This will interest anyone who watches this thread....
jama.jamanetwork.com
JAMA. 2015;313(15):1550-1563. doi:10.1001/jama.2015.3253.
Preliminary Communication | April 21, 2015
Outcomes Following Gene Therapy in Patients With Severe Wiskott-Aldrich Syndrome
Salima Hacein-Bey Abina, PharmD, PhD1,2,3,4; H. Bobby Gaspar, MRCP, PhD5,6; Johanna Blondeau, MS1,2; Laure Caccavelli, PhD1,2; Sabine Charrier, PhD7,8; Karen Buckland, PhD5,6; Capucine Picard, MD, PhD9,10,11; Emmanuelle Six, PhD10,12; Nourredine Himoudi, PhD5,6; Kimberly Gilmour, PhD5,6; Anne-Marie McNicol, PhD5,6; Havinder Hara, MS5,6; Jinhua Xu-Bayford, DipHE6; Christine Rivat, PhD5,6; Fabien Touzot, MD, PhD1,2,10,11; Fulvio Mavilio, PhD8; Annick Lim, MS13; Jean-Marc Treluyer, MD, PhD14; Sébastien Héritier, MD10,11; Francois Lefrère, MD1; Jeremy Magalon, PharmD1,2; Isabelle Pengue-Koyi, PharmD, PhD1,2,10; Géraldine Honnet, MD8; Stéphane Blanche, MD10,11; Eric A. Sherman, BA15; Frances Male, BA15; Charles Berry, PhD15; Nirav Malani, MS15; Frederic D. Bushman, PhD15; Alain Fischer, MD, PhD10,11,12,16; Adrian J. Thrasher, MB, BS, PhD5,6; Anne Galy, PhD7,8; Marina Cavazzana, MD, PhD1,2,10,12
1Biotherapy Department, Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique–Hôpitaux de Paris, INSERM, Paris, France
3Unité de Technologies Chimiques et Biologiques pour la Santé, Centre National de la Recherche Scientifique 8258, INSERM U1022, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
4Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Assistance Publique–Hôpitaux de Paris, Paris, France
5Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England
6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England
7INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France
8Genethon, Evry, France
9Centre d’Étude des Déficits Immunitaires, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Paris, France
10Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France
11Immunology and Pediatric Hematology Department, Assistance Publique–Hôpitaux de Paris, Paris, France
12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematopoiesis, Paris, France
13Groupe Immunoscope, Immunology Department, Institut Pasteur, Paris, France
14Clinical Research Center Necker–Enfants Malades and Cochin Hospital Assistance Publique–Hôpitaux de Paris, Paris Descartes University
15Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia
16Collège de France, Paris
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. |
