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

Chuanfeng Wu, Cynthia E. Dunbar

Frontiers of Medicine 2011, Volume 5, Issue 4,   Pages 356-371 doi: 10.1007/s11684-011-0159-1

Abstract: Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the abilityTo date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomesHowever, adverse events were observed during some of these HSC gene therapy clinical trials, linked totherapy protocols.therapy forward into broader clinical application.

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

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Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

Ru Zhang,Qiang Wang,Lin Zhang,Saijuan Chen

Frontiers of Medicine 2015, Volume 9, Issue 1,   Pages 90-99 doi: 10.1007/s11684-015-0390-2

Abstract:

Gene therapy provides a potential cure for hemophilia B, and significant progress has been achievedin liver-directed gene transfer mediated by adeno-associated viral vectors.vectors and hFIX expression cassette may positively contribute to the ultimate success of hemophilia B genetherapy.therapy of hemophilia B.

Keywords： factor IX     hemophilia B     liver-specific regulatory elements     hydrodynamic gene transfer    

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Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX

Wei Lu,Qingzhang Zhou,Hao Yang,Hao Wang,Yexing Gu,Qi Shen,Jinglun Xue,Xiaoyan Dong,Jinzhong Chen

Frontiers of Medicine 2016, Volume 10, Issue 2,   Pages 212-218 doi: 10.1007/s11684-016-0438-y

Abstract: Gene therapy might be the ultimate strategy for the disease.However, two main problems that should be solved in gene therapy for hemophilia B are immunity and safetyimmunogenicity and high transfection efficiency in liver cells, might be a potential vector for hemophilia B genetherapy.Our study provides a potential gene therapy method for hemophilia B.

Keywords： hemophilia B     AAV8     hFIX     gene therapy    

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Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing

Yu Cao, Xiaoxuan Liu, Ling Peng

Frontiers of Chemical Science and Engineering 2017, Volume 11, Issue 4,   Pages 663-675 doi: 10.1007/s11705-017-1623-5

Abstract: Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined molecular architecture and multivalent cooperativity. However, the clinical translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufacturing practice standard. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramolecular structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amount and superior quality. Indeed, the concept of supramolecular dendrimers has proved to be very promising, and has opened up a new avenue for dendrimer-mediated siRNA delivery. A series of self-assembling supramolecular dendrimers have consequently been established, some of them out-performing the currently available nonviral vectors in delivering siRNA to various cell types and , including human primary cells and stem cells. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating self-assembling amphiphilic dendrimers to construct supramolecular dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramolecular dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.

Keywords： gene therapy     RNAi therapeutics     dendrimer     nanovectors     gene silencing    

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Investigation of gene therapy of denovirus in immune suppression

XIA Xi, WANG Beibei, CAO Li, CHEN Gang, WU Peng, LU Yunping, ZHOU Jianfeng, MA Ding

Frontiers of Medicine 2008, Volume 2, Issue 4,   Pages 386-390 doi: 10.1007/s11684-008-0074-2

Abstract: The aim of this paper is to investigate the safety of reconstructed adenovirus in immunosuppressive therapeutics and to explore the role of ciclosporin A in antagonizing the elimination of the vector. Several rats were given retroperitoneal injection of purified ADV-TK in order to obtain models. After 14 days’ treatment of ciclosporin A, samples of different periods were obtained, then stained with hematoxylin-eosin (HE) to detect inflammation reactions. Immunohistochemistry was used to examine the expression of adenovirus in organs. The results are as follows: (1) In HE stained sections of the organs, some transitory and reversible inflammation was detected. (2) In immunohistochemistry assay, reconstructed adenovirus decreased gradually as time went by in the control group, while it did not happen in the experimental group in which the adenovirus showed a relative increase compared with their counterparts ( < 0.05). (3) The distributions of adenovirus in the liver, spleen and lung were higher than those in the other organs detected. Reconstructed adenovirus as a vector is definitely safe in immunosuppressive therapeutics, and ciclosporin A, to some extent, is able to consequently inhibit the immune response of the rats and prolong the existing period of adenovirus.

Keywords： different     reversible inflammation     immunohistochemistry     reconstructed adenovirus     ciclosporin    

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Construction of lentiviral vector carrying Rab9 gene and its expression in mouse brain

Youguo HAO, Min ZHANG, Jinzhi XU, Bitao BU, Jiajun WEI

Frontiers of Medicine 2009, Volume 3, Issue 2,   Pages 141-147 doi: 10.1007/s11684-009-0041-6

Abstract: To explore the possibility of Rab9-related gene therapy for neurodegenerative diseases, we packed LentivirusWestern blotting revealed that the Rab9 gene expression in BALB/c mice brain was up-regulated significantlyLentivirus encoding Rab9 can increase the expression of Rab9 gene effectively, which might offer a novel

Keywords： Rab9     lentivirus     gene therapy     gene transfer    

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Adenovirus-mediated antisense ERK2 gene therapy ameliorates chronic allograft nephropathy in a rat model

Zhao DING, Zhishui CHEN, Xilin CHEN, Ming CAI, Hui GUO, Nianqiao GONG

Frontiers of Medicine 2009, Volume 3, Issue 2,   Pages 204-210 doi: 10.1007/s11684-009-0039-0

Abstract: therapy group.In the gene therapy group, the fibrosis was ameliorated and fewer T lymphocytes and ED-1 monocytes infiltratedThere was no significant difference in the expression of E-Cadherin between the gene therapy group andCompared with the empty control group, the expression of TGF-β1 in the gene therapy group was down-regulatedAdanti-ERK2 gene therapy protects the renal allograft and attenuates graft fibrosis, which may be correlated

Keywords： anti-ERK2     renal transplantation     epithelial mesenchymal transition     chronic allograft nephropathy    

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Antitumor immunity of human SART3 gene vaccine against mouse tumor

HE Yu, YANG Shuhua, LIU Yong, LI Tao

Frontiers of Medicine 2008, Volume 2, Issue 1,   Pages 51-57 doi: 10.1007/s11684-008-0010-5

Abstract: To determine whether squamous cell carcinoma antigen recognized by human T cell 3 (SART3) gene can induceantitumor immunity against tumor cells which express the gene, we constructed mouse tumor cells expressingAfter subcutaneous injection with SART3 gene vaccine, cytotoxic T lymphocyte (CTL) activity was measuredagainst tumor cells expressing human SART3 (LM8-SART3) which may provide new possibilities in antitumor therapy

Keywords： antitumor therapy     occurrence     implantation     DNA vaccine     SART3 DNA    

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NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation

Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li

Frontiers of Medicine 2019, Volume 13, Issue 6,   Pages 646-657 doi: 10.1007/s11684-018-0643-y

Abstract: gene is thought to be a tumor-suppressor gene.Our previous study found that overexpression of gene in PC3 cell line could slow down the tumor proliferationThus, we supposed to have an “enhanced firepower” effect by combining overexpressed gene therapy andI radiation therapy uptake by overexpressed hNIS protein.therapy and I radiation therapy mediated by overexpressed hNIS protein had the best tumor proliferative

Keywords： androgen-independent prostate cancer     normal epithelial cell-specific 1/kallikrein 10     sodium/iodide symporter     radiation therapy    

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Adenovirus-mediated tissue inhibitor of metalloproteinase-3 gene transfection inhibits rabbit intervertebral

Xudong YU MM, Zengwu SHAO MD, Liming XIONG MD, Weiwei XU MM, Hezhong WANG MM, Huifa XU MM,

Frontiers of Medicine 2009, Volume 3, Issue 4,   Pages 415-420 doi: 10.1007/s11684-009-0072-z

Abstract: Thompson’s grading system, reverse-transcription polymerase chain reaction (RT-PCR) assay for TIMP-3 gene

Keywords： tissue inhibitor of metalloproteinase-3     intervertebral disc     rabbit     gene therapy    

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Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthritis

Xin Wu, Xiaobao Sheng, Rong Sheng, Hongjuan Lu, Huji Xu

Frontiers of Medicine 2019, Volume 13, Issue 4,   Pages 411-419 doi: 10.1007/s11684-018-0659-3

Abstract: Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA. We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.

Keywords： rheumatoid arthritis     gene     clinical markers     therapy    

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Development of a magnetite-gene complex for gene transfection

Jian XIN BM, Ze-Feng XIA MD, Kai-Xiong TAO MD, Kai-Lin CAI PhD, Gao-Xiong HAN MD, Xiao-Ming SHUAI MD, Ji-Liang WANG MD, Han-Song DU MD, Guo-Bin WANG PhD, Yan LUO MM,

Frontiers of Medicine 2010, Volume 4, Issue 2,   Pages 241-246 doi: 10.1007/s11684-010-0032-7

Abstract: The key to successful gene therapy is to find a suitable method and carrier for transfection to allowa gene to be transferred into a cell and integrated into the target gene.this study was to determine whether biomagnetic material could be combined with the nucleic acid for geneoxide nanoparticles (DCIONPs) were prepared and mixed with the plasmid pGenesil-1 containing the test geneUsing different gene carriers, Lipofectamine 2000, Sofast, and DCIONPs, the large intestine cancer (Lovo

Keywords： nanoparticle     magnetite     gene therapy     magnetofection    

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Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis

Yue Yu, Jie He

Frontiers of Medicine 2013, Volume 7, Issue 2,   Pages 157-171 doi: 10.1007/s11684-013-0272-4

Abstract: Molecular biology techniques, particularly gene expression microarrays, proteomics, and next-generationThis review focuses on the molecular classification of NSCLC based on gene expression microarray technology

Keywords： non-small-cell lung cancer     molecular typing     individualized medicine     molecular-targeted therapy     gene expression    

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Long-term correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed of the human heavy chain and the rat light chain

Frontiers of Medicine 2022, Volume 16, Issue 4,   Pages 584-595 doi: 10.1007/s11684-021-0844-7

Abstract: rat hybrid FVIII with an enhanced procoagulant potential for adeno-associated virus (AAV)-delivered genetherapy was developed.In conclusion, the application of the hybrid FVIII (hHC+ rLC) via an AAV-delivered gene therapy substantiallyThese data might be of help to the development of optimized FVIII expression cassette for HA gene therapy

