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

Frontiers of Medicine 2011年第4期5卷 356-371页

作者： Chuanfeng Wu Cynthia E.Dunbar Hematology Branch National HeartLung and Blood InstituteNational Institutes of HealthBethesdaMD 20892USA

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.

关键词： gene therapy hematopoietic stem cells insertional mutagenesis genotoxicity induced pluripotent stem cell

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T-DNA transfer and integration as a tool for insertional mutagenesis in the taxol-producing fungus

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High Technology Letters 2008年第1期14卷 92-97页

作者：迟彦 Ping Wenxiang Li Shanshan Zhu Jing Ma Xi Gao Fengshan Zhou Dongpo Key Laboratory of Microbe Heilongjiang University Harbin 150080 P.R. China Key Laboratory of Bio-organic Chemistry Dalian University Dalian 116622 P. R. China

Agrobacterium tumefaciens-mediated DNA transiormation method was applied to transform Noclulisporium sylviforme fusant HDF-68, a taxol-produeing fungus. We constructed a binary vector pBI121-43 canting a hygromycin-resistant gene cassette between the right and left borders of T-DNA, Optimal co-cultivation of *** with A. tumefaciens containing pBI121-43 led to 110- 130 hygromycin-resistant transformants per＂ million eonidia. Putative transformants were found to be mitotically stable. The molecular analysis of transformants demonstrated the random integration of single copy of the T-DNA into the host genome. This transformation system serves as a basic tool for insertional mutagenesis in N. sylviforme fusant HDF-68, and the development of such svstem lays a solid foundation for constructing high-yied gene engineering strain and clarifying taxol biosynthesis pathway in this fungus.

关键词： taxol T-DNA insertional mutagenesis

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Retroviral insertional mutagenesis Screen for Genes Involved in Human Disease Modeling in Zebrafish

Retroviral Insertional Mutagenesis Screen for Genes Involved...

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“基因、进化与生理功能多样性”海内外学术研讨会暨中国生理学会第七届比较生理学学术会议

作者： Ying Zhang~1,Nai-Zhong Zheng~1,Shuo Lin~(1,2),Bo Zhang~1 1 Key Laboratory of Cell Proliferation and Differentiation,Center of Developmental Biology and Genetics,College of Life Sciences,Peking University,Ministry of Education,Beijing 2 Department of Molecular,Cell & Developmental Biology,University of California,Los Angeles, Los Angeles,CA 90095-1606,USA

Through retrovirus insertion based mutagenesis screen in zebrafish（Danio reiro） we have obtained several insertions that reside in *** and WDR55 are two candidate genes we conducted further *** encodes a cytokine induced anti-apoptosis protein with a methyltransferase domain, whose ortholog in mice is called Anamorsin. Ciapinl/Anamorsin represents a novel antiapoptotic protein that shares no homology with Bcl-2 and Capase family *** mouse embryos has been reported to be smaller in size compared with wild type littermates, show defects in definitive hemato-poiesis in fetal livers,and begin to die between E12.5 and *** mount in situ hybridization in zebrafish embryos revealed a broad expression pattern of *** ciapinl embryos exhibits edema in pericardial ***55 is a member of WDR-containing protein *** studies have shown that PeBoW complex,which contains a component of WDR12,is required for matura- tion of 60S ribosomal *** is also reported that WDR55 is involved in rRNA processing and cell *** data showed that WDR55 zebrafish embryos begin to die between 7 days post fertilization（dpf） and 10 *** mount in situ hybridization with markers of hematopoietic stem cells c-myb and runxl showed decreased expression in WDR55 *** may imply a function of WDR55 in definitive *** study is interesting because ribosome deficiency has been implicated in several human diseases such as Diamond-Blackfan Anemia that has congenital erythroid *** zebrafish mutants might be useful for modeling and understanding pathogenesis of these human diseases.

关键词： Zebrafish insertional mutagenesis Retrovirus Cardiovascular development

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Update on genome wide mutagenesis by retroviral insertions in zebrafish

Update on genome wide mutagenesis by retroviral insertions i...

