Hybrid herpes simplex virus/Epstein–Barr virus amplicon viral vectors confer enhanced transgene expression in primary human tumors and human bone marrow‐derived mesenchymal stem cells

Sia, Kian Chuan; Chong, Wei Kin; Ho, Ivy A. W.; Yulyana, Yulyana; Endaya, Berwini; Huynh, Hung; Lam, Paula Yeng Po

doi:10.1002/jgm.1506

Cited by 11 publications

(11 citation statements)

References 39 publications

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“…Hybridized EBNA-1 elements of the EBV vector with herpes simplex virus type-1 (HSV-1) have shown high vector levels and prolonged transgene expression. EBNA-based episome may represent an alternative nonintegrating platform for anticancer-engineered MSC therapy [51].…”

Section: Transfection Methodsmentioning

confidence: 99%

Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Bao

Zhao

Nieß

et al. 2012

Stem Cells and Development

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Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumortargeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host.

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Section: Transfection Methodsmentioning

confidence: 99%

Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Bao

Zhao

Nieß

et al. 2012

Stem Cells and Development

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“…This is because the transgene expression can only be sustained up to a maximum of 14 days due to the nonintegrating nature of the HSV-1 virions [25]. We have recently generated a HSV/Epstein Barr virus (EBV) hybrid vector and showed stable luciferase gene expression in the mouse brain for up to 1 year [53]. Thus, to improve the stability, the pHGCX-TRAIL construct can be subcloned into the HSV/EBV hybrid vector for stable gene expression.…”

mentioning

confidence: 99%

Carbenoxolone Enhances TRAIL-Induced Apoptosis Through the Upregulation of Death Receptor 5 and Inhibition of Gap Junction Intercellular Communication in Human Glioma

Yulyana

Endaya

et al. 2013

Stem Cells and Development

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is much sought after. In this study, we combined the tumor selectivity of TRAIL and tumor-homing properties of mesenchymal stem cells (MSC) with gap junction (GJ) inhibitory effect of carbenoxolone (CBX) to target orthotopic glioma. MSC were engineered to express TRAIL (MSC-TRAIL) by incorporating the secretable trimeric form of TRAIL into a Herpes Simplex Virus (HSV) type I amplicon vector. Our results showed that combined treatment of MSC-TRAIL and CBX enhanced glioma cell death, especially in three primary human glioma isolates, of which two of those are marginally sensitive to TRAIL. CBX enhanced TRAIL-induced apoptosis through upregulation of death receptor 5, blockade of GJ intercellular communication, and downregulation of connexin 43. Dual arm therapy using TRAIL and CBX prolonged the survival of treated mice by *27% when compared with the controls in an intracranial glioma model. The enhanced efficacy of TRAIL in combination with CBX coupled with the minimal cytotoxic nature of CBX suggested a favorable clinical usage of this treatment regimen.

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“…Enhanced efficacy has also been shown by the fusion of yCD to the HSV-1 tegument protein (VP22), which increases the spread of the fusion proteins to surrounding recipient cells. 45,46 Besides the genetic manipulation of the therapeutic gene, one can also improve on the stability of the viral vectors by the incorporation of nonintegrating episomal elements such as the EBNA-1/oriP system, 47,48 or the employment of a replication-competent HSV-1 viruses. Nakamura et al 49 demonstrated that such a mutant virus that expressed the yCD had greater therapeutic effect than the oncolysis induced by the viral replication alone.…”

Section: Discussionmentioning

confidence: 99%

“…Whole cellular DNA was extracted using the QIAamp DNA mini kit (Qiagen) according to the manufacturer's instruction with RNase treatment. The DNA samples were then subjected to quantitative PCR analysis to determine the vector genome copy number as described previously 47 using a Rotor-Gene Q real-time PCR system (Qiagen) with QuantiTect SYBR Green PCR Kit (Qiagen).…”

Section: Vector Genome Copy Number Analysismentioning

confidence: 99%

“…27 Detail procedure for the establishment of HCC 26-1004 in SCID mice was described previously. 47 Single cell suspensions were prepared by gently disrupting the tumors with fine forceps in the presence of 0.5 mg ml -1 collagenase (type IV, pH 7.5; Sigma, St Louis, MO, USA). Procedure to isolate the single cell suspension was performed according to Pichard et al 65 For the establishment of PLC/PRF/5-DsRed2 tumor xenograft, five million of the cells were resuspended in 20 ml of PBS and subcapsularly injected into the left lateral liver lobe of 6-week-old female SCID mice by using a 27-G needle.…”

Section: Western Blot Analysismentioning

confidence: 99%

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Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging

et al. 2011

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Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5Â10 6 TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC.

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Hybrid herpes simplex virus/Epstein–Barr virus amplicon viral vectors confer enhanced transgene expression in primary human tumors and human bone marrow‐derived mesenchymal stem cells

Abstract: Taken together, we have demonstrated that these hybrid vectors could be promising tools as carriers of therapeutic genes in mesenchymal stem cells or even provide an alternative non-integrating platform for the generation of induced pluripotent stem cells.

Cited by 11 publications

References 39 publications

Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

Carbenoxolone Enhances TRAIL-Induced Apoptosis Through the Upregulation of Death Receptor 5 and Inhibition of Gap Junction Intercellular Communication in Human Glioma

Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging

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