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1. Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

Author: Panagiotis Antoniou, Giulia Hardouin, Pierre Martinucci, Giacomo Frati, Tristan Felix, Anne Chalumeau, Letizia Fontana, Jeanne Martin, Cecile Masson, Megane Brusson, Giulia Maule, Marion Rosello, Carine Giovannangeli, Vincent Abramowski, Jean-Pierre de Villartay, Jean-Paul Concordet, Filippo Del Bene, Wassim El Nemer, Mario Amendola, Marina Cavazzana, Anna Cereseto, Oriana Romano, Annarita Miccio, Demokritos University of Thrace, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biodiversité et Biotechnologie Fongiques (BBF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d’Excellence GR-Ex, Paris, France, University of Trento [Trento], National Research Council [Italy] (CNR), Institut Curie [Paris], Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe labellisée Ligue contre le Cancer, Muséum national d'Histoire naturelle (MNHN), Université Paris sciences et lettres (PSL), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), Etablissement Français du Sang Provence-Alpes Côte-d'Azur et Corse (EFS), Généthon, Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Giovannangeli, Carine, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Multidisciplinary, [SDV]Life Sciences [q-bio], beta-Thalassemia, General Physics and Astronomy, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Chemistry, Anemia, Sickle Cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Hematopoietic Stem Cells, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, gamma-Globins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fetal Hemoglobin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the −200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy – even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies.
Published: 2022
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2. 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., Cavazzana, M., Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Great Ormond Street Hospital for Children [London] (GOSH), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Medizinische Universität Wien = Medical University of Vienna, NHS Foundation Trust [London], The Royal Marsden, Généthon, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), University of Pennsylvania School of Veterinary Medicine, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Collège de France (CdF (institution)), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 693762,GENEFORCURE, Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], Benson-Rumiz, Alicia, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and GENEFORCURE - GENEFORCURE - 693762 - INCOMING
Subjects: Adult, MESH: Genetic Therapy / methods, Adolescent, MESH: Hematopoietic Stem Cell Transplantation, Genetic Vectors, MESH: Lentivirus / genetics, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, Clinical Trials, Phase II as Topic, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Wiskott-Aldrich Syndrome / genetics, Humans, Child, MESH: Treatment Outcome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Clinical Trials, Phase I as Topic, MESH: Wiskott-Aldrich Syndrome / therapy, Lentivirus, MESH: Genetic Vectors, Hematopoietic Stem Cell Transplantation, Infant, Genetic Therapy, General Medicine, MESH: Wiskott-Aldrich Syndrome / immunology, Wiskott-Aldrich Syndrome, Targeted gene repair, Treatment Outcome, MESH: Clinical Trials, Phase I as Topic, Child, Preschool, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Primary immunodeficiency disorders, MESH: Clinical Trials, Phase II as Topic, Wiskott-Aldrich Syndrome Protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Patients with Wiskott–Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS., Long-term monitoring of patients with Wiskott–Aldrich syndrome following lentiviral gene therapy shows a safe profile and a reduction in the frequency of autoimmune manifestations and bleeding events, despite incomplete platelet reconstitution.
Published: 2022
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3. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

Author: Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Descartes - Paris 5 (UPD5)-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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, X-linked severe combined immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Stimulus Report, 3. Good health, Transplantation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, In utero, Child, Preschool, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bone marrow, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
Published: 2019
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4. Primary Hyperparathyroidism in Sickle Cell Disease: An Unknown Complication of the Disease in Adulthood

Author: Pablo Bartolucci, Jean-Benoît Arlet, Lorraine Clavier, Marie Courbebaisse, Charlène Bomahou, Jean-Antoine Ribeil, Elsa Denoix, Jacques Pouchot, François Lionnet, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Médecine Interne = Hôpital de jour de médecine [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, Adenoma, endocrine system diseases, Osteoporosis, lcsh:Medicine, Parathyroid hormone, 030209 endocrinology & metabolism, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, primary hyperparathyroidism, 10. No inequality, Parathyroid adenoma, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, lcsh:R, hypercalcemia, Retrospective cohort study, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, osteoporosis, 3. Good health, 030220 oncology & carcinogenesis, adenoma, sickle cell disease, Complication, business, Primary hyperparathyroidism
Abstract: Primary hyperparathyroidism (pHPT) is the third most common endocrine disorder and usually affects patients between 60 and 70 years of age. To our knowledge, this condition has never been studied in young patients with sickle cell disease (SCD). Our objective was to describe the clinical and biological characteristics of pHPT in adult patients with SCD and its management. We conducted a retrospective study that included SCD patients who were diagnosed with pHPT in four SCD referral centers. pHPT was defined by the presence of elevated serum calcium levels with inappropriate normal or increased parathyroid hormone (PTH) serum levels or histopathological evidence of parathyroid adenoma or hyperplasia. Patients with severe renal impairment (GFR &lt, 30 mL/min) were excluded. Twenty-eight patients (18 women, 64%, 22 homozygous genotype, 79%) were included. The median age at pHPT diagnosis was 41 years (interquartile range &ndash, IQR- 31.5&ndash, 49.5). The median serum calcium and PTH concentration were, respectively, 2.62 mmol/L (IQR 2.60&ndash, 2.78) and 105 pg/mL (IQR 69&ndash, 137). Bone mineral density (BMD) revealed very low BMD (&minus, 2.5 SD) in 44% of patients explored (vs. 12.5% among 32 SCD patients matched for SCD genotype, sex, age, and BMI, p = 0.03). Fourteen patients (50%) received surgical treatment, which was successful in all cases, but four of these patients (29%) presented with pHPT recurrence after a median time of 6.5 years. Three of these patients underwent a second cervical surgery that confirmed the presence of a new parathyroid adenoma. These results suggest that SCD is a condition associated with pHPT in young subjects. SCD patients with pHPT have a high risk of very low BMD. A diagnosis of pHPT should be suspected in the presence of mild hypercalcemia or low BMD in SCD patients.
Published: 2020
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5. Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma

