Salima Hacein-Bey Abina1, H Bobby Gaspar2, Johanna Blondeau3, Laure Caccavelli3, Sabine Charrier4, Karen Buckland2, Capucine Picard5, Emmanuelle Six6, Nourredine Himoudi2, Kimberly Gilmour2, Anne-Marie McNicol2, Havinder Hara2, Jinhua Xu-Bayford7, Christine Rivat2, Fabien Touzot8, Fulvio Mavilio9, Annick Lim10, Jean-Marc Treluyer11, Sébastien Héritier12, Francois Lefrère13, Jeremy Magalon3, Isabelle Pengue-Koyi8, Géraldine Honnet9, Stéphane Blanche12, Eric A Sherman14, Frances Male14, Charles Berry14, Nirav Malani14, Frederic D Bushman14, Alain Fischer15, Adrian J Thrasher2, Anne Galy4, Marina Cavazzana8. 1. 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. 2. 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. 3. 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. 4. INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France. 5. 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. 6. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematopoiesis, Paris, France. 7. Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England. 8. 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. 9. Genethon, Evry, France. 10. Groupe Immunoscope, Immunology Department, Institut Pasteur, Paris, France. 11. Clinical Research Center Necker-Enfants Malades and Cochin Hospital Assistance Publique-Hôpitaux de Paris, Paris Descartes University. 12. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France. 13. Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 14. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia. 15. 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.
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.
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 toxicitywas 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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