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Transduction of Human Cells with Polymer-complexed Ecotropic Lentivirus for Enhanced Biosafety
Published on: July 24, 2011
Lentiviral HSV-Tk.007-mediated suicide gene therapy is not toxic for normal brain cells
Jubayer A Hossain1,2,3, Lars Rømo Ystaas1,2, Jelena Mrdalj4,5
1Department of Biomedicine, University of Bergen, Bergen, Norway.
Background:
Gene therapeutic strategies with suicide genes are currently investigated in clinical trials for brain tumors. Previously, we have shown that lentiviral vectors delivering the suicide gene HSV-Tk to experimental brain tumors promote a highly significant treatment effect and thus are promising vectors for clinical translation.
Methods:
In the present study, we tested lentiviral vectors delivering the suicide gene HSV-Tk.007, a highly active mutant of HSV-Tk, to rat brains as a preclinical toxicity study. We injected 10(6) vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped functional lentiviral particles harboring the suicide gene HSV-Tk.007 into the brain of healthy, immunocompetent rats. During prodrug treatment with ganciclovir (GCV), we measured weight and assessed the behavior of the rats in an open field test. After 14 days of GCV treatment, we analyzed HSV-Tk.007 expression in different brain cell populations, as well as inflammatory responses and apoptosis.
Results:
During prodrug treatment with GCV, behavior experiments did not reveal differences between the treated rats and the control groups. Analysis of HSV-Tk expression in different brain cell populations showed that transduced normal brain cells survived GCV treatment. There were no statistically significant differences in the number of transduced cells between treatment and control groups. Furthermore, inflammatory responses and apoptosis of brain cells were not observed.
Conclusions:
We show that HSV-Tk.007-mediated suicide gene therapy is not toxic to normal brain cells. This observation is of high relevance for the translation of lentivirus-mediated suicide gene therapies into the clinic for the treatment of brain tumor patients. Copyright © 2016 John Wiley & Sons, Ltd.
Insights
Suicide gene therapy using HSV-Tk.007 lentiviral vectors is safe for healthy brain cells. This preclinical study shows no toxicity, supporting its clinical use for brain tumors.
Area of Science:
- Neuro-oncology
- Gene Therapy
- Viral Vectors
Background:
- Suicide gene therapy is explored for brain tumors.
- Lentiviral vectors with HSV-Tk show promise for clinical translation.
Purpose of the Study:
- To assess the preclinical toxicity of lentiviral vectors delivering the HSV-Tk.007 suicide gene in rat brains.
- To evaluate the safety of HSV-Tk.007-mediated gene therapy in healthy brain tissue.
Main Methods:
- Injected lentiviral particles with HSV-Tk.007 into healthy rat brains.
- Administered ganciclovir (GCV) prodrug treatment for 14 days.
- Monitored rat weight, behavior, cell expression, inflammation, and apoptosis.
Main Results:
- No significant behavioral or weight changes were observed during GCV treatment.
- Transduced normal brain cells survived GCV treatment without increased apoptosis or inflammation.
- No statistically significant differences in cell transduction were found between groups.
Conclusions:
- HSV-Tk.007-mediated suicide gene therapy demonstrates no toxicity in normal brain cells.
- These findings support the clinical translation of lentivirus-mediated suicide gene therapies for brain tumors.
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