Author: Delville, Marianne, Touzot, Fabien, Couzin, Chloé, Hmitou, Isabelle, Djerroudi, Lounes, Ouedrani, Amani, Lefrère, François, Tuchman-Durand, Caroline, Mollet, Chloé, Fabreguettes, Jean-Roch, Ferry, Nicolas, Laganier, Laurent, Magnani, Alessandra, Magrin, Elisa, Jolaine, Valérie, Saez-Cirion, Asier, Wolstein, Orit, Symonds, Geoffrey, Frange, Pierre, Moins-Teisserenc, Hélène, Chaix-Baudier, Marie-Laure, Toubert, Antoine, Larghero, Jérôme, Parquet, Nathalie, Brignier, Anne C., Barré-Sinoussi, Françoise, Oksenhendler, Eric, Cavazzana, Marina, Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-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), 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], Agence Générale des Equipements et Produits de Santé [Paris] (AGEPS), Hopital Saint-Louis [AP-HP] (AP-HP), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [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)-Institut National de la Santé et de la Recherche Médicale (INSERM), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), CSL Behring, CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), 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)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Direction Internationale de l'Institut Pasteur, This work is supported by INSERM ANRS 13043, MIGAC funding of the Centre d’Investigation Clinique of the Biotherapy Department, and CSL Behring, LLC (Calimmune, Inc.). CSL Behring, LLC also provided the vector. Assistance Publique des Hôpitaux de Paris is the study promoter., Saez-Cirion, Asier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), HIV, Inflammation et persistance, Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [SDV] Life Sciences [q-bio], lcsh:Genetics, lcsh:QH426-470, lcsh:Cytology, [SDV]Life Sciences [q-bio], virus diseases, lcsh:QH573-671, Article
Abstract: Although the risk of developing lymphoma has decreased in the highly active antiretroviral therapy era, this cancer remains the major cause of mortality in HIV-infected patients. Autologous hematopoietic stem cell transplantation (ASCT) outcome does not differ for HIV-infected versus HIV-uninfected patients. We propose to develop a new treatment for HIV-associated high-risk lymphoma based on autologous transplantation of two genetically modified products: CD4(+) T lymphocytes and CD34(+) hematopoietic stem cells (HSPCs). The cells will be transduced ex vivo with the Cal-1 lentiviral vector encoding for both a short hairpin RNA (shRNA) against CCR5 (sh5) and the HIV-1 fusion inhibitor C46. The transduced cells will be resistant to HIV infection by two complementary mechanisms: impaired binding of the virus to the cellular CCR5 co-receptor and decreased fusion of the virus as C46 interacts with gp41 and inhibits HIV infection. This phase I/II pilot study, also entitled GENHIV, will involve two French participating centers: Saint Louis Hospital and Necker Hospital in Paris. We plan to enroll five HIV-1-infected patients presenting with high-risk lymphoma and require a treatment with ASCT. The primary objective of this study is to evaluate the safety, feasibility, and success of engraftment of Cal-1 gene-transduced CD4(+) T lymphocytes and CD34(+) HSPCs.
Published: 2019
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6. Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency

Author: David Fenard, Ornellie Bernadin, Anais Girard-Gagnepain, Camille Lévy, Chantal Lagresle-Peyrou, Kuiying Ma, Rana Mhaidly, Hanem Sadek, Marina Cavazzana, Fouzia Amirache, Caroline Costa, Ranjita Devi Moirangthem, Isabelle André, François-Loïc Cosset, Els Verhoeyen, Christian Reimann, Didier Nègre, Agata Cieslak, Vahid Asnafi, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-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), Lucerne Cantonal Hospital [Luzern, Switzerland], Généthon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genethon - Inserm UMR_S951, Immunologie moléculaire et biothérapies innovantes (IMBI), GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Généthon, Association française contre les myopathies (AFM-Téléthon)-Association française contre les myopathies (AFM-Téléthon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie moléculaire et biothérapies innovantes, École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Genethon-École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Genethon-Généthon, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Human Virology Department, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Nice Sophia Antipolis (UNS), Département de Biothérapie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, medicine.medical_treatment, Genetic enhancement, [SDV]Life Sciences [q-bio], CD34, chemical and pharmacologic phenomena, Mice, SCID, Hematopoietic stem cell transplantation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, complex mixtures, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, medicine, Animals, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Severe combined immunodeficiency, integumentary system, Stem Cells, Lentivirus, hemic and immune systems, Gene Therapy, Hematology, bacterial infections and mycoses, medicine.disease, T cell deficiency, 3. Good health, Cell biology, Haematopoiesis, 030104 developmental biology, 030220 oncology & carcinogenesis, Stem cell, Papio
Abstract: T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7–stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34+ cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC−/− engraftment, high transduction levels (80%-90%) were maintained in all T-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC−/− recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients.
Published: 2019
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7. Loss of ARHGEF1 causes a human primary antibody deficiency

Author: Anne Durandy, Sébastien Lofek, Hicham Lamrini, Eric Oksenhendler, Loic Chentout, Isabelle André-Schmutz, Elizabeth Macintyre, Sven Kracker, Marie-Céline Deau, Marc Bras, Lucie Heurtier, Amélie Trinquand, Marina Cavazzana, Amine Bouafia, Véronique Meignin, Olivier Alibeu, Alain Fischer, Julie Bruneau, Thierry Jo Molina, Capucine Picard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratoire d'Anatomie Pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], 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), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5), Hôpital Hôtel Dieu, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Developpement Normal et Pathologique du Système Immunitaire, Service d'Immunopathologie Clinique, ANR-15-CE15-0020,PIKimun,Caractérisation de la voie PI3K / AKT / mTOR - dans les lymphocytes humains(2015), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
Subjects: 0301 basic medicine, Male, RHOA, Primary Immunodeficiency Diseases, T-Lymphocytes, [SDV]Life Sciences [q-bio], GTP-Binding Protein alpha Subunits, G12-G13, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, medicine, Humans, Lymphocytes, Protein kinase B, PI3K/AKT/mTOR pathway, B cell, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, rho-Associated Kinases, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Chemistry, Siblings, Germinal center, General Medicine, Marginal zone, Actin cytoskeleton, Germinal Center, Molecular biology, 3. Good health, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Commentary, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, rhoA GTP-Binding Protein, Immunologic Memory, Proto-Oncogene Proteins c-akt, Rho Guanine Nucleotide Exchange Factors, Research Article, Signal Transduction
Abstract: ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody–deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients’ blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients’ lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients’ cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.
Published: 2019
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8. 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
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9. A clinical trial combining megakaryocytes and haematopoietic stem cells to promote engraftment after autologous transplantation

