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Reviews

Modalities and future prospects of gene therapy in heart transplantation

^a Departments of Cardiology and Cardiovascular Surgery, Fondazione CardioCentro Ticino, Lugano, Switzerland
^b Departments of Cardiology and Cardiovascular Surgery, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland
^c Geneva-Lausanne Transplant Network, Hôpital Universitaire de Genève (HUG) and CHUV, Geneva and Lausanne, Switzerland

Received 2 June 2008; received in revised form 28 January 2009; accepted 28 January 2009.

^_* Corresponding author. Address: CardioCentro Ticino, via Tesserete, 6900 Lugano, Switzerland. (Email: giuseppe.vassalli{at}cardiocentro.org).

Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia–reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact.

Key Words: Heart transplantation • Gene therapy • Rejection • Graft vasculopathy • Tolerance