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Characterization of infectivity of knob-modified adenoviral vectors in glioma
C P L Paul1, M Everts, J N Glasgow
1Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Abstract:
Malignant glioma continues to be a major target for gene therapy and virotherapy due to its aggressive growth and the current lack of effective treatment. However, these approaches have been hampered by inefficient infection of glioma cells by viral vectors,particularly vectors derived from serotype 5 adenoviruses (Ad5). This results from limited cell surface expression of the primary adenovirus receptor, coxsackie-adenovirus-receptor (CAR), on tumor cells. To circumvent this problem, Ad fiber pseudotyping,the genetic replacement of either the entire fiber or fiber knob domain with its structural counterpart from another human Ad serotype that recognizes a cellular receptor other than CAR, has been shown to enhance Ad infectivity in a variety of tumor types,including human glioma. Here, we have extended the paradigm of genetic pseudotyping to include fiber domains from non-human or"xenotype" Ads for infectivity enhancement of human glioma cell populations. In this study, we evaluated the gene transfer efficiency of a panel of Ad vectors which express one of five different "xenotype"fiber knob domains, including those derived from murine,ovine, porcine and canine species, in both human glioma cell lines as well as primary glioma tumor cells from patients. Adenovirus vectors displaying either canine Ad or porcine Ad fiber elements had the highest gene transfer to both glioma cell lines and primary tumor cells. The correlation between the viral infectivity of modified adenovirus vectors and expression of human CAR and CD46(an adenovirus type B receptor) on the surfaces of tumor cells was also analyzed. Taken together, human adenovirus vectors modified with "xenotype" fiber elements could be excellent candidates to target human glioma.
Insights
Gene therapy for malignant glioma shows promise using modified adenovirus vectors. Xenotype fiber elements from canine and porcine adenoviruses significantly enhanced gene transfer to glioma cells, offering a new therapeutic avenue.
Area of Science:
- Oncolytic Virotherapy
- Gene Therapy
- Adenovirus Vector Engineering
Background:
- Malignant glioma is an aggressive brain tumor with limited treatment options.
- Gene and virotherapy for glioma face challenges due to inefficient viral vector infection.
- Adenovirus serotype 5 (Ad5) vectors are hindered by low coxsackie-adenovirus-receptor (CAR) expression on glioma cells.
Purpose of the Study:
- To enhance adenovirus vector infectivity in human glioma cells using "xenotype" fiber pseudotyping.
- To evaluate the gene transfer efficiency of adenovirus vectors with xenotype fiber knob domains.
- To analyze the correlation between viral infectivity and tumor cell receptor expression (CAR and CD46).
Main Methods:
- Genetic pseudotyping of adenovirus vectors with fiber knob domains from five "xenotype" adenoviruses (murine, ovine, porcine, canine).
- Testing gene transfer efficiency in human glioma cell lines and primary patient-derived glioma tumor cells.
- Assessing the expression levels of CAR and CD46 on tumor cell surfaces.
Main Results:
- Adenovirus vectors displaying canine Ad or porcine Ad fiber elements demonstrated the highest gene transfer efficiency.
- Significant enhancement of gene transfer was observed in both glioma cell lines and primary tumor cells.
- Correlation analysis revealed relationships between viral infectivity and CAR/CD46 expression.
Conclusions:
- "Xenotype" adenovirus vectors, particularly those with canine or porcine fiber elements, show potential for targeting human glioma.
- Fiber pseudotyping with xenotype domains offers a strategy to overcome CAR-dependent entry barriers.
- Modified adenovirus vectors represent promising candidates for future glioma gene therapy and virotherapy applications.