Author: Michelle Rozenzwajg, Farhad Heshmati, Marie-Laure Tanguy, Vincent Vieillard, Ramdane Belhocine, Helene Trebeden-Negre, Françoise Norol, François Lefrère, Sylvain Choquet, Nabih Azar, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Biostatistique, Santé Publique et Information Médicale [CHU Pitié-Salpêtrière] (BIOSPIM ), Département de Biothérapie [CHU Necker], 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), Unité de Médecine Transfusionnelle, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Thérapie cellulaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de biostatistiques et information médicale [CHU Pitié-Salpêtrière], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and CHU Cochin [AP-HP]
Subjects: Adult, Male, 0301 basic medicine, Transplantation Conditioning, Antigens, CD34, Transplantation, Autologous, 03 medical and health sciences, Humans, Medicine, Autologous transplantation, ComputingMilieux_MISCELLANEOUS, business.industry, Lymphoma, Non-Hodgkin, Hematopoietic Stem Cell Transplantation, Recovery of Function, Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, Allografts, Hematopoietic Stem Cells, Stem cell niche, 3. Good health, Clinical trial, Haematopoiesis, 030104 developmental biology, Cancer research, Female, Stem cell, business, Megakaryocytes
Abstract: International audience
Published: 2018
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10. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Author: Maria Elena Maccari, Hassan Abolhassani, Asghar Aghamohammadi, Alessandro Aiuti, Olga Aleinikova, Catherine Bangs, Safa Baris, Federica Barzaghi, Helen Baxendale, Matthew Buckland, Siobhan O. Burns, Caterina Cancrini, Andrew Cant, Pascal Cathébras, Marina Cavazzana, Anita Chandra, Francesca Conti, Tanya Coulter, Lisa A. Devlin, J. David M. Edgar, Saul Faust, Alain Fischer, Marina Garcia Prat, Lennart Hammarström, Maximilian Heeg, Stephen Jolles, Elif Karakoc-Aydiner, Gerhard Kindle, Ayca Kiykim, Dinakantha Kumararatne, Bodo Grimbacher, Hilary Longhurst, Nizar Mahlaoui, Tomas Milota, Fernando Moreira, Despina Moshous, Anna Mukhina, Olaf Neth, Benedicte Neven, Alexandra Nieters, Peter Olbrich, Ahmet Ozen, Jana Pachlopnik Schmid, Capucine Picard, Seraina Prader, William Rae, Janine Reichenbach, Stephan Rusch, Sinisa Savic, Alessia Scarselli, Raphael Scheible, Anna Sediva, Svetlana O. Sharapova, Anna Shcherbina, Mary Slatter, Pere Soler-Palacin, Aurelie Stanislas, Felipe Suarez, Francesca Tucci, Annette Uhlmann, Joris van Montfrans, Klaus Warnatz, Anthony Peter Williams, Phil Wood, Sven Kracker, Alison Mary Condliffe, Stephan Ehl, Federal Ministry of Education and Research (Germany), Novartis, GlaxoSmithKline, University of Tehran, Service de Médecine Interne, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de Biothérapie [CHU Necker], 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 Medical Oncology, Regina Elena Cancer Institute, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Istanbul University, Addenbrookes Hospital, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Immunologie Hématologie et Rhumatologie Pédiatrique [Necker, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Clinical Epidemiology, Deutches Krebsforschungszentrum, Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, European Laboratory for Food Induced Diseases, Università degli studi di Napoli Federico II, Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-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) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maccari, Maria Elena, Abolhassani, Hassan, Aghamohammadi, Asghar, Aiuti, Alessandro, Aleinikova, Olga, Bangs, Catherine, Baris, Safa, Barzaghi, Federica, Baxendale, Helen, Buckland, Matthew, Burns, Siobhan O., Cancrini, Caterina, Cant, Andrew, Cathebras, Pascal, Cavazzana, Marina, Chandra, Anita, Conti, Francesca, Coulter, Tanya, Devlin, Lisa A., Edgar, J. David M., Faust, Saul, Fischer, Alain, Prat, Marina Garcia, Hammarstrom, Lennart, Heeg, Maximilian, Jolles, Stephen, Karakoc-Aydiner, Elif, Kindle, Gerhard, Kiykim, Ayca, Kumararatne, Dinakantha, Grimbacher, Bodo, Longhurst, Hilary, Mahlaoui, Nizar, Milota, Tomas, Moreira, Fernando, Moshous, Despina, Mukhina, Anna, Neth, Olaf, Neven, Benedicte, Nieters, Alexandra, Olbrich, Peter, Ozen, Ahmet, Schmid, Jana Pachlopnik, Picard, Capucine, Prader, Seraina, Rae, William, Reichenbach, Janine, Rusch, Stephan, Savic, Sinisa, Scarselli, Alessia, Scheible, Raphael, Sediva, Anna, Sharapova, Svetlana O., Shcherbina, Anna, Slatter, Mary, Soler-Palacin, Pere, Stanislas, Aurelie, Suarez, Felipe, Tucci, Francesca, Uhlmann, Annette, van Montfrans, Joris, Warnatz, Klaus, Williams, Anthony Peter, Wood, Phil, Kracker, Sven, Condliffe, Alison Mary, Ehl, Stephan, Cathébras, Pascal, Hammarström, Lennart, Milota, Toma, Montfrans, Joris van, and Warnatz, Klau
Subjects: 0301 basic medicine, Oncology, activated phosphoinositide 3-kinase δ syndrome, [SDV]Life Sciences [q-bio], SIROLIMUS, registry, Activated phosphoinositide 3-kinase δ syndrome, Immunology and Allergy, Registries, Young adult, Non-U.S. Gov't, Child, MUTATION, Societies, Medical, ComputingMilieux_MISCELLANEOUS, Research Support, Non-U.S. Gov't, Middle Aged, PIK3R1, 3. Good health, Europe, Settore MED/02, natural history, Child, Preschool, Perspective, Cohort, Sirolimus/therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Immunosuppressive Agents, medicine.drug, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Registry, activated phosphoinositide 3-kinase delta syndrome, Adolescent, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases, Immunology, Natural history, Research Support, Asymptomatic, 03 medical and health sciences, Young Adult, Medical, Internal medicine, Journal Article, medicine, Humans, Rapamycin, Preschool, Sirolimus, Immunologic Deficiency Syndromes/drug therapy, Cytopenia, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bronchiectasis, business.industry, rapamycin, Immunologic Deficiency Syndromes, PIK3CD, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, Primary immunodeficiency, Immunosuppressive Agents/therapeutic use, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Societies, business, lcsh:RC581-607
Abstract: Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies., This study was supported by the German Federal Ministry of Education and Research (BMBF 01E01303). The ESID-APDS registry is supported by the pharmaceutical companies Novartis, GlaxoSmithKline, and UCB UK.
Published: 2018
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11. Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

Author: Tayebeh Soheili, Amandine Durand, Samia Martin, Fernando E. Sepulveda, Chantal Lagresle-Peyrou, Fulvio Mavilio, Julie Rivière, Marina Cavazzana, Isabelle André-Schmutz, Hanem Sadek, Geneviève de Saint Basile, Généthon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biothérapie [CHU Necker], 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), GENETHON (CNRS-FRE3018), GENETHON 3-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association française contre les myopathies (AFM-Téléthon), GENETHON 3, and CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Hemophagocytic lymphohistiocytosis, business.industry, Genetic enhancement, Hematopoietic stem cell, Hematology, Familial Hemophagocytic Lymphohistiocytosis, Gene Therapy, Immune dysregulation, medicine.disease_cause, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Immune system, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, UNC13D, Stem cell, business, ComputingMilieux_MISCELLANEOUS
Abstract: Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)–like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC UNC13D gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8 + T lymphocytes’ cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation.
Published: 2017
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12. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome

