Targeting of breast metastases using a viral gene vector with tumour-selective transcription
Simon Rajendran1, Sara Collins, Jan P van Pijkeren
1Cork Cancer Research Centre, Mercy University Hospital, Cork, Ireland.
Background:
Adeno-associated virus (AAV) vectors have significant potential as gene delivery vectors for cancer gene therapy. However, broad AAV2 tissue tropism results in nonspecific gene expression.
Materials And Methods:
We investigated use of the C-X-C chemokine receptor type 4 (CXCR4) promoter to restrict AAV expression to tumour cells, in subcutaneous MCF-7 xenograft mouse models of breast cancer and in patient samples, using bioluminescent imaging and flow cytometric analysis.
Results:
Higher transgene expression levels were observed in subcutaneous MCF-7 tumours relative to normal tissue (muscle) using the CXCR4 promoter, unlike a ubiquitously expressing Cytomegalovirus promoter construct, with preferential AAVCXCR4 expression in epithelial tumour and CXCR4-positive cells. Transgene expression following intravenously administered AAVCXCR4 in a model of liver metastasis was detected specifically in livers of tumour bearing mice. Ex vivo analysis using patient samples also demonstrated higher AAVCXCR4 expression in tumour compared with normal liver tissue.
Conclusion:
This study demonstrates for the first time, the potential for systemic administration of AAV2 vector for tumour-selective gene therapy.
Insights
This study shows that using the CXCR4 promoter with adeno-associated virus (AAV) vectors can achieve tumor-selective gene expression, improving cancer gene therapy potential.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Adeno-associated virus (AAV) vectors show promise for cancer gene therapy.
- Non-specific gene expression due to broad AAV2 tissue tropism is a limitation.
Purpose of the Study:
- To investigate the use of the C-X-C chemokine receptor type 4 (CXCR4) promoter to restrict AAV expression to tumor cells.
- To evaluate AAV vector tropism and gene expression in breast cancer models and patient samples.
Main Methods:
- Utilized subcutaneous MCF-7 xenograft mouse models and patient samples.
- Employed bioluminescent imaging and flow cytometric analysis to assess transgene expression.
- Investigated AAV vectors with CXCR4 promoter versus Cytomegalovirus (CMV) promoter.
Main Results:
- AAV vectors with the CXCR4 promoter demonstrated higher transgene expression in tumors compared to normal tissue.
- Preferential AAVCXCR4 expression was observed in epithelial tumor and CXCR4-positive cells.
- Systemic administration of AAVCXCR4 specifically targeted tumors in liver metastasis models and patient samples.
Conclusions:
- The CXCR4 promoter enables tumor-selective gene expression for AAV vectors.
- This approach holds potential for systemic administration in cancer gene therapy.
- Demonstrates a novel strategy for targeted delivery of therapeutic genes to tumors.
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