title: PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector.
abstract: Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors.
authors.affiliation: Division of Gene Therapy and Hepatology, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fontanellas
authors.forename: S
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: A
authors.initials: A
authors.lastname: Sampedro
authors.forename: M
authors.initials: M
authors.lastname: Collantes
authors.forename: A
authors.initials: A
authors.lastname: Azpilicueta
authors.forename: I
authors.initials: I
authors.lastname: Mauleón
authors.forename: A
authors.initials: A
authors.lastname: Pañeda
authors.forename: G
authors.initials: G
authors.lastname: Quincoces
authors.forename: J
authors.initials: J
authors.lastname: Prieto
authors.forename: I
authors.initials: I
authors.lastname: Melero
authors.forename: I
authors.initials: I
authors.lastname: Peñuelas
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002452:Cell Count; D002461:Cell Line, Transformed; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006147:Guanine; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000000981:diagnostic imaging* / Q000201:enzymology*; D008251:Macaca; D023421:Models, Animal; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
chemical_list: D019275:Radiopharmaceuticals; C053539:penciclovir; D006147:Guanine; D013937:Thymidine Kinase; D000212:Acyclovir