Author: Amandine Baptiste, Thibaud Lefebvre, Olivier Ernst, Emmanuelle Chauzit, Jean-Pierre Vannier, Agnès Guerci-Bresler, Christian Rose, Zoubida Karim, Hervé Puy, Aspasia Stamatoullas, Mariane De Montalembert, Valentine Brousse, Krimo Bouabdallah, Mohamed Touati, C. Dumesnil, Agnès Lahary, Marina Cavazzana, Caroline Elie, Jean-Antoine Ribeil, Service de pédiatrie générale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Centre de Référence de la Drépanocytose-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Hôpital Charles Nicolle [Rouen], Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], 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], CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'informatique médicale et biostatistiques [CHU Necker], Radiologie interventionnelle, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie, Hôpital Saint-Vincent-de-Paul, TAN, Yossan-Var, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence de la Drépanocytose, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Blood transfusion, Physiology, Thalassemia, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lcsh:Medicine, 030204 cardiovascular system & hematology, Gastroenterology, Physical Chemistry, Biochemistry, Diagnostic Radiology, 0302 clinical medicine, hemic and lymphatic diseases, Medicine and Health Sciences, Erythropoiesis, 10. No inequality, Child, lcsh:Science, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Chelation, Radiology and Imaging, Heart, Hematology, Middle Aged, Magnetic Resonance Imaging, Sickle cell anemia, Clinical Laboratory Sciences, 3. Good health, [SDV] Life Sciences [q-bio], Chemistry, Genetic Diseases, 030220 oncology & carcinogenesis, Physical Sciences, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Iron Overload, Adolescent, Anemia, Imaging Techniques, Iron, Anemia, Sickle Cell, Research and Analysis Methods, Iron Chelating Agents, 03 medical and health sciences, Autosomal Recessive Diseases, Hepcidin, Diagnostic Medicine, Internal medicine, medicine, Humans, Blood Transfusion, Clinical Genetics, Ferritin, Sickle Cell Disease, Chemical Bonding, business.industry, Transfusion Medicine, Myelodysplastic syndromes, Myocardium, lcsh:R, Biology and Life Sciences, Proteins, Protein Complexes, medicine.disease, Hematopoiesis, Hemoglobinopathies, Myelodysplastic Syndromes, biology.protein, Cardiovascular Anatomy, lcsh:Q, business, Physiological Processes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P
Published: 2017
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13. Gene Therapy in a Patient with Sickle Cell Disease

Author: Bénédicte Neven, Emmanuel Payen, Olivier Negre, Yves Beuzard, Mariane de Montalembert, Pablo Bartolucci, Laure Caccavelli, Thibaud Lefebvre, Robert W. Ross, Laura Sandler, Philippe Leboulch, Stany Chrétien, Michaela Semeraro, Sandeep Soni, Hervé Puy, Salima Hacein-Bey-Abina, Stéphane Blanche, Gabor Istvan Veres, Jean-Antoine Ribeil, Wassim El Nemer, David Grevent, Jean-François Meritet, Philippe Bourget, Alessandra Magnani, Marina Cavazzana, Elisa Magrin, Leslie Weber, Département de Biothérapie [CHU Necker], 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), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'Immunologie [AP-HP Hôpital Kremlin-Bicêtre] (GHU Paris-Sud), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Commission de l'Energie Atomique et Alternative [Fontenay-aux-Roses], Université Paris-Sud - Paris 11 (UP11), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Référence des Syndromes Drépanocytaires Majeurs [AP-HP Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), GR-Ex, Laboratoire d'Excellence, GR-Ex, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], Bluebird bio, Inc, Service de pédiatrie générale [CHU Necker], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Ramathibodi Hospital [Bangkok, Thailand] (Mahidol University), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Payen, Emmanuel, Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Anemia, Genetic enhancement, 03 medical and health sciences, hemic and lymphatic diseases, Internal medicine, medicine, Bluebird Bio, Missense mutation, Adverse effect, ComputingMilieux_MISCELLANEOUS, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Haematopoiesis, 030104 developmental biology, Stem cell, business, Busulfan, medicine.drug
Abstract: Sickle cell disease results from a homozygous missense mutation in the ß-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector-mediated addition of an antisickling ß-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling ß-globin remained high (approximately 50% of ß-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526 .).
Published: 2017
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14. Immune thrombocytopenia in adults: a prospective cohort study of clinical features and predictors of outcome

Author: Anne-Sophie Morin, Marc Michel, Daniel Adoue, Bertrand Godeau, Olivier Fain, Nathalie Costedoat-Chalumeau, Brigitte Pan-Petesch, Nadine Magy-Bertrand, Bernard Bonnotte, Clementine Nordon, Karim Sacre, François Lefrère, Mehdi Khellaf, Jean-François Viallard, Jean-Marc Durand, Lamiae Grimaldi-Bensouda, Lucien Abenhaim, Nathalie Morel, Antoinette Perlat, Philippe Quittet, LASER Paris, CHU Henri Mondor, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Saint-Eloi, Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Morvan [Brest], Service d'Accueil des Urgences (Urgences - Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pontchaillou [Rennes], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biothérapie [CHU Necker], 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), Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hopital de Périgueux (CH Périgueux), Hopital de Périgueux, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Médecine Interne [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de médecine interne et immunologie clinique (SOC 1) [CHU de Dijon], Service d'ORL et de chirurgie cervicale, CHU Grenoble, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), London School of Hygiene and Tropical Medicine (LSHTM), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), HAL UPMC, Gestionnaire, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint Eloi (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], CHU Henri Mondor [Créteil], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole ( IUCT Oncopole - UMR 1037 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Médecine interne [CHU St-Antoine], CHU Saint-Antoine [APHP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Hôpital Jean Verdier, CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Service d'Accueil des Urgences ( Urgences - Henri Mondor ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri-Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP]
Subjects: Adult, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Anti-nuclear antibody, Adolescent, [SDV]Life Sciences [q-bio], Logistic regression, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Odds Ratio, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Humans, Prospective Studies, Registries, Risk factor, Young adult, Family history, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Aged, Purpura, Thrombocytopenic, Idiopathic, business.industry, Disease Management, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Odds ratio, Articles, Middle Aged, 3. Good health, Surgery, Patient Outcome Assessment, Phenotype, 030220 oncology & carcinogenesis, Population Surveillance, Female, France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, Cohort study, Follow-Up Studies
Abstract: for the PGRx-ITP Study Group; International audience; This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10×109/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome.
Published: 2016
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15. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

