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Journal of Transplantation
Volume 2012 (2012), Article ID 740653, 10 pages
http://dx.doi.org/10.1155/2012/740653
Research Article

Gene Transfer of Heme Oxygenase-1 Using an Adeno-Associated Virus Serotype 6 Vector Prolongs Cardiac Allograft Survival

1Department of Anesthesiology Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
2Department of Cardiothoracic Surgery, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
3Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Alumni Hall Room 326, 11021 Campus Street, Loma Linda, CA 92350, USA

Received 18 May 2012; Revised 7 September 2012; Accepted 7 September 2012

Academic Editor: Simon Robson

Copyright © 2012 Jacqueline M. Evans et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction. Allograft survival can be prolonged by overexpression of cytoprotective genes such as heme oxygenase-1 (HO-1). Modifications in vector design and delivery have provided new opportunities to safely and effectively administer HO-1 into the heart prior to transplantation to improve long-term graft outcome. Methods. HO-1 was delivered to the donor heart using an adeno-associated virus vector (AAV) with a pseudotype 6 capsid and vascular endothelial growth factor (VEGF) to enhance myocardial tropism and microvascular permeability. Survival of mouse cardiac allografts, fully or partially mismatched at the MHC, was determined with and without cyclosporine A. Intragraft cytokine gene expression was examined by PCR. Results. The use of AAV6 to deliver HO-1 to the donor heart, combined with immunosuppression, prolonged allograft survival by 55.3% when donor and recipient were completely mismatched at the MHC and by 94.6% if partially mismatched. The combination of gene therapy and immunosuppression was more beneficial than treatment with either AAV6-HO-1 or CsA alone. IL-17a, b, e and f were induced in the heart at rejection. Conclusions. Pretreatment of cardiac allografts with AAV6-HO-1 plus cyclosporine A prolonged graft survival. HO-1 gene therapy represents a beneficial adjunct to immunosuppressive therapy in cardiac transplantation.