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2010·第一届斑马鱼学术研讨会

作者： Shuo Lin Key Laboratory of Cell Proliferation and Differentiation,Center of Developmental Biology and Genetics,College of Life Sciences,Peking University,Ministry of Education,Beijing,100871, P.R.China Department of Molecular,Cell & Developmental Biology,University of California Los Angeles, Los Angeles,CA,USA

It is well established that genetic studies in zebrafish can provide insights into the function of the conserved vertebrate genes and therefore lead to better understanding of human diseases and *** the zebrafish genome sequencing project nearly completed,it is now theoretically possible to identify mutations in all zebrafish genes with the ultimate goal of systematically testing each mutation for *** this goal,we have developed an efficient and streamlined platform using proviral insertions coupled with high-throughput sequencing and mapping technologies capable of mutagenizing essentially all of the identifiable candidate genes in zebrafish *** are undertaking a genome wide mutagenesis effort to construct a library of zebrafish strains in which approximately 12,000 zebrafish genes representing nearly 50%of the predicted vertebrate genes have been disrupted with a retrovirus *** the resources generated will be made available to the community at a minimal *** will be mapped to the zebrafish genome and both mapping data and mutagenized fish lines can be *** update of this project will be presented with a hope to include additional efforts from Chinese zebrafish research community.

关键词： retrovirus insertional mutagenesis high-throughput sequencing

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Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery

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The Innovation 2020年第2期1卷 49-58页

作者： Kaitao Zhao Andrew Liu Yuchen Xia State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology School of Basic Medical SciencesWuhan UniversityWuhan 430071China Laboratory of Molecular Cardiology National Heart Lung Blood InstituteNational Institutes of HealthBethesdaMD 20814USA

Hepatitis B virus(HBV),which was discovered in 1965,is a threat to global public *** infects human hepatocytes and leads to acute and chronic liver diseases,and there is no *** cells infected by HBV,viral DNA can be integrated into the cellular *** DNA integration is a complicated process during the HBV life *** HBV integration normally results in replication-incompetent transcripts,it can still act as a template for viral protein *** note,it is a primary driver of hepatocellular carcinoma(HCC).Recently,with the development of detection methods and research models,the molecular biology and the pathogenicity of HBV DNA integration have been better ***,we review the advances in the research of HBV DNA integration,including molecular mechanisms,detection methods,research models,the effects on host and viral gene expression,the role of HBV integrations in the pathogenesis of HCC,and potential treatment ***,we discuss possible future research prospects of HBV DNA integration.

关键词： HEPATITIS B VIRUS INTEGRATION NON-HOMOLOGOUS END JOINING insertional mutagenesis HEPATOCELLULAR CARCINOMA

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An efficient system for Ds transposon tagging in Brachypodium distachyon L.

An efficient system for Ds transposon tagging in Brachypodiu...

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中国植物学会第十六次全国会员代表大会暨85周年学术年会

作者： Hongyu Wu Xiaodong Xue Caihua Qin Yi Xu Yuyu Guo Xiang Li Wei Lv Qinxia Li Chuangxue Mao Luzhao Li Suzhen Zhao Xiaoquan Qi Hailong An State Key Laboratory of Crop Biology College of Life SciencesShandong Agricultural University The Key Laboratory of Plant Molecular Physiology Institute of BotanyChinese Academy of Sciences

Transposon tagging is a powerful tool that has been widely applied in several species for insertional mutagenesis in *** distachyon L.（***） is a monocot plant used as a model system to study temperate cereals,representing some of the world’s most important food *** have been several efforts aimed at the creation of T-DNA insertional mutant populations,but there has been a lack research aimed on using transposon strategies,which have been widely successful in other monocot ***,we describe the application of a maize Ds transposon tagging system in *** 35 S::AcTPase cassette（Ac transposase gene driven by 35 S promoter） and Ds element（Ds with a ZmUbi1::GFP cassette inside） were constructed within the same T-DNA and transformed into *** *** Ds element was readily transposed to other chromosomes or to the same chromosome through homologous chromosome synapsis,recombination,and segregation,resulting in the production of Ds lines lacking the T-DNA and Ac transposase subsequent generations.241 T0 lines were analyzed and part of them were found to be highly efficient at the production of Ds-only plants in their ***,about 10% of progeny plants of high efficiency lines were confirmed to be genetically stable,Dsonly *** the thermal asymmetric interlaced PCR（hiTAIL-PCR）,710 independent Ds flanking sequences were isolated from Ds-only ***,a large collection of mutants with visible developmental phenotypes were identified via this transposon tagging *** system is relatively simple and rapid in comparison to traditional T-DNA insertion strategies,because once efficiency lines are obtained they can be re-used to generate more lines from non-transposed plants without the use of time consuming tissue culture steps.

关键词： Brachypodium distachyon L. Ds transposon tagging germinal transposition insertional mutagenesis flanking sequence mutant

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