title: Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.
  
  
  METHODS
  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
  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.
authors.affiliation: 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.
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey Abina
authors.affiliation: 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.
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.affiliation: 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.
authors.forename: Johanna
authors.initials: J
authors.lastname: Blondeau
authors.affiliation: 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.
authors.forename: Laure
authors.initials: L
authors.lastname: Caccavelli
authors.affiliation: INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Charrier
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Buckland
authors.affiliation: 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.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Six
authors.affiliation: 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.
authors.forename: Nourredine
authors.initials: N
authors.lastname: Himoudi
authors.affiliation: 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: 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.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: McNicol
authors.affiliation: 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.
authors.forename: Havinder
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xu-Bayford
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Rivat
authors.affiliation: 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.
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.affiliation: Genethon, Evry, France.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.affiliation: Groupe Immunoscope, Immunology Department, Institut Pasteur, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.affiliation: Clinical Research Center Necker-Enfants Malades and Cochin Hospital Assistance Publique-Hôpitaux de Paris, Paris Descartes University.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Héritier
authors.affiliation: Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Lefrère
authors.affiliation: 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.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Magalon
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pengue-Koyi
authors.affiliation: Genethon, Evry, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Honnet
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sherman
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Frances
authors.initials: F
authors.lastname: Male
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Charles
authors.initials: C
authors.lastname: Berry
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Nirav
authors.initials: N
authors.lastname: Malani
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: 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.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.affiliation: 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.
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authors.lastname: Cavazzana
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005240:Feasibility Studies; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016086:Lentivirus; D008297:Male; D012720:Severity of Illness Index; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics*
chemical_list: D051300:Wiskott-Aldrich Syndrome Protein Family