Non-invasive imaging of cardiac transgene expression with PET: comparison of the human sodium/iodide symporter gene and HSV1-tk as the reporter gene.
OBJECTIVE
Genes encoding for intracellular enzymes or transmembrane proteins are suitable as reporters, but may differ in terms of applicability for cardiac imaging. The aim of this study was to compare the human sodium iodide symporter gene (hNIS) with the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) as the reporter gene in non-invasive imaging of cardiac transgene expression with positron emission tomography (PET).


METHODS
Equal doses of adenoviral vectors encoding for hNIS, wild-type HSV1-tk, mutant HSV1-sr39tk or LacZ as the control gene were directly injected into the myocardium of 34 animals. Two days later, dynamic PET was performed with a clinical scanner, using reporter probes specific for the respective reporter gene. Imaging with (13)N-ammonia was also performed to identify cardiac regions of interest.


RESULTS
Kinetics differed significantly: (124)I as the probe for hNIS showed rapid early uptake, remaining stable over time. Maximal myocardial concentration was 3.61+/-1.15%. The nucleoside (18)F-FHBG, as the specific probe for HSV1-sr39tk, showed increasing uptake over time, but maximal accumulation was significantly lower (1.45+/-0.54%, P=0.0009). (124)I-FIAU, as the specific probe for wild-type HSV1-tk, showed early uptake with subsequent washout. Maximal accumulation was lowest (0.63+/-0.23%, P<0.0001). Post-mortem analysis by autoradiography and gamma counting confirmed the in vivo data.


CONCLUSIONS
Reporter genes encoding for transporter proteins such as hNIS are an attractive alternative to overexpression of intracellular enzymes for cardiac gene product imaging. hNIS yielded higher signal intensity and imaging contrast for PET than did HSV1-tk and HSV1-sr39tk. Therefore, this approach may be preferable for the future monitoring of cardiac gene- or cell-based therapy.
Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675, München, Germany.
Masao
M
Miyagawa
Martina
M
Anton
Bettina
B
Wagner
Roland
R
Haubner
Michael
M
Souvatzoglou
Bernd
B
Gansbacher
Markus
M
Schwaiger
Frank M
FM
Bengel
D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D017930:Genes, Reporter / Q000235:genetics; D006321:Heart / Q000000981:diagnostic imaging*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods*; D019076:Transgenes / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D000099209:Sodium-Iodide Symporters
D027981:Symporters; D013937:Thymidine Kinase; D014764:Viral Proteins; D000099209:Sodium-Iodide Symporters; C099241:thymidine kinase, Canid herpesvirus 1