroeder, M, Essink, M, Yesilipek, M, Entz Werle, N, Mahlaoui, N, Schlautmann, N, Taylor, N, Vanroyen, N, Walffraat, N, Sanal, O, Amrolia, P, Bordigoni, P, De Coppi, P, Frange, P, Orchard, P, Sedlacek, P, Shaw, P, Stephensky, P, Bacchetta, R, Bredius, R, Formankova, R, Gale, R, Seger, R, Wynn, R, Corbacioglu, S, Ehl, S, Hacein Bey, S, Hambleton, S, Mohsen, S, Mueller, S, Pai, Sy, Espanol, T, Flood, T, Guengoer, T, Bordon, V, Ormoor, V, Pashano, V, Courteille, V, Czogala, W, Qasim, W, Camci, Y, and Nademi, Z.

Subjects
Male, medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, Immunology, Graft vs Host Disease, Kaplan-Meier Estimate, Cord Blood Stem Cell Transplantation, Hematopoietic stem cell transplantation, Biochemistry, Gastroenterology, SCID HSCT, Internal medicine, medicine, Humans, Proportional Hazards Models, Retrospective Studies, Preparative Regimen, Severe combined immunodeficiency, business.industry, Umbilical Cord Blood Transplantation, Incidence, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Cell Biology, Hematology, medicine.disease, Surgery, Transplantation, Treatment Outcome, Child, Preschool, Histocompatibility, Cord blood, Female, Severe Combined Immunodeficiency, business
Abstract

Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

Published
2012

48. Lymphopoiesis in transgenic mice over-expressing Artemis

Author

Rivera-Munoz, P, primary, Abramowski, V, additional, Jacquot, S, additional, André, P, additional, Charrier, S, additional, Lipson-Ruffert, K, additional, Fischer, A, additional, Galy, A, additional, Cavazzana, M, additional, and de Villartay, J-P, additional

Published
2015
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49. Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children

Author

Frange, P., primary, Leruez-Ville, M., additional, Neven, B., additional, Mascard, L., additional, Moshous, D., additional, Touzot, F., additional, Heritier, S., additional, Chaix, M.-L., additional, Cavazzana, M., additional, Casanova, J.-L., additional, Fischer, A., additional, and Blanche, S., additional

Published
2013
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50. Genotoxic Signature in Cord Blood Cells of Newborns Exposed In Utero to a Zidovudine-Based Antiretroviral Combination

Author

Andre-Schmutz, I., primary, Dal-Cortivo, L., additional, Six, E., additional, Kaltenbach, S., additional, Cocchiarella, F., additional, Le Chenadec, J., additional, Cagnard, N., additional, Cordier, A.-G., additional, Benachi, A., additional, Mandelbrot, L., additional, Azria, E., additional, Bouallag, N., additional, Luce, S., additional, Ternaux, B., additional, Reimann, C., additional, Revy, P., additional, Radford-Weiss, I., additional, Leschi, C., additional, Recchia, A., additional, Mavilio, F., additional, Cavazzana, M., additional, and Blanche, S., additional

Published
2013
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