title: Gene therapy for severe combined immunodeficiencies.
abstract: Severe combined immune deficiencies (SCIDs) are a group of monogenic diseases resulting in profound disturbances of lymphocyte development and function. Affected individuals are prone to life-threatening infections and without treatment do not survive beyond the first year of life. Haematopoietic stem cell transplantation from a well-matched donor offers high rates of survival, but in the absence of a suitable matched donor, parental haploidentical transplants are associated with greater complications, lower success rates and in some instances poor long-term immune recovery. Alternative therapeutic options based on correction of the defective gene by retroviral gene delivery have been used to correct X-linked SCID (SCID-X1) and adenosine deaminase-deficient SCID (ADA-SCID). A number of clinical trials have established that ex vivo gene transfer into haematopoietic progenitor cells allows effective recovery of immune defects and that gene therapy can offer a successful alternative to transplantation. The development of leukaemia as a result of insertional mutagenesis in one trial of gene therapy for SCID-X1 has raised concerns regarding the toxicity of retroviral vector-based gene delivery. These side effects are now being studied in detail and measures to prevent such events through alternative vectors delivery systems are in development at present.
authors.affiliation: Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. h.gaspar@ich.ucl.ac.uk
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit; D007938:Leukemia / Q000209:etiology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D014161:Transduction, Genetic
chemical_list: C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D018123:Receptors, Interleukin; D000243:Adenosine Deaminase