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Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.
Hacein-Bey Abina, Salima; Gaspar, H Bobby; Blondeau, Johanna; Caccavelli, Laure; Charrier, Sabine; Buckland, Karen; Picard, Capucine; Six, Emmanuelle; Himoudi, Nourredine; Gilmour, Kimberly; McNicol, Anne-Marie; Hara, Havinder; Xu-Bayford, Jinhua; Rivat, Christine; Touzot, Fabien; Mavilio, Fulvio; Lim, Annick; Treluyer, Jean-Marc; Héritier, Sébastien; Lefrère, Francois; Magalon, Jeremy; Pengue-Koyi, Isabelle; Honnet, Géraldine; Blanche, Stéphane; Sherman, Eric A; Male, Frances; Berry, Charles; Malani, Nirav; Bushman, Frederic D; Fischer, Alain; Thrasher, Adrian J; Galy, Anne; Cavazzana, Marina.
Afiliación
  • Hacein-Bey Abina S; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France3Unité de.
  • Gaspar HB; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Blondeau J; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
  • Caccavelli L; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
  • Charrier S; INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France.
  • Buckland K; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Picard C; Centre d'Étude des Déficits Immunitaires, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France10Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Departmen.
  • Six E; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.
  • Himoudi N; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Gilmour K; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • McNicol AM; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Hara H; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Xu-Bayford J; Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Rivat C; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Touzot F; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France10Paris D.
  • Mavilio F; Genethon, Evry, France.
  • Lim A; Groupe Immunoscope, Immunology Department, Institut Pasteur, Paris, France.
  • Treluyer JM; Clinical Research Center Necker-Enfants Malades and Cochin Hospital Assistance Publique-Hôpitaux de Paris, Paris Descartes University.
  • Héritier S; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Lefrère F; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Magalon J; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
  • Pengue-Koyi I; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France10Paris D.
  • Honnet G; Genethon, Evry, France.
  • Blanche S; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Sherman EA; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
  • Male F; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
  • Berry C; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
  • Malani N; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
  • Bushman FD; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
  • Fischer A; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematop.
  • Thrasher AJ; Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
  • Galy A; INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France.
  • Cavazzana M; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France10Paris D.
JAMA ; 313(15): 1550-63, 2015 Apr 21.
Article en En | MEDLINE | ID: mdl-25898053
ABSTRACT
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Síndrome de Wiskott-Aldrich / Terapia Genética / Lentivirus / Trasplante de Células Madre Hematopoyéticas / Familia de Proteínas del Síndrome de Wiskott-Aldrich / Vectores Genéticos Tipo de estudio: Clinical_trials Límite: Adolescent / Child / Child, preschool / Humans / Infant / Male / Newborn Idioma: En Revista: JAMA Año: 2015 Tipo del documento: Article
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Síndrome de Wiskott-Aldrich / Terapia Genética / Lentivirus / Trasplante de Células Madre Hematopoyéticas / Familia de Proteínas del Síndrome de Wiskott-Aldrich / Vectores Genéticos Tipo de estudio: Clinical_trials Límite: Adolescent / Child / Child, preschool / Humans / Infant / Male / Newborn Idioma: En Revista: JAMA Año: 2015 Tipo del documento: Article