PET of cardiac transgene expression: Comparison of 2 approaches based on herpesviral thymidine kinase reporter gene

Masao Miyagawa, Martina Anton, Roland Haubner, Marcus V. Simoes, Christian Städele, Wolf Erhardt, Sybille Reder, Terry Lehner, Bettina Wagner, Steffi Noll, Bernhard Noll, Michaela Grote, Sanjiv S. Gambhir, Bernd Gansbacher, Markus Schwaiger, Frank M. Bengel

Research output: Contribution to journalArticle

Abstract

PET of reporter gene expression holds promise for noninvasive monitoring of gene therapy. Previously, 2 approaches based on the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) have been successfully applied to the heart. Wild-type HSV1-tk was imaged with 124I-labeled 2′-fluoro- 2′-deoxy-5-iodo-1-β-D-arabinofuranosyl-5-iodouracil (FIAU), and a mutant HSV1-tk (HSV1-sr39tk) was imaged with 18F-labeled 9-[4-fluoro-3-(hydroxymethyl) butyl]guanine (FHBG). The aim of this study was to compare these 2 combinations with regard to specificity, imaging contrast, and reporter probe kinetics using dynamic PET in small and large animals. Methods: Similar titers of adenovirus-expressing wild-type HSV1-tk (Adtk), mutant HSV1-sr39tk (Adsr39tk), or control genes were directly injected into the myocardium of 24 rats and 8 pigs. Two days later, dynamic PET was performed with a clinical scanner during the 120 min after injection of 124I-FIAU (Adtk animals and controls) or 18F-FHBG (Adsr39tk animals and controls). Imaging with 13N-ammonia was performed to identify cardiac regions of interest. Results: In rats, significant cardiac 124I-FIAU accumulation occurred in images obtained early (10-30 min) after Adtk injection. Because of tracer washout, however, no difference between Adtk-injected animals and controls was seen in the images obtained later. For 18F-FHBG, specific myocardial accumulation greater than background levels was detected in Adsr39tk-injected animals at early imaging and, in contrast to 124I-FIAU accumulation, increased over time until the latest imaging (105-120 min). At maximum, cardiac 18F-FHBG concentration showed a 4.15 ± 1.65-fold increase compared with controls (105-120 min), and cardiac 124I-FIAU concentration reached a maximal increase of 1.34 ± 0.38-fold compared with controls (10-30 min, P = 0.0014). Global cardiac reporter probe kinetics in rats were confirmed by regional myocardial analysis in pig hearts. Transgene expression was specifically visualized by both approaches. The highest target-to-background ratio of 124I-FIAU in Adtk-infected pig myocardium was 1.50 ± 0.20, versus 2.64 ± 0.49 for 18F-FHBG in Ad sr39tk-infected areas (P = 0.01). In vivo results were confirmed by ex vivo counting and autoradiography. Conclusion: Both reporter gene/probe combinations were feasible for noninvasive imaging of cardiac transgene expression in different species. Specific probe kinetics suggest different myocardial handling of pyrimidine (FIAU) and acycloguanosine (FHBG) derivatives. The results favor 18F-FHBG with mutant HSV1-sr39tk because of continuous accumulation over time and higher imaging contrast.

Original languageEnglish (US)
Pages (from-to)1917-1923
Number of pages7
JournalJournal of Nuclear Medicine
Volume45
Issue number11
StatePublished - Nov 1 2004

Keywords

  • Gene therapy
  • HSV1-tk
  • Reporter genes
  • Reporter probes

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Fingerprint Dive into the research topics of 'PET of cardiac transgene expression: Comparison of 2 approaches based on herpesviral thymidine kinase reporter gene'. Together they form a unique fingerprint.

Cite this