In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors

被引：61

作者：

Bauer, Gerhard ^{[1
,2
]}

Dao, Mo A. ^{[1
,2
]}

Case, Scott S. ^{[1
,2
]}

Meyerrose, Todd ^{[1
,2
]}

Wirthlin, Louisa ^{[1
,2
]}

Zhou, Ping ^{[1
,2
]}

Wang, Xiuli ^{[1
,2
]}

Herrbrich, Phillip ^{[1
,2
]}

Arevalo, Jesusa ^{[1
,2
]}

Csik, Susie ^{[1
,2
]}

Skelton, Dianne C. ^{[1
,2
]}

Walker, Jon ^{[1
,2
]}

Pepper, Karen ^{[1
,2
]}

Kohn, Donald B. ^{[1
,2
]}

Nolta, Jan A. ^{[1
,2
]}

机构：

[1] Univ Calif Davis, Stem Cell Program, Dept Internal Med, Sacramento, CA 95817 USA

[2] Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Dept Pediat, Los Angeles, CA 90027 USA

来源：

MOLECULAR THERAPY | 2008年 / 16卷 / 07期

关键词：

D O I：

10.1038/mt.2008.93

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Serious adverse events in some human gene therapy clinical trials have raised safety concerns when retroviral or lentiviral vectors are used for gene transfer. We evaluated the potential for generating replication-competent retrovirus (RCR) and assessed the risk of occurrence of adverse events in an in vivo system. Human hematopoietic stem and progenitor cells (HSCs) and mesenchymal stem cells (MSCs) transduced with two different Moloney murine leukemia virus (MoMuLV)-based vectors were cotransplanted into a total of 481 immune-deficient mice (that are unable to reject cells that become transformed), and the animals were monitored for 18 months. Animals with any signs of illness were immediately killed, autopsied, and subjected to a range of biosafety studies. There was no detectable evidence of insertional mutagenesis leading to human leukemias or solid tumors in the 18 months during which the animals were studied. In 117 serum samples analyzed by vector rescue assay there was no detectable RCR. An additional 149 mice received HSCs transduced with lentiviral vectors, and were followed for 2-6 months. No vector-associated adverse events were observed, and none of the mice had detectable human immunodeficiency virus (HIV) p24 antigen in their sera. Our in vivo system, therefore, helps to provide an assessment of the risks involved when retroviral or lentiviral vectors are considered for use in clinical gene therapy applications.

引用

页码：1308 / 1315

页数：8

共 43 条

[1] Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34(+) cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes [J].