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Combined Genetic and Chemical Capsid Modifications of Adenovirus-Based Gene Transfer Vectors for Shielding and Targeting
Published on: October 26, 2018
Recent advances in genetic modification of adenovirus vectors for cancer treatment
Yuki Yamamoto1, Masaki Nagasato1, Teruhiko Yoshida2
1Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Adenoviruses are widely used to deliver genes to a variety of cell types and have been used in a number of clinical trials for gene therapy and oncolytic virotherapy. However, several concerns must be addressed for the clinical use of adenovirus vectors. Selective delivery of a therapeutic gene by adenovirus vectors to target cancer is precluded by the widespread distribution of the primary cellular receptors. The systemic administration of adenoviruses results in hepatic tropism independent of the primary receptors. Adenoviruses induce strong innate and acquired immunity in vivo. Furthermore, several modifications to these vectors are necessary to enhance their oncolytic activity and ensure patient safety. As such, the adenovirus genome has been engineered to overcome these problems. The first part of the present review outlines recent progress in the genetic modification of adenovirus vectors for cancer treatment. In addition, several groups have recently developed cancer-targeting adenovirus vectors by using libraries that display random peptides on a fiber knob. Pancreatic cancer-targeting sequences have been isolated, and these oncolytic vectors have been shown by our group to be associated with a higher gene transduction efficiency and more potent oncolytic activity in cell lines, murine models, and surgical specimens of pancreatic cancer. In the second part of this review, we explain that combining cancer-targeting strategies can be a promising approach to increase the clinical usefulness of oncolytic adenovirus vectors.
Insights
Engineered adenoviruses show improved cancer targeting and oncolytic activity. Genetic modifications enhance gene delivery efficiency and potency for pancreatic cancer treatment, increasing clinical utility.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Viral vector engineering
Background:
- Adenoviruses are versatile gene delivery vectors used in clinical trials for gene therapy and oncolytic virotherapy.
- Clinical application of adenovirus vectors faces challenges including non-specific targeting, hepatic tropism, and induction of immune responses.
- Genetic modifications are crucial for enhancing adenovirus vector oncolytic activity and patient safety.
Purpose of the Study:
- To review recent advancements in genetically modified adenovirus vectors for cancer treatment.
- To highlight the development of cancer-targeting adenovirus vectors using peptide libraries displayed on fiber knobs.
- To discuss the potential of combining cancer-targeting strategies to improve the clinical usefulness of oncolytic adenovirus vectors.
Main Methods:
- Genetic engineering of the adenovirus genome to overcome limitations in targeted gene delivery.
- Development of cancer-targeting adenovirus vectors through libraries displaying random peptides on fiber knobs.
- Isolation of pancreatic cancer-targeting sequences and evaluation of their efficacy in preclinical models.
Main Results:
- Engineered adenovirus vectors demonstrate enhanced gene transduction efficiency and potent oncolytic activity.
- Pancreatic cancer-targeting sequences have been identified, leading to improved vector performance in cell lines, murine models, and surgical specimens.
- Targeted adenovirus vectors show increased efficacy in preclinical models of pancreatic cancer.
Conclusions:
- Genetic modification of adenovirus vectors is essential for improving their therapeutic potential in cancer treatment.
- Cancer-targeting strategies, particularly those involving peptide display on fiber knobs, show promise for enhancing vector specificity and efficacy.
- Combining targeting strategies offers a promising approach to increase the clinical applicability of oncolytic adenovirus vectors.
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