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A Rabbit Model of Durable Transgene Expression in Jugular Vein to Common Carotid Artery Interposition Grafts
Published on: September 10, 2018
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Efficient gene transfer and durable transgene expression in grafted rabbit veins
Liang Du1, Jingwan Zhang, Alexander W Clowes
11 Department of Medicine/Cardiology, University of Washington , Seattle, WA 98195.
Human Gene Therapy
|November 11, 2014
Summary
Gene therapy can prevent vein graft atherosclerosis, a common complication of bypass surgery. Delaying gene transfer until the vein adapts to arterial circulation ensures long-term expression and graft patency.
Area of Science:
- Vascular biology
- Gene therapy
- Biomedical engineering
Background:
- Venous bypass grafts are crucial for treating obstructive coronary artery disease.
- Accelerated atherosclerosis limits the long-term effectiveness of venous bypass grafts.
- Developing strategies to prevent vein graft atherosclerosis is essential for improving patient outcomes.
Purpose of the Study:
- To investigate the potential of gene therapy to prevent vein graft atherosclerosis.
- To determine the optimal timing for gene transfer in venous bypass grafts.
- To assess the durability of transgene expression and its effect on graft remodeling.
Main Methods:
- Utilized a rabbit jugular vein-to-carotid interposition grafting model.
- Employed adenoviral vectors for gene transfer into venous bypass grafts.
- Investigated both immediate and delayed (28 days post-grafting) gene transduction strategies.
- Quantified transgene expression, vector DNA, and mRNA levels over time.
- Monitored graft neointimal growth, medial thickening, and lumen diameter changes.
Main Results:
- Immediate gene transfer resulted in rapid loss of transgene expression within 3 days.
- Delayed transduction (28 days post-grafting) prevented early transgene loss and ensured stable expression for at least 6 months.
- Helper-dependent adenoviral (HDAd) vectors demonstrated durable expression of apolipoprotein A-I.
- Despite initial neointimal growth and medial thickening, delayed gene transfer led to outward remodeling, preserving graft lumen diameter.
- Gene therapy effectively prevented vein graft atherosclerosis.
Conclusions:
- Delayed gene transfer to arterialized venous bypass grafts is a promising strategy for preventing atherosclerosis.
- Helper-dependent adenoviral vectors offer durable transgene expression for therapeutic applications.
- This approach holds potential for improving long-term patency and clinical outcomes in patients undergoing bypass surgery.
