Polyinosinic acid blocks adeno-associated virus macrophage endocytosis in vitro and enhances adeno-associated virus liver directed gene therapy in vivo

Dijk, Remco van; Montenegro-Miranda, Paula S.; Rivière, Christel; Schilderink, Ronald; Bloemendaal, Lysbeth ten; Gorp, Jacqueline van; Duijst, Suzanne; Waart, Dirk R. de; Beuers, Ulrich; Haisma, Hidde J.; Bosma, Piter J.

doi:10.1089/hgtb.2013.086

Cited by 7 publications

(10 citation statements)

References 33 publications

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“…AAV8 was chosen as it potently infects hepatocytes as well as Kupffer cells in mice. 27,28 Indeed, we confirmed robust in vivo Kupffer cell infection by immunofluorescence using a GFP-encoding AAV8 and a specific macrophage marker (Supplementary Figure S6a,b), (f) Quantification of the data from e. Values were normalized to photon counts in livers of mice treated with the same luciferase vector without parasite infection, to eliminate miRNA-independent effects of the parasite on luciferase expression, and then to the respective luc-empty control. Luciferase values are inversely correlated with expression of the two miRNAs, i.e., a miRNA increase will result in lower luciferase expression.…”

Section: Viral Vectors For Ectopic Mir-155 Dysregulationsupporting

confidence: 59%

AAV8-Mediated In Vivo Overexpression of miR-155 Enhances the Protective Capacity of Genetically Attenuated Malarial Parasites

et al. 2014

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Malaria, caused by protozoan Plasmodium parasites, remains a prevalent infectious human disease due to the lack of an efficient and safe vaccine. This is directly related to the persisting gaps in our understanding of the parasite's interactions with the infected host, especially during the clinically silent yet essential liver stage of Plasmodium development. Previously, we and others showed that genetically attenuated parasites (GAP) that arrest in the liver induce sterile immunity, but only upon multiple administrations. Here, we comprehensively studied hepatic gene and miRNA expression in GAP-injected mice, and found both a broad activation of IFNγ-associated pathways and a significant increase of murine microRNA-155 (miR-155), that was especially pronounced in non-parenchymal cells including liver-resident macrophages (Kupffer cells). Remarkably, ectopic upregulation of this miRNA in the liver of mice using robust hepatotropic adeno-associated virus 8 (AAV8) vectors enhanced GAP's protective capacity substantially. In turn, this AAV8-mediated miR-155 expression permitted a reduction of GAP injections needed to achieve complete protection against infectious parasite challenge from previously three to only one. Our study highlights a crucial role of mammalian miRNAs in Plasmodium liver infection in vivo and concurrently implies their great potential as future immune-augmenting agents in improved vaccination regimes against malaria and other diseases.

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Section: Viral Vectors For Ectopic Mir-155 Dysregulationsupporting

confidence: 59%

AAV8-Mediated In Vivo Overexpression of miR-155 Enhances the Protective Capacity of Genetically Attenuated Malarial Parasites

et al. 2014

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“…Data interpretation is confounded, however, by the fact that the efficiency of AAV8-mediated gene transfer in adult mice was not reported, and the approach used to deliver Cre recombinase is not absolutely specific for hepatocytes. These are important considerations because uptake of AAV8 by hepatic macrophages is known to limit the effectiveness of liver-directed gene delivery,23 and adeno-associated viruses have proven to be effective vectors for gene transfer in other liver cell types, such as HSC 24–26. Also, certain progenitor cells in healthy adult livers express transthyreitin27 and the Brenner lab has reported microarray data showing 4–20-fold induction of transthyreitin mRNA expression in MF-HSC harvested from mice after carbon tetrachloride (CCL 4 ) treatment or BDL-induced liver injury 28…”

Section: Discussionmentioning

confidence: 99%

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy

Swiderska‐Syn

Syn

Xie

et al. 2013

Gut

100

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Objective Smoothened (SMO), a co-receptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblasts (MF) in liver regeneration by conditional deletion of SMO in αSMA+ cells after partial hepatectomy (PH). Design αSMA-Cre-ERT2×SMO/flox mice were treated with vehicle (Veh) or tamoxifen (TMX), and sacrificed 24 to 96 hrs post-PH. Regenerating livers were analyzed for proliferation, progenitors, and fibrosis by qRT-PCR and quantitative-IHC. Results were normalized to liver-segments resected at PH. For lineage-tracing studies, αSMA-Cre-ERT2×ROSA-Stop-flox-YFP mice were treated with Veh or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 hrs post-PH were analysed for YFP by FACS. Results Post-PH, Veh-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis, and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis, and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes, and up to 25% of hepatocytes were YFP+ by 48-72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+cells. Conclusion Hedgehog signaling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.

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“…80,83 Interestingly, poly I also effectively suppressed the clearance of viral vectors by Kupffer cells or LSECs. [98][99][100] Along with the avoidance of clearance, enhancement of carrier uptake into target cells is a critical issue. For this purpose, various lines of research have addressed the installation of ligands specifically recognizing target cells into nucleic acid carriers.…”

Section: Control Of In Vivo Distributionmentioning

confidence: 99%

Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA

Uchida

Kataoka

2019

J Biomedical Materials Res

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Nonviral delivery of plasmid (p)DNA or messenger (m)RNA is a safe and promising therapeutic option to continuously supply therapeutic proteins into diseased tissues. In most cases of in vivo pDNA and mRNA delivery, these nucleic acids are loaded into carriers based on cationic polymers and/or lipids to prevent nuclease‐mediated degradation before reaching target cells. The carriers should also evade host clearance mechanisms, including uptake by scavenger cells and filtration in the spleen. Installation of ligands onto the carriers can facilitate their rapid uptake into target cells. Meanwhile, carrier toxicity should be minimized not only for preventing undesirable adverse responses in patients, but also for preserving the function of transfected cells to exert therapeutic effects. Long‐term progressive improvement of platform technologies has helped overcome most of these issues, though some still remain hindering the widespread clinical application of nonviral pDNA and mRNA delivery. This review discusses design concepts of nonviral carriers for in vivo delivery and the issues to be overcome, focusing especially on our own efforts using polyplex micelles. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 978–990, 2019.

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Polyinosinic acid blocks adeno-associated virus macrophage endocytosis in vitro and enhances adeno-associated virus liver directed gene therapy in vivo

Cited by 7 publications

References 33 publications

AAV8-Mediated In Vivo Overexpression of miR-155 Enhances the Protective Capacity of Genetically Attenuated Malarial Parasites

AAV8-Mediated In Vivo Overexpression of miR-155 Enhances the Protective Capacity of Genetically Attenuated Malarial Parasites

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy

Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA

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