1. ¹Division of Cardiothoracic Surgery, Department of Surgery, UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
2. ²Division of Cardiology, Department of Medicine, UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
3. ³Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA Medical Center, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA
4. ⁴Department of Radiology & Bio-X, Stanford University, Stanford, CA 94305, USA

Correspondence: Luyi Sen, Fax: (310) 206-9133. E-mail: lsen@mednet.ucla.edu.

Received 10 August 2004; Accepted 4 March 2005.

Abstract

We developed a clinically applicable approach for noninvasive monitoring of reporter–therapeutic linked gene expression in the whole heart of large animals using PET imaging and further validated the efficacy and cardiac adverse effects of reporter–therapeutic linked gene transfer in a rabbit cervical heterotopic functional heart transplant model. Cationic liposome complexed with a vector containing a herpes simplex virus type 1 mutant thymidine kinase (HSV1-sr39tk) as the reporter gene and a recombinant human immunosuppressive cytokine, interleukin-10 (hIL-10), as the therapeutic gene was ex vivo intracoronarily delivered into cardiac allografts before implantation. Long-term HSV1-sr39tk and hIL-10 transgene and protein overexpression associated with myocardial PET reporter probe 9-(4-[¹⁸F]fluoro-3-hydroxymethylbutyl)guanine ([¹⁸F]FHBG) accumulation was observed in the allografts. The expression of the HSV1-sr39tk gene was significantly correlated with the hIL-10 gene expression and the total myocardial [¹⁸F]FHBG accumulation quantified as a percentage of intravenously injected [¹⁸F]FHBG dose. A homogeneous distribution of [¹⁸F]FHBG accumulation was seen in the whole heart similar to the distribution of [¹⁸F]fluorodeoxyglucose, a PET glucose metabolism probe. The immunosuppressive therapeutic efficacy remained the same in allografts treated with reporter–therapeutic linked gene and therapeutic gene only. No cardiac adverse effect was found. Our results demonstrate for the first time that PET reporter–therapeutic linked gene imaging is applicable for noninvasively monitoring ex vivo intracoronarily delivered therapeutic transgene expression in the whole heart.