Author: Jacek Majewski, Marielle E. van Gijn, Alain Fischer, Geneviève de Saint Basile, Capucine Picard, Nada Jabado, Els Verhoeyen, Sonia Luce, Tayebeh Soheili, Nathalie Lambert, Amandine Durand, Armelle Bohineust, Claire Hivroz, Virginie Gandemer, Farid Ouchani, Chantal Brouzes, Catherine Heijmans, Anne Durandy, Isabelle Pic, Myriam Chouteau, Marina Cavazzana, Virgil A. S. H. Dalm, Nizar Mahlaoui, Aude Magerus-Chatinet, François-Loïc Cosset, Isabelle André-Schmutz, Delphine Monnier, Sven Kracker, Chantal Lagresle-Peyrou, Jean-Louis Stephan, Frédéric Rieux-Laucat, Hanem Sadek, Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), McGill University and Genome Quebec Innovation Centre, CHU Necker - Enfants Malades [AP-HP], Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants - Reine Fabiola, Dpt of Genetics [Utrecht], University Medical Center [Utrecht], Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], CHU Saint-Etienne, the Genome Quebec Innovation Centre, McGill University, Collège de France (CdF), French National Research Agency, French National Institute of Health and Medical Research (INSERM), La Ligue contre le Cancer and La Fondation ARC pour la Recherche sur le Cancer, Université Paris Descartes - Paris 5 (UPD5)-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), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CIC-BT 502 INSERM, Departement de Biotherapie, Laboratoire d'hématologie ( ERL 8254 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire ( HITC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-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) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-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)-Centre National de la Recherche Scientifique (CNRS), Immunology, and Internal Medicine
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Moesin, Immunology, Nonsense mutation, macromolecular substances, CD8-Positive T-Lymphocytes, Biology, Infections, primary immunodeficiency, migration, medicine.disease_cause, ezrin-radixin-moesin protein, Hypogammaglobulinemia, 03 medical and health sciences, Cell Movement, Radixin, Cell Adhesion, Journal Article, medicine, Humans, Immunology and Allergy, Missense mutation, Lymphocyte Count, Child, moesin, Genetic Association Studies, Immunodeficiency, Aged, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, Microfilament Proteins, Immunologic Deficiency Syndromes, Leukopenia, medicine.disease, Pedigree, 3. Good health, adhesion, 030104 developmental biology, Child, Preschool, Cancer research, Primary immunodeficiency, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.
Published: 2016
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16. Hsp70 est un nouveau régulateur majeur de l'érythropoïèse empêchant le clivage du facteur de transcription GATA-1 par la caspase-3 au cours de la différenciation

Author: Ribeil , Jean-Antoine, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biothérapie [CHU Necker], 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), Université Paris-Diderot - Paris VII, Olivier Hermine, CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP]
Subjects: Erythropoïèse, [ SDV ] Life Sciences [q-bio], Caspase-3, [SDV]Life Sciences [q-bio], Erythropoiesis, Erythropoïétine, Erythropoietin, GATA-1, Hsp70
Abstract: Red blood cells production depends on apoptosis rate of erythroid precursors. This process is mainly regulated by the erythropoietin (Epo). Thus, Epo starvation results in caspase-3 (casp-3) activation and as a consequence GATA-1 is cleaved and apoptosis of immature erythroblasts occurs. Casp-3 activation is also absolutely required for the morphological changes that occur during normal human terminal erythroid differentiation. In this context, although that caspase-3 is activated, apoptosis and GATA-1 cleavage do not occur. The aim of this thesis, was to study if the inducible form of Hsp70 which is chaperon protein that play a major role as a modulator of apoptosis. Here, we show that inducible Hsp70 is constituvely expressed during human terminal erythroid differentiation, in both nuclear and cytoplasmic erythroblast compartments. Hsp70 and co-localizes with GATA-1 in the nucleus at the onset of caspases activation during terminal erythroid differentiation. Hsp70 nuclear localization is regulated by Epo: after Epo starvation, while Hsp70 nuclear localization is lost, GATA-1 is cleaved. Transfection of siRNA Hsp70, reduces significantly Hsp 70 expression, and is associated with GATA-1 cleavage at the onset of casp-3 activation occuring during erythroid differentiation. Hsp70 inhibition leads to stop differentiation and increase cell death. Therefore, Hsp70 exerts a new critical anti-apoptotic role during terminal erythropoiesis. We propose a model in which, Epo determines the fate of erythroblasts (apoptosis vs. differentiation) downstream of casp-3 activation by regulating the nuclear localization of Hsp70.; La production de globules rouges dépend du taux apoptose des précurseurs érythroïdes et est principalement régulé par l'érythropoïétine (Epo). La privation en Epo aboutit à l'activation de la caspase-3 (casp-3) qui clive GATA-1 ce qui entraîne l'apoptose des érythroblastes immatures. L'activation de la casp-3 est également indispensable aux modifications morphologiques caractéristiques observées au cours de la différenciation érythroïde terminale humaine, sans qu'il n'y ait ni d'apoptose ni de clivage de GATA-1. L'objectif de cette thèse était de mettre en évidence si Hsp70 inductible, dont un des rôles principaux est la régulation de l'apoptose, est impliquée dans la protection sélective des substrats de la casp-3 activée au cours de la différenciation érythroïde terminale humaine. Nous avons mis en évidence que lors de la différentiation érythroïde terminale pendant la phase d'activation des caspases, Hsp70 a une expression nucléo-cytoplasmique constitutive et co-localise avec GATA-1 dans le noyau. La localisation nucléaire d'Hsp70 est régulée par l'Epo : après privation des cellules en Epo, il y a une importante diminution de la localisation nucléaire d'Hsp70 et GATA-1 est clivée. L'inhibition de l'expression d'Hsp70 par une approche siRNA a comme conséquence le clivage de GATA-1 lors de l'activation de la casp-3 avec un arrêt de différenciation et une augmentation de la mort cellulaire. Hsp70 est une nouvelle protéine anti-apoptotique de la différenciation érythroïde terminale. Nous proposons un modèle dans lequel l'Epo détermine le destin des érythroblastes (apoptose vs différenciation) en aval de la casp-3 en régulant la localisation nucléaire d'Hsp70.
Published: 2010

17. Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy

Author: Ulrich Abel, Céline Bellesme, Denice Mittelstaedt, Christof von Kalle, Bruno l’Homme, Gabor Istvan Veres, Nizar Mahlaoui, Najiba Lahlou, Patrick Aubourg, Ina Kutschera, Stéphane Blanche, Emmanuel Payen, Salima Hacein-Bey-Abina, Laure Caccavelli, Manfred Schmidt, Marina Cavazzana-Calvo, Liliane Dal-Cortivo, Nathalie Cartier, François Lefrère, Philippe Leboulch, Muriel Audit, Michel Vidaud, Pierre Bougnères, Cynthia C. Bartholomae, Veronique Kiermer, Alain Fischer, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biothérapie [CHU Necker], 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), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire du D eveloppement Normal et Pathologique du Syst eme Immunitaire, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Vincent de Paul, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Bluebird bio, Inc, National Referral Center for Rare Epilepsies - Department of Pediatric Neurology, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Nature Publishing Group, Nature Publishing Group, New York, Oregon State University (OSU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute for Radiological Protection and Nuclear Safety, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -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 ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Immunologie et chimie thérapeutiques ( ICT ), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut des Maladies Emergentes et des Thérapies Innovantes ( IMETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Thérapie génique et contrôle de l'expansion cellulaire ( UMR E007 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Transplantation Conditioning, Genetic enhancement, CD34, Gene Expression, ATP Binding Cassette Transporter, Subfamily D, Member 1, Cell therapy, Mice, 0302 clinical medicine, Transduction, Genetic, Adrenoleukodystrophy, Child, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Fatty Acids, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell, Brain, Cell Differentiation, 3. Good health, Haematopoiesis, medicine.anatomical_structure, Disease Progression, Female, Microglia, Stem cell, Virus Integration, Genetic Vectors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Transplantation, Autologous, 03 medical and health sciences, medicine, Animals, Humans, Cell Lineage, 030304 developmental biology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Genetic Therapy, Myeloablative Agonists, medicine.disease, Hematopoietic Stem Cells, Hematopoiesis, Transplantation, Immunology, HIV-1, Leukocytes, Mononuclear, ATP-Binding Cassette Transporters, 030217 neurology & neurosurgery
Abstract: Slowing Brain Disease with Gene Therapy X-linked adrenoleukodystrophy (ALD), the hereditary brain demyelinating disorder that was featured in the movie “ Lorenzo's Oil ,” is typically treated by transplantation of bone marrow from matched donors. This treatment slows progression of the disease by introducing cells that differentiate into myelin-producing cells. Cartier et al. (p. 818 ; see Perspective by Naldini ) tested an alternative gene therapy–based approach in two young patients without matched donors. A lentiviral vector was used to introduce a wild-type copy of the ALD gene into the patients' hematopoietic stem cells ex vivo. The modified cells were then infused back into the patients. Expression of the transferred gene was still detectable in the patients' blood cells 2 years later, and both patients showed neurological improvement and a delay in disease progression comparable to that seen with bone marrow transplants.
Published: 2009
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18. Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells

Author: Pierre Charneau, Julia Hauer, Julie Rivière, Marc Le Lorc'h, Jean-Pierre de Villartay, Pauline Soulas-Sprauel, Anne Galy, Michèle Malassis-Séris, Johanna Blondeau, Alexandrine Garrigue, Alain Fischer, Frederique Pâques, Nicole Brousse, Marina Cavazzana-Calvo, Serge Romana, Fatine Benjelloun, Daniel Stockholm, Annick Lim, Corinne Demerens-de Chappedelaine, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Généthon, Développement des Lymphocytes, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Histologie-Embryologie et Cytogénétique Assistance Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et Cytologie Pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Cellectis SA, CELLECTIS, Virologie moléculaire et Vectorologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Unité d'Immunologie et Hématologie Pédiatrique, Service d'Hématologie, Département de Biothérapie [CHU Necker], 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), This work was funded by grants from Institut National de la Santé et de la Recherche (INSERM), the Association Française contre les Myopathies (AFM) contract GAT0203, the Consortium National de Recherche en Génomique, the EC contract QLK3-CT-1999-00859, the Consert contract no. 005242, the Inherinet contract QLK3-CT-2001-00427, the Agence Nationale de la Recherche grant 05-MRAR-004, and a grant from Amgen-France (M. de Garidel and C. Cailliot). F.B.'s fellowship was provided by the AFM. P.S.S. was supported by INSERM, Electricité de France, and the Fondation Singer Polignac. J.H. is a fellow of the Deutsche Akademie der Naturforscher Leopoldina (BMBF-LPD 9901/8-149), Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Genethon, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Male, CD3 Complex, MESH: Antigens, CD3, Genetic enhancement, T-Lymphocytes, MESH: Interleukin-2 Receptor alpha Subunit, MESH: Antigens, CD4, MESH: Flow Cytometry, MESH: Mice, Knockout, MESH: Hematopoietic Stem Cells, Mice, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Genetic Vectors, Transduction, Genetic, Chromosome instability, MESH : Antigens, CD44, Drug Discovery, MESH : Female, MESH: Animals, Cells, Cultured, MESH: Lentivirus, Mice, Knockout, 0303 health sciences, B-Lymphocytes, Hematopoietic Stem Cell Transplantation, Nuclear Proteins, MESH : Interleukin-2 Receptor alpha Subunit, MESH: Transduction, Genetic, Flow Cytometry, MESH : Genetic Vectors, 3. Good health, Haematopoiesis, MESH : Lentivirus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Hyaluronan Receptors, 030220 oncology & carcinogenesis, Knockout mouse, CD4 Antigens, [SDV.IMM]Life Sciences [q-bio]/Immunology, Molecular Medicine, Female, Stem cell, MESH : Gene Therapy, MESH: Cells, Cultured, MESH : Flow Cytometry, MESH : Male, CD8 Antigens, Genetic Vectors, MESH : Severe Combined Immunodeficiency, MESH: Severe Combined Immunodeficiency, MESH : Transduction, Genetic, Thymus Gland, Biology, MESH: Antigens, CD44, MESH : B-Lymphocytes, Viral vector, 03 medical and health sciences, MESH : Hematopoietic Stem Cell Transplantation, MESH: B-Lymphocytes, MESH : Mice, MESH : Cells, Cultured, Genetics, medicine, Animals, MESH : Thymus Gland, Molecular Biology, MESH: Mice, MESH: Hematopoietic Stem Cell Transplantation, 030304 developmental biology, MESH : T-Lymphocytes, Pharmacology, Severe combined immunodeficiency, MESH : Hematopoietic Stem Cells, Lentivirus, Interleukin-2 Receptor alpha Subunit, MESH : Nuclear Proteins, MESH: Thymus Gland, Genetic Therapy, medicine.disease, Endonucleases, Hematopoietic Stem Cells, MESH: Male, Transplantation, MESH: T-Lymphocytes, Immunology, Cancer research, MESH : Mice, Knockout, MESH : Antigens, CD4, Severe Combined Immunodeficiency, MESH : Animals, MESH : Antigens, CD3, MESH: Antigens, CD8, MESH: Gene Therapy, MESH : Antigens, CD8, MESH: Nuclear Proteins, MESH: Female
Abstract: International audience; Patients with mutations in the Artemis gene display a complete absence of T- and B lymphocytes, together with increased cellular radiosensitivity; this leads to a radiosensitive severe combined immunodeficiency (RS-SCID). Allogenic hematopoietic stem-cell (HSC) transplantation is only partially successful in the absence of an human leukocyte antigen-genoidentical donor, and this has prompted a search for alternative therapeutic approaches such as gene therapy. In this study, a self-inactivated lentiviral vector expressing Artemis was used to complement the Artemis knockout mouse (Art(-/-)). Transplantation of Artemis-transduced HSCs into irradiated Art(-/-) mice restored a stable (over a 15-month period of follow-up) and functional T- and cell repertoire that was comparable to that of control mice. The success of secondary transplantations demonstrated that the HSCs had been transduced. One of thirteen mice developed a thymoma 6 months after gene therapy. Although thymic cells were seen to be carrying two lentiviral integration sites, there was no evidence of lentivirus-driven oncogene activation. The Art(-/-) mice were found to be prone to develop T-cell lymphomas, either spontaneously or after irradiation. These data indicate that the observed lymphoproliferation was probably the consequence of the chromosomal instability associated with the Artemis-deficient background. As a whole, our work provides a basis for supporting the gene therapy approach in Artemis-deficient SCID.
Published: 2008
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19. Serum-free culture medium and IL-7 costimulation increase the sensitivity of ELISpot detection

