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A sensitive noninvasive method for monitoring successful liver-directed gene transfer of the low-density lipoprotein receptor in Watanabe hyperlipidemic rabbits in vivo.

Identifieur interne : 003142 ( Main/Exploration ); précédent : 003141; suivant : 003143

A sensitive noninvasive method for monitoring successful liver-directed gene transfer of the low-density lipoprotein receptor in Watanabe hyperlipidemic rabbits in vivo.

Auteurs : RBID : pubmed:14724675

English descriptors

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.

DOI: 10.1038/sj.gt.3302206
PubMed: 14724675

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Le document en format XML

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<title xml:lang="en">A sensitive noninvasive method for monitoring successful liver-directed gene transfer of the low-density lipoprotein receptor in Watanabe hyperlipidemic rabbits in vivo.</title>
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<name sortKey="Tietge, U J F" uniqKey="Tietge U">U J F Tietge</name>
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<nlm:affiliation>Department of Medicine and NWFZ, Charité Campus Mitte, Humboldt University, Berlin, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Medicine and NWFZ, Charité Campus Mitte, Humboldt University, Berlin</wicri:regionArea>
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<name sortKey="Cichon, G" uniqKey="Cichon G">G Cichon</name>
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<name sortKey="B Ttner, C" uniqKey="B Ttner C">C Büttner</name>
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<name sortKey="Genschel, J" uniqKey="Genschel J">J Genschel</name>
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<name sortKey="Heeren, J" uniqKey="Heeren J">J Heeren</name>
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<name sortKey="Gielow, P" uniqKey="Gielow P">P Gielow</name>
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<name sortKey="Grewe, N" uniqKey="Grewe N">N Grewe</name>
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<name sortKey="Dogar, M" uniqKey="Dogar M">M Dogar</name>
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<name sortKey="Beisiegel, U" uniqKey="Beisiegel U">U Beisiegel</name>
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<name sortKey="Manns, M P" uniqKey="Manns M">M P Manns</name>
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<name sortKey="Lochs, H" uniqKey="Lochs H">H Lochs</name>
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<name sortKey="Burchert, W" uniqKey="Burchert W">W Burchert</name>
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<term>Adenoviridae (genetics)</term>
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<term>Female</term>
<term>Gene Expression</term>
<term>Genetic Therapy (methods)</term>
<term>Genetic Vectors (administration & dosage)</term>
<term>Hyperlipoproteinemias (metabolism)</term>
<term>Hyperlipoproteinemias (therapy)</term>
<term>Indium Radioisotopes (diagnostic use)</term>
<term>Injections, Intravenous</term>
<term>Lipoproteins, LDL (administration & dosage)</term>
<term>Lipoproteins, LDL (pharmacokinetics)</term>
<term>Liver (metabolism)</term>
<term>Liver (radionuclide imaging)</term>
<term>Rabbits</term>
<term>Receptors, LDL (genetics)</term>
<term>Receptors, LDL (metabolism)</term>
<term>Transduction, Genetic (methods)</term>
<term>Transgenes</term>
<term>Treatment Outcome</term>
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<term>Lipoproteins, LDL</term>
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<term>Lipoproteins, LDL</term>
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<term>Female</term>
<term>Gene Expression</term>
<term>Injections, Intravenous</term>
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<term>Transgenes</term>
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<div type="abstract" xml:lang="en">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.</div>
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<AbstractText>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.</AbstractText>
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