1. Outcomes Following Gene Therapy in Patients With Severe Wiskott-Aldrich Syndrome
- Author
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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)
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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.
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- 2015