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Yigang Wang - One of the best experts on this subject based on the ideXlab platform.
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Suicide Gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing cxcr4 msccxcr4
PLOS ONE, 2012Co-Authors: Jialiang Liang, Xiyong Yu, Atif Ashraf, Meifeng Xu, Ronald W. Millard, Kishore K. Wary, Muhammad Ashraf, Wei Huang, Yigang WangAbstract:Background: Our previous studies indicated that MSCCXCR4 improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSCCXCR4 in neovascularization of infarcted myocardium using a Suicide Gene approach. Methods: MSCs were transduced with either lentivirus-null vector/GFP (MSCNull as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The Suicide Gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSCNull or MSCCXCR4 were transduced with Suicide Gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. Results: The expression of VEGF-A and HIF-1 alpha was significantly higher in MSCCXCR4 as compared to MSCNull under hypoxia. Additionally, MSCCXCR4 enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSCCXCR4 under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with Suicide Gene activation. In vivo studies: MSCCXCR4 implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSCCXCR4 were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. Conclusion: The transplanted MSCCXCR4 enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation.
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Suicide Gene Reveals the Myocardial Neovascularization Role of Mesenchymal Stem Cells Overexpressing CXCR4 (MSCCXCR4)
PLoS ONE, 2012Co-Authors: Jialiang Liang, Xiyong Yu, Atif Ashraf, Meifeng Xu, Ronald W. Millard, Kishore K. Wary, Muhammad Ashraf, Wei Huang, Yigang WangAbstract:BACKGROUND: Our previous studies indicated that MSC(CXCR4) improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSC(CXCR4) in neovascularization of infarcted myocardium using a Suicide Gene approach. METHODS: MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null) as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The Suicide Gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null) or MSC(CXCR4) were transduced with Suicide Gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. RESULTS: The expression of VEGF-A and HIF-1α was significantly higher in MSC(CXCR4) as compared to MSC(Null) under hypoxia. Additionally, MSC(CXCR4) enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4) under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with Suicide Gene activation. In vivo studies: MSC(CXCR4) implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4) were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. CONCLUSION: The transplanted MSC(CXCR4) enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation.
Jialiang Liang - One of the best experts on this subject based on the ideXlab platform.
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Suicide Gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing cxcr4 msccxcr4
PLOS ONE, 2012Co-Authors: Jialiang Liang, Xiyong Yu, Atif Ashraf, Meifeng Xu, Ronald W. Millard, Kishore K. Wary, Muhammad Ashraf, Wei Huang, Yigang WangAbstract:Background: Our previous studies indicated that MSCCXCR4 improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSCCXCR4 in neovascularization of infarcted myocardium using a Suicide Gene approach. Methods: MSCs were transduced with either lentivirus-null vector/GFP (MSCNull as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The Suicide Gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSCNull or MSCCXCR4 were transduced with Suicide Gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. Results: The expression of VEGF-A and HIF-1 alpha was significantly higher in MSCCXCR4 as compared to MSCNull under hypoxia. Additionally, MSCCXCR4 enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSCCXCR4 under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with Suicide Gene activation. In vivo studies: MSCCXCR4 implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSCCXCR4 were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. Conclusion: The transplanted MSCCXCR4 enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation.
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Suicide Gene Reveals the Myocardial Neovascularization Role of Mesenchymal Stem Cells Overexpressing CXCR4 (MSCCXCR4)
PLoS ONE, 2012Co-Authors: Jialiang Liang, Xiyong Yu, Atif Ashraf, Meifeng Xu, Ronald W. Millard, Kishore K. Wary, Muhammad Ashraf, Wei Huang, Yigang WangAbstract:BACKGROUND: Our previous studies indicated that MSC(CXCR4) improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSC(CXCR4) in neovascularization of infarcted myocardium using a Suicide Gene approach. METHODS: MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null) as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The Suicide Gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null) or MSC(CXCR4) were transduced with Suicide Gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. RESULTS: The expression of VEGF-A and HIF-1α was significantly higher in MSC(CXCR4) as compared to MSC(Null) under hypoxia. Additionally, MSC(CXCR4) enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4) under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with Suicide Gene activation. In vivo studies: MSC(CXCR4) implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4) were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. CONCLUSION: The transplanted MSC(CXCR4) enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation.