Keywords： hemophilia A     adeno-associated virus (AAV)     human/rat hybrid factor VIII     gene therapy     dual chain strategy    

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Cotransfecting norepinephrine transporter and vesicular monoamine transporter 2 genes for increased retention of metaiodobenzylguanidine labeled with iodine 131 in malignant hepatocarcinoma cells

Yanlin Zhao,Xiao Zhong,Xiaohong Ou,Huawei Cai,Xiaoai Wu,Rui Huang

Frontiers of Medicine 2017, Volume 11, Issue 1,   Pages 120-128 doi: 10.1007/s11684-017-0501-3

Abstract:

Norepinephrine transporter (NET) transfection leads to significant uptake of iodine-131-labeled metaiodobenzylguanidine (131I-MIBG) in non-neuroendocrine tumors. However, the use of 131I-MIBG is limited by its short retention time in target cells. To prolong the retention of 131I-MIBG in target cells, we infected hepatocarcinoma (HepG2) cells with Lentivirus-encoding human NET and vesicular monoamine transporter 2 (VMAT2) genes to obtain NET-expressing, NET-VMAT2-coexpressing, and negative-control cell lines. We evaluated the uptake and efflux of 131I-MIBG both in vitro and in vivo in mice bearing transfected tumors. NET-expressing and NET-VMAT2-coexpressing cells respectively showed 2.24 and 2.22 times higher 131I-MIBG uptake than controls. Two hours after removal of 131I-MIBG-containing medium, 25.4% efflux was observed in NET-VMAT2-coexpressing cells and 38.6% in NET-expressing cells. In vivo experiments were performed in nude mice bearing transfected tumors; results revealed that NET-VMAT2-coexpressing tumors had longer 131I-MIBG retention time than NET-expressing tumors. Meanwhile, NET-VMAT2-coexpressing and NET-expressing tumors displayed 0.54% and 0.19%, respectively, of the injected dose per gram of tissue 24 h after 131I-MIBG administration. Cotransfection of HepG2 cells with NET and VMAT2resulted in increased 131I-MIBG uptake and retention. However, the degree of increase was insufficient to be therapeutically effective in target cells.

Keywords： norepinephrine transporter     vesicular monoamine transporter 2     -MIBG     gene therapy     lentivirus    

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Title Author Date Type Operation

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

Chuanfeng Wu, Cynthia E. Dunbar

Journal Article

Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B

Ru Zhang,Qiang Wang,Lin Zhang,Saijuan Chen

Journal Article

Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX

Wei Lu,Qingzhang Zhou,Hao Yang,Hao Wang,Yexing Gu,Qi Shen,Jinglun Xue,Xiaoyan Dong,Jinzhong Chen

Journal Article

Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing

Yu Cao, Xiaoxuan Liu, Ling Peng

Journal Article

Investigation of gene therapy of denovirus in immune suppression

XIA Xi, WANG Beibei, CAO Li, CHEN Gang, WU Peng, LU Yunping, ZHOU Jianfeng, MA Ding

Journal Article

Construction of lentiviral vector carrying Rab9 gene and its expression in mouse brain

Youguo HAO, Min ZHANG, Jinzhi XU, Bitao BU, Jiajun WEI

Journal Article

Adenovirus-mediated antisense ERK2 gene therapy ameliorates chronic allograft nephropathy in a rat model

Zhao DING, Zhishui CHEN, Xilin CHEN, Ming CAI, Hui GUO, Nianqiao GONG

Journal Article

Antitumor immunity of human SART3 gene vaccine against mouse tumor

HE Yu, YANG Shuhua, LIU Yong, LI Tao

Journal Article

NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation

Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li

Journal Article

Adenovirus-mediated tissue inhibitor of metalloproteinase-3 gene transfection inhibits rabbit intervertebral

Xudong YU MM, Zengwu SHAO MD, Liming XIONG MD, Weiwei XU MM, Hezhong WANG MM, Huifa XU MM,

Journal Article

Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthritis

Xin Wu, Xiaobao Sheng, Rong Sheng, Hongjuan Lu, Huji Xu

Journal Article

Development of a magnetite-gene complex for gene transfection

Jian XIN BM, Ze-Feng XIA MD, Kai-Xiong TAO MD, Kai-Lin CAI PhD, Gao-Xiong HAN MD, Xiao-Ming SHUAI MD, Ji-Liang WANG MD, Han-Song DU MD, Guo-Bin WANG PhD, Yan LUO MM,

Journal Article

Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis

Yue Yu, Jie He

Journal Article

Long-term correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FVIII composed of the human heavy chain and the rat light chain

Journal Article

Cotransfecting norepinephrine transporter and vesicular monoamine transporter 2 genes for increased retention of metaiodobenzylguanidine labeled with iodine 131 in malignant hepatocarcinoma cells

Yanlin Zhao,Xiao Zhong,Xiaohong Ou,Huawei Cai,Xiaoai Wu,Rui Huang

Journal Article