Reporter gene PET/CT imaging strategy tracks mechanisms of cardiac gene therapy

CONTEXT: Dr. Markus Schwaiger and colleagues at the Technical University of Munich, Germany, have demonstrated that successful transfer of the vascular endothelial growth factor (VEGF) gene results in an increase of tissue perfusion without impairing cardiac contractile function or morphology.

RESULTS: Four pigs were injected with an adenoviral vector (Ad4tk) that transferred the therapeutic VEGF gene and the PET reporter gene HSV1-tk (herpes simplex virus type 1 thymidine kinase) into their myocardia. An adenovirus expressing only HSV1-tk or VEGF in separate regions was also administered. The animals were scanned with fluorine-18 FDG-PET/CT two days later. Uptake indicated successful gene transfer. Myocardial perfusion increased in VEGF-treated areas. CT revealed no abnormalities in cardiac contractile function. F-18 galacto-RDG PET/CT performed on one animal three days after gene transfer and on another seven days after transfer showed no significant uptake in VEGF-treated regions, indicating an absence of elevated av-integrin expression associated with angiogenesis. Schwaiger and coinvestigator Frank Bengel suspect that the effect of VEGF on vasodilation and microvascular permeability restricts integrin expression.

IMAGE: Molecular PET/CT of pig heart. Left ventricular short-axis images of heart two days after gene transfer by direct intramyocardial adenovirus injection. The injection site is marked by a titanium clip, as depicted on the multislice CT image (top). The corresponding PET image (bottom) shows regional accumulation of a reporter probe, indicating successful transfer and expression of a reporter gene. A fusion image (middle) confirms colocalization of gene expression and clip-marked injection site.

IMPLICATIONS: This PET-CT technique will enable researchers to understand the genomic/proteomic changes, physiological effects, and morphologic alterations associated with cardiac gene therapy, according to Bengel. Refinements will permit them to monitor protein expression for weeks rather than days.