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Updated: May 29, 2026
Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
A transductionally retargeted adenoviral vector for virotherapy of Her2/neu-expressing prostate cancer
M K Magnusson1, R Kraaij, R M Leadley
1Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg , 405 30 Gothenburg, Sweden.
Abstract:
The efficacy of adenovirus (Ad)-based gene therapy of solid tumors, such as prostate cancer, is limited. One of the many problems is that the virus infects many different cell types in the body, resulting in high toxicity, whereas the target cancer cells are often less prone to wild-type Ad infection. Our aim was to develop genetically de- and retargeted Ad vectors to reduce off-target effects and increase target infection for prostate cancer. We have previously reported an Ad5 vector specific for the cancer-associated receptor Her2/neu, created by inserting Her2/neu-reactive Affibody(®) molecules (ZH) into the HI loop of a coxsackievirus and adenovirus receptor binding-ablated fiber (Ad[ZH/1]). In addition to virus retargeting to Her2/neu, this virus was further modified from wild-type Ad by changing the RGD motif in the penton base to EGD and by substitution of the KKTK motif in the third shaft repeat to RKSK, resulting in the vector Ad[ZH/3]. The ZH-containing vectors could be produced to high titers and were specific for their target, resulting in efficient infection and killing of Her2/neu-positive androgen-dependent PC346C prostate cancer cells in vitro. Here we show that the oncolytic Ad[ZH/3] vector significantly prolonged survival time and reduced serum prostate-specific antigen levels in an orthotopic prostate tumor model in nude mice to the same extent as wild-type Ad5. Our results show that Her2/neu targeting using Ad-based vectors for prostate cancer is feasible and may serve as a basis for the development of gene therapy of human prostate cancer as well as other Her2/neu-expressing cancers.
Insights
This study developed a targeted adenovirus (Ad) gene therapy vector for prostate cancer. The modified Ad vector specifically targets Her2/neu-positive cancer cells, reducing toxicity and improving efficacy in mouse models.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer research
Background:
- Adenovirus (Ad)-based gene therapy for solid tumors shows limited efficacy due to toxicity and poor tumor cell infection.
- Wild-type Ad infects various cell types, causing off-target effects, while cancer cells may be less susceptible.
- Prostate cancer therapy requires strategies to enhance tumor-specific viral infection and reduce systemic toxicity.
Purpose of the Study:
- To develop genetically de- and retargeted Ad vectors for enhanced prostate cancer infection and reduced off-target effects.
- To create an Ad vector targeting the cancer-associated receptor Her2/neu for prostate cancer gene therapy.
- To evaluate the in vivo efficacy of the retargeted Ad vector in an orthotopic prostate tumor model.
Main Methods:
- Genetically modified Ad5 vector (Ad[ZH/3]) incorporating Her2/neu-reactive Affibody molecules (ZH) into a modified fiber protein.
- Modification of Ad5 to ablate wild-type receptor binding and alter penton base and fiber shaft motifs (RGD to EGD, KKTK to RKSK).
- In vitro assessment of viral specificity and efficacy against Her2/neu-positive prostate cancer cells (PC346C).
- In vivo evaluation in an orthotopic prostate tumor model in nude mice, measuring survival time and prostate-specific antigen (PSA) levels.
Main Results:
- The ZH-containing Ad vectors were produced at high titers and demonstrated specificity for Her2/neu-positive cells.
- Efficient in vitro infection and killing of Her2/neu-positive prostate cancer cells (PC346C) were observed.
- The oncolytic Ad[ZH/3] vector significantly prolonged survival and reduced serum PSA levels in mice, comparable to wild-type Ad5.
- Her2/neu targeting with Ad-based vectors proved feasible for prostate cancer treatment.
Conclusions:
- Her2/neu targeting using genetically modified adenovirus vectors is a feasible strategy for prostate cancer gene therapy.
- The developed Ad[ZH/3] vector demonstrates reduced off-target effects and enhanced tumor-specific infection.
- This approach may form the basis for treating human prostate cancer and other Her2/neu-expressing malignancies.
