title: Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?
abstract: More than 20 years ago, X-linked severe combined immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. This gene therapy has successfully enabled correction of the T cell defect. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.
authors.affiliation: 1 Biotherapy Department, Necker Children's Hospital , Assistance Publique-Hôpitaux de Paris, Paris.|2 Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest , Assistance Publique-Hôpitaux de Paris, INSERM, Paris.|3 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute , Paris.|4 INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis , Paris.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: 2 Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest , Assistance Publique-Hôpitaux de Paris, INSERM, Paris.|3 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute , Paris.|4 INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis , Paris.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Six
authors.affiliation: 2 Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest , Assistance Publique-Hôpitaux de Paris, INSERM, Paris.|3 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute , Paris.|4 INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis , Paris.
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.affiliation: 2 Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest , Assistance Publique-Hôpitaux de Paris, INSERM, Paris.|3 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute , Paris.|4 INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis , Paris.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
authors.affiliation: 1 Biotherapy Department, Necker Children's Hospital , Assistance Publique-Hôpitaux de Paris, Paris.|2 Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest , Assistance Publique-Hôpitaux de Paris, INSERM, Paris.|5 UTCBS CNRS 8258-INSERM U1022, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes , Paris.|6 Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud , AP-HP, Le-Kremlin-Bicêtre, France .
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002986:Clinical Trials as Topic; D017988:Gammaretrovirus / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000737:chemistry* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D016086:Lentivirus / Q000235:genetics* / Q000276:immunology; D061214:Patient Safety; D012190:Retroviridae / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016662:Virus Integration / Q000235:genetics; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*