title: The leukemogenic risk of integrating retroviral vectors in hematopoietic stem cell gene therapy applications.
abstract: Hematopoietic stem cell gene transfer using integrating vectors has been actively investigated for more than two decades as a prospective treatment for several congenital and acquired human diseases, and retroviral vectors encoding potentially therapeutic genes have been the most rigorously pursued. Early trials in humans testing retroviral vectors in several clinical settings supported the safety of this approach, and recent studies have demonstrated remarkable efficacy in children with severe combined immunodeficiency. The anticipated success established the therapeutic potential of hematopoietic stem cell gene transfer, but the subsequent development of leukemia in two treated children has re-emphasized the risks related to gene therapy. In this review, we describe this complication, discuss the leukemogenic risk of integrating retroviral vectors, and propose strategies to decrease the likelihood of its occurrence.
authors.affiliation: Molecular and Clinical Hematology Branch, National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Building 10, Room 9N116, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kang
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D000818:Animals; D002648:Child; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D007938:Leukemia / Q000209:etiology* / Q000517:prevention & control / Q000821:virology; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000628:therapy; D016896:Treatment Outcome; D016662:Virus Integration