Graft permeabilization facilitates gene therapy of transplant arteriosclerosis in a rabbit model

Circulation
M RekhterD Gordon

Abstract

Smooth muscle cell (SMC) replication plays a central role in the pathogenesis of transplant arteriosclerosis. One strategy to eliminate dividing cells is to express a herpesvirus thymidine kinase (tk) gene that phosphorylates the nucleoside analogue ganciclovir into a toxic form leading to cell killing. However, medial SMCs are resistant to gene transfer unless the artery undergoes deendothelialization. We hypothesized that manipulations that increase the "porosity" of the artery can make SMCs prone to gene transfer without denudation. In organ culture of rabbit aorta, longitudinal stretch and supraphysiological pressure applied for 3 hours during incubation with adenoviral vector facilitated gene transfer into medial SMCs without denudation. Of the SMCs, 10.2+/-3.8% expressed a reporter gene of human placental alkaline phosphatase (hpAP), whereas SMCs in control arteries did not express hpAP. To evaluate the feasibility of transgene expression in arterial grafts, we performed such permeabilization-assisted reporter gene transfer into aortas of donor Dutch Belted rabbits and transplanted them into carotid arteries of recipient New Zealand White rabbits. Unstretched transfected grafts were used as a control. SMCs expressed hpAP ...Continue Reading

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Citations

Mar 18, 2005·Annals of Biomedical Engineering·Sarah AnderNaomi Chesler
Apr 25, 2000·Annual Review of Medicine·M Weis, W von Scheidt
Jul 29, 1999·The Journal of Surgical Research·J S MatsumuraW H Pearce
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Related Concepts

Adenoviruses
Metazoa
Ascending Aorta Structure
Arteriosclerosis
Cell Division Phases
Muscle, Smooth, Vascular
Organ Culture Techniques
Permeability
Chinchilla Rabbits
Thymidine Kinase

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