scholarly journals Lipid nanoparticles incorporating a GalNAc ligand enable in vivo liver ANGPTL3 editing in wild-type and somatic LDLR knockout non-human primates

2021 ◽  
Author(s):  
Lisa N Kasiewicz ◽  
Souvik Biswas ◽  
Aaron Beach ◽  
Huilan Ren ◽  
Chaitali Dutta ◽  
...  
Keyword(s):  
Gene Editing ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Nanoparticles ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Wild Type ◽  
Guide Rna ◽  
Delivery Technology

Standard lipid nanoparticles (LNPs) deliver gene editing cargoes to hepatocytes through receptor-mediated uptake via the low-density lipoprotein receptor (LDLR). Homozygous familial hypercholesterolemia (HoFH) is a morbid genetic disease characterized by complete or near-complete LDLR deficiency, markedly elevated blood low-density lipoprotein cholesterol (LDL-C) levels, and premature atherosclerotic cardiovascular disease. In order to enable in vivo liver gene editing in HoFH patients, we developed a novel LNP delivery technology that incorporates a targeting ligand - N-acetylgalactosamine (GalNAc) - which binds to the asialoglycoprotein receptor (ASGPR). In a cynomolgus monkey (Macaca fascicularis) non-human primate (NHP) model of HoFH created by somatic knockout of the LDLR gene via CRISPR-Cas9, treatment with GalNAc-LNPs formulated with an adenine base editor mRNA and a guide RNA (gRNA) targeting the ANGPTL3 gene yielded ~60% whole-liver editing and ~94% reduction of blood ANGPTL3 protein levels, whereas standard LNPs yielded minimal editing. Moreover, in wild-type NHPs, the editing achieved by GalNAc-LNPs compared favorably to that achieved by standard LNPs, suggesting that GalNAc-LNP delivery technology may prove useful across a range of in vivo therapeutic applications targeting the liver.

scholarly journals Participation of the urokinase receptor in neutrophil efferocytosis

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 860-870 ◽  
Author(s):  
Young-Jun Park ◽  
Gang Liu ◽  
Yuko Tsuruta ◽  
Emmanuel Lorne ◽  
Edward Abraham
Keyword(s):  
Cell Migration ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Urokinase Receptor ◽  
Low Density ◽  
Related Protein ◽  
Wild Type ◽  
Arginine Glycine Aspartic Acid

AbstractThe urokinase receptor (uPAR) plays an important role in regulation of fibronolysis, cell migration, and adhesion. In this study, we examined whether uPAR plays a role in modulating efferocytosis of neutrophils. Macrophages from uPAR−/− mice demonstrated enhanced ability to engulf viable wild-type (WT) neutrophils in vitro and in vivo in the lungs. The increased phagocytic activity of uPAR−/− macrophages was abrogated by incubation with soluble uPAR (suPAR), arginine-glycine-aspartic acid (RGD)–containing peptides, or anti-integrin antibodies. There was increased uptake of viable uPAR−/− neutrophils by WT macrophages. Incubation of uPAR−/− neutrophils with suPAR or anti-integrin antibodies diminished uptake by WT macrophages to baseline. Uptake of uPAR−/− neutrophils by uPAR−/− macrophages was not enhanced. However, incubation of uPAR−/− neutrophils or uPAR−/− macrophages, but not both, with suPAR enhanced the uptake of viable uPAR−/− neutrophils by uPAR−/− macrophages. The adhesion of WT neutrophils to uPAR−/− macrophages was higher than to WT macrophages. uPAR−/− neutrophils demonstrated increased adhesion to suPAR, which was abrogated by blocking of low-density lipoprotein related protein and integrins. Expression of uPAR on the surface of apoptotic neutrophils was reduced compared with levels on viable neutrophils. These results demonstrate a novel role for uPAR in modulating recognition and clearance of neutrophils.

Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo

Circulation ◽  
1996 ◽  
Vol 94 (7) ◽  
pp. 1698-1704 ◽  
Author(s):  
Klaus Juul ◽  
Lars B. Nielsen ◽  
Klaus Munkholm ◽  
Steen Stender ◽  
Børge G. Nordestgaard
Keyword(s):  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density

scholarly journals Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

1986 ◽  
Vol 234 (1) ◽  
pp. 245-248 ◽  
Author(s):  
W Jessup ◽  
G Jurgens ◽  
J Lang ◽  
H Esterbauer ◽  
R T Dean
Keyword(s):  
Apolipoprotein B ◽  
Negative Charge ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Peroxidation Product ◽  
Modified Low Density Lipoproteins ◽  
Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

scholarly journals Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein (LDL-).

