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Plectin-1 Targeted AAV Vector for the Molecular Imaging of Pancreatic Cancer
Prasad R Konkalmatt1, Defeng Deng, Stephanie Thomas
1Department of Biomedical Engineering, University of Virginia Charlottesville, VA, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant disease that is the fourth leading cause of cancer-related death in the US. Gene therapy using AAV vectors to selectively deliver genes to PDAC cells is an attractive treatment option for pancreatic cancer. However, most AAV serotypes display a broad spectrum of tissue tropism and none of the existing serotypes specifically target PDAC cells. This study tests the hypothesis that AAV2 can be genetically re-engineered to specifically target PDAC cells by modifying the capsid surface to display a peptide that has previously been shown to bind plectin-1. Toward this end, a Plectin-1 Targeting Peptide (PTP) was inserted into the loop IV region of the AAV2 capsid, and the resulting capsid (AAV-PTP) was used in a series of in vitro and in vivo experiments. In vitro, AAV-PTP was found to target all five human PDAC cell lines tested (PANC-1, MIA PaCa-2, HPAC, MPanc-96, and BxPC-3) preferentially over two non-neoplastic human pancreatic cell lines (human pancreatic ductal epithelial and human pancreatic stellate cells). In vivo, mice bearing subcutaneous tumor xenografts were generated using the PANC-1 cell line. Once tumors reached a size of ∼1-2 mm in diameter, the mice were injected intravenously with luciferase reporter vectors packaged in the either AAV-PTP or wild type AAV2 capsids. Luciferase expression was then monitored by bioluminescence imaging on days 3, 7, and 14 after vector injection. The results indicate that the AAV-PTP capsid displays a 37-fold preference for PANC-1 tumor xenographs over liver and other tissues; whereas the wild type AAV2 capsid displays a complementary preference for liver over tumors and other tissues. Together, these results establish proof-of-principle for the ability of PTP-modified AAV capsids to selectively target gene delivery to PDAC cells in vivo, which opens promising new avenues for the early detection, diagnosis, and treatment of pancreatic cancer.
Insights
Researchers engineered AAV2 capsids to target pancreatic ductal adenocarcinoma (PDAC). The modified AAV-PTP selectively targeted PDAC cells in vitro and in vivo, showing promise for gene therapy in pancreatic cancer.
Area of Science:
- Oncology
- Gene Therapy
- Biotechnology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options.
- Current gene therapy vectors, like adeno-associated virus (AAV), lack specificity for PDAC cells.
- Targeted delivery of therapeutic genes to PDAC is crucial for effective treatment.
Purpose of the Study:
- To genetically re-engineer AAV2 capsids for selective targeting of PDAC cells.
- To evaluate the in vitro and in vivo efficacy of engineered AAV capsids for PDAC gene delivery.
- To establish proof-of-principle for AAV-PTP in targeting pancreatic cancer.
Main Methods:
- A Plectin-1 Targeting Peptide (PTP) was inserted into the AAV2 capsid (AAV-PTP).
- In vitro studies assessed AAV-PTP targeting of PDAC cell lines versus normal pancreatic cells.
- In vivo studies used bioluminescence imaging to compare AAV-PTP and wild-type AAV2 targeting in tumor xenografts.
Main Results:
- AAV-PTP demonstrated preferential targeting of all five tested human PDAC cell lines in vitro.
- In vivo, AAV-PTP showed a 37-fold greater preference for PDAC tumor xenografts compared to wild-type AAV2.
- Wild-type AAV2 preferentially targeted the liver, unlike the engineered AAV-PTP.
Conclusions:
- Engineered AAV-PTP capsids can selectively target PDAC cells in vitro and in vivo.
- This targeted delivery approach holds significant potential for pancreatic cancer gene therapy.
- Further development of AAV-PTP opens new avenues for early detection and treatment of pancreatic cancer.
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