Author: Emanuela Martinuzzi, Matthieu Scotto, Vedran Brezar, Peter van Endert, Jean-Antoine Ribeil, Emmanuelle Énée, Roberto Mallone, Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biothérapie [CHU Necker], 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), Mallone, Roberto, 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), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP]
Subjects: Male, medicine.medical_treatment, Cell Culture Techniques, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, Culture Media, Serum-Free, Epitope, 0302 clinical medicine, Insulin-Secreting Cells, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, ELISPOT, Antibodies, Monoclonal, Middle Aged, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Cytokine, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, Enzyme-Linked Immunosorbent Assay, Statistics, Nonparametric, Interferon-gamma, 03 medical and health sciences, Immune system, CD28 Antigens, HLA-A2 Antigen, medicine, Humans, Aged, 030304 developmental biology, business.industry, Interleukin-7, T lymphocyte, Diabetes Mellitus, Type 1, biology.protein, Interleukin-2, business, CD8, 030215 immunology
Abstract: International audience; The identification of parameters maximizing detection sensitivity in ELISpot assays is important to transfer this technology into the clinical setting for identifying rare Ag-specific CD8(+) T cells. We have therefore considered human IFN-gamma CD8(+) T cell responses against viral epitopes to analyze different variables which could be critical during the epitope-specific stimulation period. Two parameters were found to greatly enhance detection sensitivity (i.e., to specifically increase epitope-driven signal while keeping background noise to a minimum): use of human serum-free vs. serum-supplemented culture medium (2.4-fold median increase) and addition of low dose IL-7 (1.5-fold increase). Incorporating both of these parameters into the ELISpot procedure proved capable of greatly amplifying (35.1-fold increase) the low grade CD8(+) T cell responses directed against beta-cell epitopes of type 1 diabetes patients, as compared to a previously optimized procedure using human serum-supplemented medium and low dose IL-2. Implementation of this ELISpot procedure should expedite development of "immune staging" protocols for autoimmune as well as tumor and infectious diseases.
Published: 2008
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20. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients

Author: Alain Fischer, Pierre Charneau, Chantal Lagresle-Peyrou, Monique Forveille, Kheira Beldjord, Christophe Hue, Fatine Benjelloun, Marina Cavazzana-Calvo, Isabelle André-Schmutz, Salima Hacein-Bey-Abina, Delphine Bonhomme, Jean-Pierre de Villartay, Anne Durandy, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cythéris, Laboratoire d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Biothérapie [CHU Necker], 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), Service d'Hématologie, Virologie moléculaire et Vectorologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Hématologie Pédiatriques, This work was supported by grants from INSERM, Association Française contre les Myopathies (AFM) contract GAT0203, Consortium National de Recherche en Génomique, EC contract QLK3-CT-1999-00859, Consert no. 005242, Inherinet contract QLK3-CT-2001-00427, Agene nationale de la recherche 05-MRAR-004 and Amgen-France, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 ( UPD5 ) -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)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH: Mice, Inbred NOD, Genetic enhancement, CD34, Antigens, CD34, Mice, SCID, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, Mice, Inbred NOD, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Drug Discovery, MESH: Animals, MESH : Homeodomain Proteins, MESH: Mice, SCID, MESH: Bone Marrow Transplantation, Bone Marrow Transplantation, MESH: Lentivirus, B-Lymphocytes, 0303 health sciences, biology, MESH: Bone Marrow Cells, Antibodies, Monoclonal, Nuclear Proteins, Cell Differentiation, MESH: Immunoglobulin M, 3. Good health, DNA-Binding Proteins, MESH: Interleukin-2 Receptor beta Subunit, MESH : Lentivirus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH : Antibodies, Monoclonal, 030220 oncology & carcinogenesis, MESH : Antigens, CD34, Molecular Medicine, Antibody, MESH : Cell Differentiation, MESH: Cell Differentiation, MESH : Immunoglobulin M, Bone Marrow Cells, Human leukocyte antigen, Recombination-activating gene, MESH : B-Lymphocytes, 03 medical and health sciences, Antigen, MESH: B-Lymphocytes, MESH : Mice, MESH: Homeodomain Proteins, Genetics, medicine, Animals, Humans, Molecular Biology, MESH: Mice, MESH : Interleukin-2 Receptor beta Subunit, 030304 developmental biology, Homeodomain Proteins, Pharmacology, Severe combined immunodeficiency, MESH: Humans, MESH : Mice, Inbred NOD, Lentivirus, MESH : Humans, MESH : Nuclear Proteins, MESH : Bone Marrow Transplantation, MESH: Antigens, CD34, Endonucleases, medicine.disease, MESH : Mice, SCID, Interleukin-2 Receptor beta Subunit, Transplantation, Immunoglobulin M, Immunology, biology.protein, Cancer research, MESH : Animals, MESH: Nuclear Proteins, MESH : Bone Marrow Cells
Abstract: International audience; Severe combined immunodeficiency (SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34(+) cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis-transduced cells, human B-cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.
Published: 2008
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21. Outcomes Following Gene Therapy in Patients With Severe Wiskott-Aldrich Syndrome

