Published ahead of print on December 27, 2002, doi:10.1164/rccm.200210-1217OC
Am. J. Respir. Crit. Care Med., Volume 167, Number 9, May 2003, 1257-1263
A more recent version of this article appeared on May 1, 2003
Submitted on October 24, 2002
Accepted on December 26, 2002
Imaging Pulmonary Gene Expression With Positron Emission Tomography (PET)
Jean-Christophe Richard1, Zhaouhi Zhou1, Datta E Ponde1, Carmen S Dence1, Phillip Factor2, Paul N Reynolds3, Gary D Luker1, Vijay Sharma1, Tom Ferkol4, David Piwnica-Worms1, and Daniel P Schuster5*
1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA,
2 Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, Evanston, Illinois, USA; Northwestern University Medical School, Chicago, Illinois, USA,
3 Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Royal Adelaide Hospital, Adelaide, South Australia, Australia,
4 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA,
5 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
* To whom correspondence should be addressed. E-mail: schusted{at}msnotes.wustl.edu.
We evaluated positron emission tomographic imaging of pulmonary transgene expression, using an enhanced mutant Herpes Simplex Virus-1 thymidine kinase as the reporter gene, in the lungs of normal rats. Sixteen rats were studied 3 days after intratracheal administration of 5x109 - 1x1011 viral particles of a replication-incompetent adenovirus containing a fusion gene of the mutant kinase and green fluorescent protein. Three rats infected with adenovirus containing no insert (null vector) served as a control. Images were obtained 1 hour after intravenous injection of (9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine, an imaging substrate for the viral kinase. After euthanasia, tissue radioactivity was determined in a gamma counter, and thymidine kinase activity and green fluorescent protein levels were measured in lung tissue samples. Imaging and gamma counting radioactivity measurements were strongly and linearly correlated (R2=0.96, p<0.001). Imaging detected thymidine kinase expression above background (null vector) in 15/16 rats, even at low viral doses that produced little to no measurable green fluorescent protein expression. Lung (9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine uptake (as assessed by imaging) correlated with in vitro assays of both kinase activity (R2=0.48, p<0.001) and fluorescent protein (R2=0.46, p<0.001). We conclude that positron emission tomographic imaging is a sensitive and quantitative method for detecting pulmonary reporter gene expression non-invasively.
Key words: Positron emission tomography, rats, FHBG, green fluorescent protein, reporter gene
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