Analyzing the Genotoxicity of Retroviral Vectors in Hematopoietic Cell Gene Therapy

被引：33

作者：

Biasco, Luca ^{[1
,2
,3
]}

Rothe, Michael ^{[4
,5
]}

Buening, Hildegard ^{[4
,5
]}

Schambach, Axel ^{[4
,5
,6
]}

机构：

[1] San Raffaele Telethon Inst Gene Therapy, Milan, Italy

[2] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Gene Therapy Program, Boston, MA USA

[3] UCL, Inst Child Hlth, London, England

[4] Hannover Med Sch, Inst Expt Hematol, Carl Neuberg Str 1, D-30625 Hannover, Germany

[5] Hannover Med Sch, REBIRTH Cluster Excellence, Hannover, Germany

[6] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA

来源：

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT | 2018年 / 8卷

关键词：

INSERTIONAL MUTAGENESIS; LENTIVIRAL VECTORS; INTEGRATION SITES; CLONAL SELECTION; MEDIATED PCR; ACTIVATION; SCID-X1; SAFETY; DESIGN;

D O I：

10.1016/j.omtm.2017.10.002

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Retroviral vectors, including those derived from gammaretroviruses and lentiviruses, have found their way into the clinical arena and demonstrated remarkable efficacy for the treatment of immunodeficiencies, leukodystrophies, and globinopathies. Despite these successes, gene therapy unfortunately also has had to face severe adverse events in the form of leukemias and myelodysplastic syndromes, related to the semi-random vector integration into the host cell genome that caused deregulation of neighboring proto-oncogenes. Although improvements in vector design clearly lowered the risk of this insertional mutagenesis, analysis of potential genotoxicity and the consequences of vector integration remain important parameters for basic and translational research and most importantly for the clinic. Here, we review current assays to analyze biodistribution and genotoxicity in the pre-clinical setting and describe tools to monitor vector integration sites in vector-treated patients as a biosafety readout.

引用

页码：21 / 30

页数：10

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