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In Vivo Gene Transfer to the Rabbit Common Carotid Artery Endothelium
Published on: May 6, 2018
Adenovirus-mediated gene transfer in vivo: an approach to reduce oxidative stress
1Cardiovascular Center, Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, USA.
Abstract:
Replication-deficient adenoviruses are used as vectors to study function of genes and to treat hypertension and cardiovascular diseases in preclinical studies. The purpose of this chapter is to provide an example of applications of the "first-generation," E1-deleted and partially E3-deleted, human adenovirus type 5 vector, to test the hypothesis that gene transfer of a primary antioxidant enzyme, human extracellular superoxide dismutase (ECSOD), reduces arterial pressure in a genetic animal model of hypertension. Two concepts in application of gene transfer in vascular biology are illustrated. First, the liver, by iv injection of an adenoviral vector, can function as the source for abundant amounts of a transgene product, with profound vascular effects, when the transgene encodes a secreted protein. Second, the specific function of a domain of the transgene product can be studied by preparation and injection of isogenic vectors that express the identical product with or without a domain.
Insights
Gene transfer of human extracellular superoxide dismutase (ECSOD) using adenoviral vectors effectively reduced arterial pressure in a genetic hypertension model. This study highlights the liver
Area of Science:
- Vascular Biology
- Gene Therapy
- Cardiovascular Research
Background:
- Replication-deficient adenoviruses are established vectors for gene function studies and preclinical cardiovascular disease treatment.
- Hypertension and cardiovascular diseases remain significant global health challenges requiring novel therapeutic strategies.
Purpose of the Study:
- To test if gene transfer of human extracellular superoxide dismutase (ECSOD) using a first-generation adenovirus type 5 vector reduces arterial pressure in a genetic animal model of hypertension.
- To illustrate key concepts in gene transfer applications within vascular biology.
Main Methods:
- Utilized a first-generation, E1-deleted, partially E3-deleted human adenovirus type 5 vector for gene delivery.
- Administered the adenoviral vector intravenously (iv) to a genetic animal model of hypertension.
- Prepared and injected isogenic vectors to assess the function of specific domains within the transgene product.
Main Results:
- Gene transfer of human ECSOD via adenoviral vector injection into the liver resulted in reduced arterial pressure in the hypertension model.
- Demonstrated that the liver can serve as a potent source of secreted transgene products with significant vascular effects.
- Showcased the ability to investigate specific protein domain functions through isogenic vector comparisons.
Conclusions:
- Adenoviral-mediated gene transfer of ECSOD is a viable strategy for reducing arterial pressure in hypertension.
- The liver is an effective organ for systemic gene therapy targeting vascular diseases when delivering secreted proteins.
- Gene transfer techniques allow for detailed functional analysis of protein domains in vivo.
