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Published ahead of print on December 27, 2002, doi:10.1164/rccm.200210-1217OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1257-1263, (2003)
© 2003 American Thoracic Society

Imaging Pulmonary Gene Expression with Positron Emission Tomography

Jean-Cristophe Richard, Zhaohui Zhou, Datta E. Ponde, Carmen S. Dence, Philip Factor, Paul N. Reynolds, Gary D. Luker, Vijay Sharma, Tom Ferkol, David Piwnica-Worms and Daniel P. Schuster

Washington University School of Medicine, St. Louis, Missouri; Evanston Northwestern Healthcare, Evanston; Northwestern University Medical School, Chicago, Illinois; Department of Medicine, Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama; and Royal Adelaide Hospital, Adelaide, South Australia

Correspondence and requests for reprints should be addressed to Daniel P. Schuster, M.D., University Box 8225, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110. 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 an intratracheal administration of 5 x 109 to 1 x 1011 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 control subjects. Images were obtained 1 hour after an 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 of 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 noninvasively.

Key Words: positron emission tomography • rats • green fluorescent protein • reporter gene




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