Stem cell gene therapy:the risks of insertional mutagenesis and approaches to minimize genotoxicity

作     者：Chuanfeng Wu Cynthia E.Dunbar 

作者机构：Hematology BranchNational HeartLung and Blood InstituteNational Institutes of HealthBethesdaMD 20892USA 

出 版 物：《Frontiers of Medicine》 (医学前沿（英文版）)

年 卷 期：2011年第5卷第4期

页      面：356-371页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Heart  Lung  and Blood Institute  NHLBI  (ZIAHL002339) 

主　　题：gene therapy hematopoietic stem cells insertional mutagenesis genotoxicity induced pluripotent stem cell 

摘      要：Virus-based vectors are widely used in hematopoietic stem cell(HSC)gene therapy,and have the ability to integrate permanently into genomic DNA,thus driving long-term expression of corrective genes in all hematopoietic *** date,HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency(SCID-X1),adenosine deaminase deficiency(ADA-SCID),adrenoleukodystrophy(ALD),thalassemia,chronic granulomatous disease(CGD),and Wiskott-Aldrich syndrome(WAS).However,adverse events were observed during some of these HSC gene therapy clinical trials,linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of *** studies have been performed to understand the molecular basis of vector-mediated genotoxicity,with the aim of developing safer vectors and lower-risk gene therapy *** review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors,discuss the available assays for predicting genotoxicity and mapping vector integration sites,and introduce newlydeveloped approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.