Attilio Bondanza - One of the best experts on this subject based on the ideXlab platform.
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improving the safety of cell therapy with the tk Suicide Gene
Frontiers in Pharmacology, 2015Co-Authors: Raffaella Greco, Attilio Bondanza, Giacomo Oliveira, Maria Teresa Lupo Stanghellini, Luca Vago, Jacopo Peccatori, Nicoletta Cieri, Sarah Marktel, Sara Mastaglio, Claudio BordignonAbstract:While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is alloGeneic haematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk haematological malignancies. The potential of alloGeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumour effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The Suicide Gene approach is based on the transfer of a Suicide Gene into donor lymphocytes, for a safe infusion of a wide T cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the Suicide Gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in Suicide Genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of alloGeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.
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Suicide Gene therapy to increase the safety of chimeric antigen receptor redirected t lymphocytes
Journal of Cancer, 2011Co-Authors: Monica Casucci, Attilio BondanzaAbstract:Chimeric antigen receptors (CARs) are Generated by fusing the antigen-binding motif of a monoclonal antibody (mAb) with the signal transduction machinery of the T-cell receptor (TCR). The Genetic modification of T lymphocytes with chimeric receptors specific for tumor-associated antigens (TAAs) allows for the redirection towards tumor cells. Clinical experience with CAR-redirected T cells suggests that antitumor efficacy associates with some degree of toxicity, especially when TAA expression is shared with healthy tissues. This situation closely resembles the case of alloGeneic hematopoietic stem cell transplantation (HSCT), wherein allorecognition causes both the graft-versus-leukemia (GVL) effect and graft-versus-host disease (GVHD). Suicide Gene therapy, i.e. the Genetic induction of a conditional Suicide phenotype into donor T cells, enables dissociating the GVL effect from GVHD. Applying Suicide Gene modification to CAR-redirected T cells may therefore greatly increase their safety profile and facilitate their clinical development.
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il 7 and il 15 allow the Generation of Suicide Gene modified alloreactive self renewing central memory human t lymphocytes
Blood, 2009Co-Authors: Shin Kaneko, Attilio Bondanza, Sara Mastaglio, Maurilio Ponzoni, Francesca Sanvito, Luca Aldrighetti, Marina Radrizzani, Simona La Setacatamancio, Elena Provasi, Anna MondinoAbstract:Long-term clinical remissions of leukemia, after alloGeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective Suicide in donor T cells is a current Gene therapy approach to abrogate GVHD. Unfortunately, Genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (TEM) phenotype of Gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of Gene-modified lymphocytes segregates with the central memory (TCM) phenotype. To this, we Generated Suicide Gene–modified TCM lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, Suicide Gene–modified TCM cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only Suicide Gene–modified T cells cultured with IL-7 and IL-15 persisted, differentiated in TEM cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the Suicide Gene machinery. These results warrant the use of Suicide Gene–modified TCM cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.
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the Suicide Gene therapy challenge how to improve a successful Gene therapy approach
Molecular Therapy, 2007Co-Authors: Chiara Bonini, Attilio Bondanza, Serena K Perna, Shin Kaneko, Catia Traversari, Fabio Ciceri, Claudio BordignonAbstract:The transfer of a Suicide Gene into donor lymphocytes to control alloreactivity in the context of alloGeneic hematopoietic stem cell transplantation (allo-HSCT) represents the widest clinical application of T-cell based Gene transfer, as shown by more than 100 patients treated worldwide to date, several phase I–II studies completed, and a registrative phase III study, sponsored by a biotech firm, about to begin. In this mini-review, we will summarize the clinical results obtained to date, and attempt to identify the steps envisaged to optimize the Suicide Gene therapy approach.
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Suicide Gene therapy of graft versus host disease induced by central memory human t lymphocytes
Blood, 2005Co-Authors: Attilio Bondanza, Catia Traversari, Maurilio Ponzoni, Francesca Sanvito, Veronica Valtolina, Zulma Magnani, Katharina Fleischhauer, Mark Bonyhadi, Salvatore Toma, Marina RadrizzaniAbstract:In alloGeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase ( TK ) Suicide Gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK + lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for Genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK + lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK + lymphocytes, the addition of CD28 costimulation through cell-sized beads resulted in the Generation of central memory (CM) TK + lymphocytes. In a quantitative model for GvHD using nonobese diabetic/severely combined immunodeficient mice, CM TK + lymphocytes were more potent than EM TK + lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK + lymphocytes. These results warrant the clinical investigation of CM Suicide Gene-modified human T lymphocytes for safe and effective allo-HCT.
