An Efficient and Safe Herpes Simplex Virus Type 1 Amplicon Vector for Transcriptionally Targeted Therapy of Human Hepatocellular Carcinomas

Abstract

Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.

HSV as a vector in vaccine development and gene therapy

“…[197][198][199] For example, transcriptional regulation can be rendered specific to human hepatocellular carcinoma cells by inserting the chimeric gene Gal4/NF-YA under the regulation of a HCC-specific hybrid promoter. 200 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in neoplastic cells. It has been reported the efficacy of amplicon delivered TRAIL and its secreted form (S-TRAIL) in treating tumors in vivo and in monitoring both gene delivery and efficacy of TRAIL-mediated apoptosis by dualsubstrate bioluminescence imaging.…”

MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells

“…A key issue in developing a safe and effective oncolytic virotherapy is the achievement of maximal killing of tumor cells while maintaining tumor specificity of viral targeting (13)(14)(15). We have recently shown that a replication-defective HSV-1 helper virus (CgalΔ3), lacking the essential ICP4 gene, became oncolytic in a tissue type-specific fashion when the ICP4 gene was provided by an amplicon expressing this gene under the regulation of a prostate-specific promoter, ARR 2 PB (16).…”

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

“…Furthermore, because the HSV-1 amplicon viral vectors can be packaged in the absence of helper virus, and they typically contain only two noncoding elements of the HSV, ori s and pac, these vectors are therefore relatively noncytotoxic and nonpathogenic when administered in vivo. 24 We have independently confirmed this by injecting the amplicon viral vectors (1Â10 6 transduction units, TU) into immunocompetent BALB/c mice via the tail vein. 25 Thus, the HSV-1 amplicon vectors should serve well as potential carrier of therapeutic genes to HCC tumors.…”