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Updated: Jun 11, 2026
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Molecular engineering and validation of an oncolytic herpes simplex virus type 1 transcriptionally targeted to
Arturo R Maldonado1, Chuck Klanke, Anil G Jegga
1Division of Pediatric General and Thoracic Surgery, The Center For Molecular Fetal Therapy, Children's Hospital Medical Center, Cincinnati, OH, USA.
Background:
Expression profile analyses of midkine (MDK), a multifunctional protein important in development but repressed postnataly, indicate that it is highly expressed in approximately 80% of adult carcinomas and many childhood cancers including malignant peripheral nerve sheath tumors (MPNST). In the present study, we sought to leverage its selective expression to develop a novel oncolytic herpes simplex virus (oHSV) capable of targeting developmentally primitive cancers that express MDK.
Methods:
We sought to increase the oncolytic efficacy of the virus by fusing the human MDK promoter to the HSV type 1 neurovirulence gene, gamma(1)34.5, whose protein product increases viral replication.
Results:
Tissue-specific MDK promoter activity in human tumor cells and transgene biological activity was confirmed in human MPNST tumor cells. In vitro replication and cytotoxicity in human fibroblasts and MPNST cells by plaque and MTT assays showed that oHSV-MDK-34.5 increased replication and cytotoxicity compared to oHSV-MDK-Luc. By contrast, no significant difference in cytotoxicity was detected between these viruses in normal human fibroblasts. oHSV-MDK-34.5 impaired in vivo tumor growth and increased median survival of MPNST tumor-bearing nude mice.
Conclusions:
The transcriptional targeting of HSV lytic infection to MDK-expressing tumor cells is feasible. oHSV-MDK-34.5 shows enhanced anti-tumor effects both in vitro and in vivo. Further studies are warranted and may lead to its use in clinical trials.
Insights
Researchers developed a novel oncolytic herpes simplex virus (oHSV) targeting midkine (MDK)-expressing cancers. This MDK-targeted oHSV demonstrated enhanced anti-tumor effects in vitro and in vivo, showing promise for future clinical applications.
Area of Science:
- Oncolytic virotherapy
- Cancer gene therapy
- Herpes simplex virus (HSV) engineering
Background:
- Midkine (MDK) is a protein highly expressed in various adult and childhood cancers, including malignant peripheral nerve sheath tumors (MPNST).
- MDK's selective expression in tumors presents a potential target for cancer therapies.
Purpose of the Study:
- To develop a novel oncolytic herpes simplex virus (oHSV) that specifically targets MDK-expressing cancers.
- To enhance the oncolytic efficacy of HSV by utilizing the MDK promoter to drive expression of a viral replication gene.
Main Methods:
- Engineered an oHSV by fusing the human MDK promoter to the HSV type 1 neurovirulence gene, gamma(1)34.5, creating oHSV-MDK-34.5.
- Assessed MDK promoter activity and transgene function in human MPNST cells.
- Evaluated viral replication and cytotoxicity in vitro using plaque and MTT assays in MPNST cells and human fibroblasts.
- Tested in vivo efficacy in MPNST tumor-bearing nude mice.
Main Results:
- Confirmed MDK promoter-driven transgene expression and biological activity in human MPNST cells.
- oHSV-MDK-34.5 exhibited increased replication and cytotoxicity against MPNST cells compared to a control virus (oHSV-MDK-Luc) with no significant difference in normal fibroblasts.
- In vivo studies showed that oHSV-MDK-34.5 impaired tumor growth and improved median survival in MPNST-bearing mice.
Conclusions:
- Transcriptional targeting of HSV lytic infection to MDK-expressing tumor cells is feasible.
- oHSV-MDK-34.5 demonstrates enhanced anti-tumor efficacy both in vitro and in vivo.
- Further research is warranted for potential clinical trials.
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