Claudio Bordignon - One of the best experts on this subject based on the ideXlab platform.
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improving the safety of cell therapy with the tk Suicide Gene
Frontiers in Pharmacology, 2015Co-Authors: Raffaella Greco, Attilio Bondanza, Giacomo Oliveira, Maria Teresa Lupo Stanghellini, Luca Vago, Jacopo Peccatori, Nicoletta Cieri, Sarah Marktel, Sara Mastaglio, Claudio BordignonAbstract:While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is alloGeneic haematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk haematological malignancies. The potential of alloGeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumour effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The Suicide Gene approach is based on the transfer of a Suicide Gene into donor lymphocytes, for a safe infusion of a wide T cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the Suicide Gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in Suicide Genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of alloGeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.
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the Suicide Gene therapy challenge how to improve a successful Gene therapy approach
Molecular Therapy, 2007Co-Authors: Chiara Bonini, Attilio Bondanza, Serena K Perna, Shin Kaneko, Catia Traversari, Fabio Ciceri, Claudio BordignonAbstract:The transfer of a Suicide Gene into donor lymphocytes to control alloreactivity in the context of alloGeneic hematopoietic stem cell transplantation (allo-HSCT) represents the widest clinical application of T-cell based Gene transfer, as shown by more than 100 patients treated worldwide to date, several phase I–II studies completed, and a registrative phase III study, sponsored by a biotech firm, about to begin. In this mini-review, we will summarize the clinical results obtained to date, and attempt to identify the steps envisaged to optimize the Suicide Gene therapy approach.
Malcolm K Brenner - One of the best experts on this subject based on the ideXlab platform.
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an inducible caspase 9 Suicide Gene to improve the safety of therapy using human induced pluripotent stem cells
Molecular Therapy, 2015Co-Authors: Shigeki Yagyu, Valentina Hoyos, Francesca Del Bufalo, Malcolm K BrennerAbstract:Human induced pluripotent stem cells (hiPSC) hold promise for reGenerative therapies, though there are several safety concerns including the risk of oncogenic transformation or unwanted adverse effects associated with hiPSC or their differentiated progeny. Introduction of the inducible caspase-9 (iC9) Suicide Gene, which is activated by a specific chemical inducer of dimerization (CID), is one of the most appealing safety strategies for cell therapies and is currently being tested in multicenter clinical trials. Here, we show that the iC9 Suicide Gene with a human EF1α promoter can be introduced into hiPSC by lentiviral transduction. The transduced hiPSC maintain their pluripotency, including their capacity for unlimited self-renewal and the potential to differentiate into three germ layer tissues. Transduced hiPSC are eliminated within 24 hours of exposure to pharmacological levels of CID in vitro, with induction of apoptosis in 94–99% of the cells. Importantly, the iC9 Suicide Gene can eradicate tumors derived from hiPSC in vivo. In conclusion, we have developed a direct and efficient hiPSC killing system that provides a necessary safety mechanism for therapies using hiPSC. We believe that our iC9 Suicide Gene will be of value in clinical applications of hiPSC-based therapy.
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inducible caspase 9 Suicide Gene to improve the safety of allodepleted t cells after haploidentical stem cell transplantation
Biology of Blood and Marrow Transplantation, 2007Co-Authors: Gianpietro Dotti, Cliona M Rooney, Helen E Heslop, Malcolm K BrennerAbstract:Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a Suicide Gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19). Even after allodepletion (using anti-CD25 immunotoxin), donor T cells could be efficiently transduced, expanded, and subsequently enriched by CD19 immunomagnetic selection to >90% purity. These engineered cells retained antiviral specificity and functionality, and contained a subset with regulatory phenotype and function. Activating iCasp9 with a small-molecule dimerizer rapidly produced >90% apoptosis. Although transGene expression was downregulated in quiescent T cells, iCasp9 remained an efficient Suicide Gene, as expression was rapidly upregulated in activated (alloreactive) T cells. We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials.
