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Non-invasive radioiodine imaging for accurate quantitation of NIS reporter gene expression in transplanted hearts

^a Mayo Clinic William J von Liebig Transplant Center, Rochester, MN 55905, USA
^b Molecular Medicine Program, Rochester, MN 55905, USA
^c Division of Cardiac Surgery, Foundation I.R.C.C.S Policlinico San Matteo, University of Pavia, Pavia, Italy

Received 10 July 2007; received in revised form 6 September 2007; accepted 10 September 2007.

^_* Corresponding author. Address: Mayo Clinic William J von Liebig Transplant Center, 9-233 Charlton Building, Rochester, MN 55905, USA. Tel.: +1 507 255 6038; fax: +1 507 255 4500. (Email: mcgregor.christopher{at}mayo.edu).

Objective: We studied the concordance of transgene expression in the transplanted heart using bicistronic adenoviral vector coding for a transgene of interest (human carcinoembryonic antigen: hCEA – beta human chorionic gonadotropin: βhCG) and for a marker imaging transgene (human sodium iodide symporter: hNIS). Methods: Inbred Lewis rats were used for syngeneic heterotopic cardiac transplantation. Donor rat hearts were perfused ex vivo for 30 min prior to transplantation with University of Wisconsin (UW) solution (n = 3), with 10⁹ pfu/ml of adenovirus expressing hNIS (Ad-NIS; n = 6), hNIS-hCEA (Ad-NIS-CEA; n = 6) and hNIS-βhCG (Ad-NIS-CG; n = 6). On postoperative day (POD) 5, 10, 15 all animals underwent micro-single photon emission computed tomography/computed tomography (SPECT/CT) imaging of the donor hearts after tail vein injection of 1000 µCi ¹²³I and blood sample collection for hCEA and βhCG quantification. Results: Significantly higher image intensity was noted in the hearts perfused with Ad-NIS (1.1 ± 0.2; 0.9 ± 0.07), Ad-NIS-CEA (1.2 ± 0.3; 0.9 ± 0.1) and Ad-NIS-CG (1.1 ± 0.1; 0.9 ± 0.1) compared to UW group (0.44 ± 0.03; 0.47 ± 0.06) on POD 5 and 10 (p < 0.05). Serum levels of hCEA and βhCG increased in animals showing high cardiac ¹²³I uptake, but not in those with lower uptake. Above this threshold, image intensities correlated well with serum levels of hCEA and βhCG (R ² = 0.99 and R ² = 0.96, respectively). Conclusions: These data demonstrate that hNIS is an excellent reporter gene for the transplanted heart. The expression level of hNIS can be accurately and non-invasively monitored by serial radioisotopic SPECT imaging. High concordance has been demonstrated between imaging and soluble marker peptides at the maximum transgene expression on POD 5.

Key Words: Gene therapy • Heart transplantation • Sodium iodide symporter (NIS) • Single photon emission computed tomography (SPECT) • Molecular imaging