title: Insertional mutagenesis by retroviral vectors: current concepts and methods of analysis.
abstract: Retroviral vectors derived from gammaretroviruses or lentiviruses have now been used extensively in clinical gene therapy trials for several diseases including primary immunodeficiencies, beta thalassaemia and adrenoleukodystrophy. Their utility in this setting has been readily demonstrated by the largely favourable outcomes in recent clinical trials, however this success has been marred by the emergence of malignancies in some trials. These malignancies were a consequence of perturbation of cellular proto-oncogene expression by the integrated retroviral vectors, the process of which is referred to as 'insertional mutagenesis' (IM). In this review, the origins of our understanding of IM are reviewed and applied to the clinical gene therapy trials conducted with retroviral vectors. Old and new methods for assessing this phenomenon are discussed with a view to provide a comprehensive account of this emerging field.
authors.affiliation: MRC/UCL Centre for Medical Molecular Virology and Wohl Virion Centre, Division of Infection & Immunity, UCL Cancer Institute, University College London, London, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Knight
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002986:Clinical Trials as Topic; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006678:HIV / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D016254:Mutagenesis, Insertional; D009857:Oncogenes; D026723:Polyadenylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000628:therapy; D000090063:Proto-Oncogene Mas; D012326:RNA Splicing; D012333:RNA, Messenger; D012190:Retroviridae / Q000235:genetics*; D019076:Transgenes; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000628:therapy
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger