Macrophage depletion increases the safety, efficacy and persistence of adenovirus-mediated gene transfer in vivo

Kuz'min, A N; Finegold, Milton; Eisensmith, Randy C.

doi:10.1038/sj.gt.3300377

Cited by 85 publications

(57 citation statements)

References 9 publications

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“…[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] These strategies have been somewhat successful, and allow repeat vector administration; however, complications and potential side-effects may make immune suppression impractical for clinical use. An alternative strategy to allow for repeat vector administration is the sequential use of different Ad serotypes.…”

Section: Introductionmentioning

confidence: 99%

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

1999

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We have developed a new helper adenovirus (Ad) based expression in mouse liver after intravenous injection of the on serotype 2, Ad2LC8cCARP, for use in the Cre/loxP sysAd2-based hdAd showed that the vector could efficiently tem (Parks et al. Proc Natl Acad Sci USA, 1996; 93: transduce the liver, and produce high levels of a foreign 13565-13570) to generate Ad vectors deleted of all protein transgene, similar to those expressed by the hdAd genercoding sequences (helper-dependent Ad vectors (hdAd) ).ated with the Ad5 helper virus. Mice immunized with hdAd2 A comparison of Ad2LC8cCARP and our original helper produced Ad2-neutralizing antibodies, which did not crossvirus (based on serotype 5, Ad5LC8cluc) showed that the react with hdAd5. To determine if successful repeat Ad two helper viruses amplified hdAd with a similar efficiency, vector administration could be achieved by sequential use and resulted in a similar yield and purity after large-scale of alternative Ad serotypes, we injected mice with hdAd2 preparation of vector. In vitro, the resulting hdAd2 had a (hSEAP) followed 3 months later by a lacZ-expressing similar transduction efficiency and expression kinetics of hdAd of either the same or different serotype. Repeated transgene (␤-gal) as the hdAd5. An important feature of administration of hdAd2 resulted in a 30-to 100-fold the helper-dependent system is that all virion components, reduction in transgene expression compared with naive except the virion DNA, derive from the helper virus. Conseanimals. In contrast, no decrease in transgene expression quently, vectors produced with help from Ad2LC8cCARP was observed when the second vector was of a different were not neutralized by antibodies against Ad5, and vecserotype. These results demonstrate that effective vector tors produced with Ad5 helper were resistant to neutralizreadministration can be achieved by the sequential use of ing antibodies against Ad2. Analysis of transgene hdAds based on alternative serotypes.

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Section: Introductionmentioning

confidence: 99%

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

1999

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“…administration of clodronate liposomes results in significantly increased transgene DNA levels in parenchymal liver cells 34 and in increased transgene expression. 33,34,38,39 Since liver sinusoidal endothelial cell function may be modified by Kupffer cells, 40,41 it cannot be excluded that part of the effect of clodronate liposomes is due to reduced activation of liver sinusoidal endothelial cells by Kupffer cells. Besides clodronate liposomes, preadministration of polyinosinic acid, a scavenger receptor A ligand, before gene transfer has been shown to prevent sequestration of adenoviral vectors in Kupffer cells and to enhance parenchymal liver cell transduction.…”

Section: Uptake Of Gene Transfer Vectors By Reticulo-endothelial Cellmentioning

confidence: 99%

The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

Jacobs

Wisse

Geest

2010

The American Journal of Pathology

109

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“…Fenestrae are clustered in sieve plates and may provide direct access for circulating gene transfer vectors to the space of Disse, in which microvilli of parenchymal liver cells protrude. 1,3 Whereas fenestrae allow transendothelial passage of gene transfer vectors, endocytosis of vectors by liver sinusoidal endothelial cells 4 and Kupffer cells [4][5][6][7] limits hepatocyte transduction. Previously, we have demonstrated that the size of sinusoidal fenestrae correlates with differences of transgene expression after adenoviral transfer in three different strains of rabbits.…”

Section: Introductionmentioning

confidence: 99%

The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer

et al. 2008

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Fenestrae allow the passage of gene transfer vectors from the sinusoidal lumen to the surface of hepatocytes. We have previously shown that the diameter of fenestrae correlates with species and strain differences of transgene expression following intravenous adenoviral transfer. In the current study, we demonstrate that the diameter of fenestrae in humans without liver pathology is 107 ± 1.5 nm. This is similar to the previously reported diameter in New Zealand White (NZW) rabbits (103 ± 1.3 nm) and is significantly smaller than in C57BL/6 mice (141±5.4 nm) and SpragueDawley rats (161 ± 2.7 nm). We show that the diameter of fenestrae in one male NZW rabbit and its offspring characterized by a more than 50-fold increase of transgene expression after adenoviral gene transfer is significantly (113 ± 1.5 nm; Po0.001) larger than in control NZW rabbits. In vitro filtration experiments using polycarbonate filters with increasing pore sizes demonstrate that a relatively small increment of the diameter of pores potently enhances passage of adenoviral vectors, consistent with in vivo data. In conclusion, the small diameter of fenestrae in humans is likely to be a major obstacle for hepatocyte transduction by adenoviral vectors.

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Macrophage depletion increases the safety, efficacy and persistence of adenovirus-mediated gene transfer in vivo

Cited by 85 publications

References 9 publications

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration

The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer

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