Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver

Hytönen, Elisa; Laurema, Anniina; Miyanohara, Atsushi; Kärjä, Vesa; Hujo, Mika; Laham-Karam, Nihay; Ylä‐Herttuala, Seppo

doi:10.1038/s41598-019-43459-1

Cited by 13 publications

(6 citation statements)

References 34 publications

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“…Viral like particles (VLPs) encapsulating pLV-(Ex) enhancer constructs or control vector without an enhancer, pLV-minP were produced in 293T cells by cotransfection with the packaging constructs pVSV-g ( 29 ), pREV ( 30 ) and pMDg ( 31 ), using calcium phosphate method as previously described ( 32 ). Empty LV were produced by transfection of only the packaging plasmids (pVSV-g, pREV, pMDg) to produce particles devoid of the vector RNA genome.…”

Section: Methodsmentioning

confidence: 99%

Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis

Mushimiyimana

Niskanen

Beter

et al. 2021

Nucleic Acids Research

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Super-enhancers are clusters of enhancers associated with cell lineage. They can be powerful gene-regulators and may be useful in cell-type specific viral-vector development. Here, we have screened for endothelial super-enhancers and identified an enhancer from within a cluster that conferred 5–70-fold increase in transgene expression. Importantly, CRISPR/Cas9 deletion of enhancers demonstrated regulation of ADAMTS18, corresponding to evidence of chromatin contacts between these genomic regions. Cell division-related pathways were primarily affected by the enhancer deletions, which correlated with significant reduction in cell proliferation. Furthermore, we observed changes in angiogenesis-related genes consistent with the endothelial specificity of this SE. Indeed, deletion of the enhancers affected tube formation, resulting in reduced or shortened sprouts. The super-enhancer angiogenic role is at least partly due to its regulation of ADAMTS18, as siRNA knockdown of ADAMTS18 resulted in significantly shortened endothelial sprouts. Hence, functional characterization of a novel endothelial super-enhancer has revealed substantial downstream effects from single enhancer deletions and led to the discovery of the cis-target gene ADAMTS18 and its role in endothelial function.

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Section: Methodsmentioning

confidence: 99%

Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis

Mushimiyimana

Niskanen

Beter

et al. 2021

Nucleic Acids Research

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“…Since high LDL levels in most of the HoFH patients are caused by a single gene loss-of-function mutation, mitigating the defective gene by introducing a functional copy of the gene could provide a permanent solution to maintaining therapeutic levels of LDL. This concept has been tested in LDLR-deficient mice using recombinant viral vectors such as a retrovirus [ 201 ], lentivirus [ 202 , 203 ], helper-dependent adenovirus [ 204 ] and adeno-associated virus [ 205 ]. Although the mouse lipoprotein profile differs from that of humans—for instance, the lack of CETP and HDL being a major circulating lipoprotein—there appears to be a marked similarity between mice and humans with regard to LDLR-mediated clearance of LDL lipoproteins.…”

Section: Gene Therapy and Genome/base Editing Approaches To Manage Re...mentioning

confidence: 99%

A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD

Srivastava

2023

Cells

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Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD).

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“…8g, h). In the same way, according to previous studies and our above in vivo assay 17,22 , New Zealand white rabbits were thereby subjected to in vivo-mediated gene therapy by lentivirus injection, followed by HFHC feeding for 8 weeks (Fig. 8i).…”

Section: Forced Hepatocyte Trim26 Activation Alleviates the Hfmcdindu...mentioning

confidence: 99%

Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation

Xu,

Tan,

Liu

et al. 2023

Nat Commun

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Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.

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Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver

Cited by 13 publications

References 34 publications

Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis

Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis

A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD

Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation

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