Author: Havinder Hara, Frances Male, Christine Rivat, Nirav Malani, Fulvio Mavilio, Jinhua Xu-Bayford, Sabine Charrier, Jean-Marc Tréluyer, Anne-Marie McNicol, Laure Caccavelli, Karen F. Buckland, Geraldine Honnet, Anne Galy, H. Bobby Gaspar, François Lefrère, Jeremy Magalon, Adrian J. Thrasher, Sébastien Héritier, Marina Cavazzana, Frederic D. Bushman, Emmanuelle Six, Nourredine Himoudi, Salima Hacein-Bey Abina, Johanna Blondeau, Isabelle Pengue-Koyi, Kimberly Gilmour, Alain Fischer, Annick Lim, Charles C. Berry, Stéphane Blanche, Fabien Touzot, Eric A. Sherman, Capucine Picard, Département de Biothérapie [CHU Necker], 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), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), University College of London [London] (UCL), NHS Foundation Trust [London], The Royal Marsden, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Généthon, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], University of Pennsylvania [Philadelphia], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), This study was sponsored by Genethon, Evry, France., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), University of Pennsylvania, and Collège de France - Chaire Médecine expérimentale (A. Fischer)
Subjects: Male, Myeloid, Wiskott–Aldrich syndrome, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Gene Expression, Hematopoietic stem cell transplantation, Severity of Illness Index, 0302 clinical medicine, MESH: Genetic Vectors, MESH: Child, Medicine, Child, MESH: Lentivirus, 0303 health sciences, MESH: Infant, Newborn, Hematopoietic Stem Cell Transplantation, General Medicine, MESH: Infant, Wiskott-Aldrich Syndrome, 3. Good health, MESH: Wiskott-Aldrich Syndrome, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Adolescent, Feasibility Studies, Humans, Infant, Infant, Newborn, Wiskott-Aldrich Syndrome Protein Family, Genetic Therapy, Genetic Vectors, Lentivirus, medicine.medical_specialty, MESH: Gene Expression, 03 medical and health sciences, MESH: Severity of Illness Index, Internal medicine, Severity of illness, Preschool, MESH: Hematopoietic Stem Cell Transplantation, 030304 developmental biology, MESH: Adolescent, MESH: Genetic Therapy, Severe combined immunodeficiency, MESH: Humans, business.industry, MESH: Child, Preschool, Newborn, medicine.disease, Comorbidity, MESH: Male, Surgery, Transplantation, MESH: Wiskott-Aldrich Syndrome Protein Family, Primary immunodeficiency, MESH: Feasibility Studies, business
Abstract: International audience; IMPORTANCE: Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen-matched allogeneic hematopoietic stem cell (HSC) transplantation is often curative but is associated with significant comorbidity. OBJECTIVE: To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome. DESIGN, SETTING, AND PARTICIPANTS: Gene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months. INTERVENTION: A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector. MAIN OUTCOMES AND MEASURES: Primary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis. RESULTS: Six of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis. CONCLUSIONS AND RELEVANCE: This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.
Published: 2015
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22. Competition within the early B-cell compartment conditions B-cell reconstitution after hematopoietic stem cell transplantation in nonirradiated recipients

Author: Chantal Lagresle-Peyrou, Christophe Hue, Marina Cavazzana-Calvo, Alain Fischer, Allen Liu, Michèle Malassis-Séris, Christian A. J. Vosshenrich, James P. Di Santo, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytokines et Développement Lymphoïde, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Supported by grants from INSERM, the Institut Pasteur, Ligue National Contre le Cancer, Ministère de la Recherche, and the Contrat Européen Consert 'Concerted Safety and Efficiency Evaluation of Retroviral Transgenesis in Gene Therapy of Inherited Diseases' (contract no. LSHB-CT-2004-005242, coordinator, G. Wagemaker). A.L. received a fellowship from Harvard University., Vosshenrich, Christian, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Transplantation Conditioning, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], Hematopoietic stem cell transplantation, Biochemistry, MESH: Hematopoietic Stem Cells, 0302 clinical medicine, b-lymphocytes, MESH: Animals, donors, MESH: Transplantation Conditioning, 0303 health sciences, Cell Differentiation, Hematology, severe combined immunodeficiency, Killer Cells, Natural, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, hematopoietic stem cell transplantation, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Transplantation Chimera, MESH: Cell Differentiation, MESH: Killer Cells, Natural, mice, bone marrow, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, MESH: Severe Combined Immunodeficiency, Biology, 03 medical and health sciences, MESH: B-Lymphocytes, medicine, Homologous chromosome, MESH: Transplantation, Homologous, Animals, Humans, Transplantation, Homologous, MESH: Mice, B cell, MESH: Hematopoietic Stem Cell Transplantation, 030304 developmental biology, Severe combined immunodeficiency, Transplantation Chimera, MESH: Humans, Compartment (ship), Cell Biology, medicine.disease, Hematopoietic Stem Cells, Transplantation, MESH: T-Lymphocytes, Bone marrow, 030215 immunology
Abstract: International audience; Severe combined immunodeficiency (SCID) is characterized by a complete block in T-lymphocyte differentiation. Most SCID also affects B-cell development or function, although a normal pool of pro-B cells is detectable. Treatment of SCID consists of allogeneic hematopoietic stem cell transplantation (HSCT), but in the absence of a myeloablative conditioning regimen, only T cells, and in some cases, natural killer (NK) cells, are of donor origin, while all other leukocytes subsets are of host origin. We hypothesized that donor B-cell development success could be conditioned by the competitive ability of recipient B-cell precursors in the bone marrow. We therefore compared the outcome of unconditioned HSCT in mice that differed with respect to their pro-B-cell compartments. B-cell reconstitution was limited in recipient mice containing a normal pro-B-cell pool, whereas immature and mature B-cell numbers reached wild-type levels in mice with compromised early B-cell precursors. Interestingly, host NK cells did not modify the outcome of unconditioned HSCT as long as the early B-cell compartment was compromised. These observations suggest that recipient B-cell precursors condition the reconstitution of the donor B-cell pool and, if extrapolative to humans, suggest that conditioning regimens targeting host pro-B cells may help improve B-cell reconstitution after allogeneic HSCT.
Published: 2006
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22 results on '"Département de Biothérapie [CHU Necker]"'

1. Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

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

3. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

4. Primary Hyperparathyroidism in Sickle Cell Disease: An Unknown Complication of the Disease in Adulthood

5. Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma

6. Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency

7. Loss of ARHGEF1 causes a human primary antibody deficiency

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

9. A clinical trial combining megakaryocytes and haematopoietic stem cells to promote engraftment after autologous transplantation

10. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

11. Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

12. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome

13. Gene Therapy in a Patient with Sickle Cell Disease

14. Immune thrombocytopenia in adults: a prospective cohort study of clinical features and predictors of outcome

15. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

16. Hsp70 est un nouveau régulateur majeur de l'érythropoïèse empêchant le clivage du facteur de transcription GATA-1 par la caspase-3 au cours de la différenciation

17. Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy

18. Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells

19. Serum-free culture medium and IL-7 costimulation increase the sensitivity of ELISpot detection

20. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients

21. Outcomes Following Gene Therapy in Patients With Severe Wiskott-Aldrich Syndrome

22. Competition within the early B-cell compartment conditions B-cell reconstitution after hematopoietic stem cell transplantation in nonirradiated recipients

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