title: A sensitive noninvasive method for monitoring successful liver-directed gene transfer of the low-density lipoprotein receptor in Watanabe hyperlipidemic rabbits in vivo.
abstract: Noninvasive tools to quantitate transgene expression directly are a prerequisite for clinical gene therapy. We established a method to determine location, magnitude, and duration of low-density lipoprotein (LDL) receptor (LDLR) transgene expression after adenoviral gene transfer into LDLR-deficient Watanabe hypercholesterolemic rabbits by following tissue uptake of intravenously injected (111)In-labeled LDL using a scintillation camera. Liver-specific tracer uptake was calculated by normalizing the counts measured over the liver to counts measured over the heart that represent the circulating blood pool of the tracer (liver/heart (L/H) ratio). Our results indicate that the optimal time point for transgene imaging is 4 h after the tracer injection. Compared with control virus-injected rabbits, animals treated with the LDLR-expressing adenovirus showed seven-fold higher L/H ratios on day 6 after gene transfer, and had still 4.5-fold higher L/H ratios on day 30. This imaging method might be a useful strategy to obtain reliable data on functional transgene expression in clinical gene therapy trials of familial hypercholesterolemia.
authors.affiliation: Department of Medicine and NWFZ, Charité Campus Mitte, Humboldt University, Berlin, Germany.
authors.forename: U J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: G
authors.initials: G
authors.lastname: Cichon
authors.forename: C
authors.initials: C
authors.lastname: Büttner
authors.forename: J
authors.initials: J
authors.lastname: Genschel
authors.forename: J
authors.initials: J
authors.lastname: Heeren
authors.forename: P
authors.initials: P
authors.lastname: Gielow
authors.forename: N
authors.initials: N
authors.lastname: Grewe
authors.forename: M
authors.initials: M
authors.lastname: Dogar
authors.forename: U
authors.initials: U
authors.lastname: Beisiegel
authors.forename: M P
authors.initials: MP
authors.lastname: Manns
authors.forename: H
authors.initials: H
authors.lastname: Lochs
authors.forename: W
authors.initials: W
authors.lastname: Burchert
authors.forename: H H-J
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006951:Hyperlipoproteinemias / Q000378:metabolism / Q000628:therapy*; D007205:Indium Radioisotopes; D007275:Injections, Intravenous; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D011817:Rabbits; D011877:Radionuclide Imaging; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D016896:Treatment Outcome
chemical_list: D007205:Indium Radioisotopes; D008077:Lipoproteins, LDL; D011973:Receptors, LDL