1994 ◽  
Vol 35 (4) ◽  
pp. 669-677
Author(s):  
H.N. Hodis ◽  
D.M. Kramsch ◽  
P. Avogaro ◽  
G. Bittolo-Bon ◽  
G. Cazzolato ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

scholarly journals Impact of Adoption of Directly Measured Low-Density Lipoprotein-Cholesterol (LDL-C) on Targets of Lipid Control and Its Comparison With Friedewald Formula-Calculated LDL Cholesterol in People With Type-2 Diabetes Mellitus

2020 ◽  
pp. 263246362097804
Author(s):  
Rejitha Jagesh ◽  
Mathew John ◽  
Manju Manoharan Nair Jalaja ◽  
Tittu Oommen ◽  
Deepa Gopinath
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Friedewald Formula

Objectives: The accurate and precise measurement of low-density lipoprotein-cholesterol (LDL-C) is important in the assessment of atherosclerotic cardiovascular disease risk (ASCVD) in people with diabetes mellitus. This study aimed at comparing directly measured LDL-C with Friedewald formula (FF)-calculated LDL-C (c-LDL-C) in people with type-2 diabetes. Methods: Fasting lipid profiles of 1905 people with type-2 diabetes, whose LDL-C was estimated by direct LDL assay, were chosen for the study. In the same group, LDL-C was calculated with FF. Correlation and agreement between these methods were analyzed at various strata of triglycerides (TGs). The possibility of misclassifying people at various levels of LDL-C targets proposed in literature was calculated. Results: The mean LDL-C levels were lower in the c-LDL-C group across various TG strata. A significant correlation was found between c-LDL-C and direct LDL-C for all the study samples ( r = 0.948, P < .001) and across all TG strata. Analysis of agreement showed a positive bias for direct LDL-C which increased at higher strata of TGs. c-LDL-C underestimated ASCVD by misclassifying people at various LDL-C target levels. Conclusion: There is a difference between direct LDL-C and c-LDL-C values in people with diabetes and this may result in misclassifying ASCVD especially at lower levels of LDL-C and higher levels of TGs.

scholarly journals Aggregation Susceptibility of Low-Density Lipoproteins—A Novel Modifiable Biomarker of Cardiovascular Risk

2021 ◽  
Vol 10 (8) ◽  
pp. 1769
Author(s):  
Katariina Öörni ◽  
Petri T. Kovanen
Keyword(s):  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Cholesterol Crystals ◽  
Ldl Particles ◽  
Arterial Intima ◽  
Matrix Bound ◽  
Atherosclerotic Cardiovascular Diseases

Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles’ aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied.

scholarly journals Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver

2021 ◽  
Vol 7 (9) ◽  
pp. eabf4398
Author(s):  
M. Kim ◽  
M. Jeong ◽  
S. Hur ◽  
Y. Cho ◽  
J. Park ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Targeted Delivery ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Nanoparticles ◽  
Liver Sinusoidal Endothelial Cells ◽  
Main Challenge ◽  
Cell Type Specific ◽  
Selective Delivery

Ionizable lipid nanoparticles (LNPs) have been widely used for in vivo delivery of RNA therapeutics into the liver. However, a main challenge remains to develop LNP formulations for selective delivery of RNA into certain types of liver cells, such as hepatocytes and liver sinusoidal endothelial cells (LSECs). Here, we report the engineered LNPs for the targeted delivery of RNA into hepatocytes and LSECs. The effects of particle size and polyethylene glycol–lipid content in the LNPs were evaluated for the hepatocyte-specific delivery of mRNA by ApoE-mediated cellular uptake through low-density lipoprotein receptors. Targeted delivery of RNA to LSECs was further investigated using active ligands. Incorporation of mannose allowed the selective delivery of RNA to LSECs, while minimizing the unwanted cellular uptake by hepatocytes. These results demonstrate that engineered LNPs have great potential for the cell type–specific delivery of RNA into the liver and other tissues.

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