Experimental therapies targeting apolipoprotein C-III for the treatment of      hyperlipidemia – spotlight on volanesorsen

Milonas, Dimitrios; Τζιόμαλος, Κωνσταντίνος

doi:10.1080/13543784.2019.1582028

Cited by 12 publications

(3 citation statements)

References 43 publications

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“…A previous study reported elevated levels of non-esteri ed fatty acids, cholesterols and triglycerides in the plasma of APOC3-transgenic mice [49]. Furthermore, Volanesorsen was shown to reduce APOC3 which in turn reduced total cholesterol, TG levels and accumulation of hepatic lipids [50]. Although APOE and APOC3 are involved in "Cholesterol metabolism", both hub genes are yet to be studied in COPD.…”

Section: Discussionmentioning

confidence: 99%

Identification of Molecular Mechanisms Underlying Sex-Associated Differences in the Chronic Obstructive Pulmonary Disease through Bioinformatics Analysis

Chen¹,

Hou²,

Han³

et al. 2021

Preprint

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Background Accumulating evidence suggests the existence sex associated differences in the Chronic Obstructive Pulmonary Disease (COPD). However, limited knowledge exists on the molecular mechanisms underlying sex associated differences in COPD patients. Methods The GSE8581 dataset obtained from the GEO database was used to analyze differentially expressed genes (DEGs). Then enrichment analysis for DEGs were conducted through Metascape. PPI and the hub genes-pathway networks were constructed using the STRING database and Cytoscape software. Finally, the CTD was used to examine the relationships between the hub DEGs and COPD. Results The results revealed that different subsets of DEGs had different characteristics in GO functions and KEGG pathways. Different subsets of hub genes were obtained based on PPI network. The study then constructed the hub genes-pathway network for different subsets to explore the key signaling pathways and hub genes involved. The findings showed that NRAS and RAC1 functioned through “Rap1 signaling pathway” and “PI3K-Akt signaling pathway”, in male COPD patients. On the other hand, “Cholesterol metabolism” was among the important pathways in female COPD patients while the hub genes, APOE and APOC3 functioned through “Cholesterol metabolism”. Moreover, “Ubiquitin mediated proteolysis” and the “p53 signaling pathway” were shown to play more important roles in male COPD patients compared to their female counterparts. Furthermore, CDK2 and UBE2N were the hub genes involved in “p53 signaling pathway” and “Ubiquitin mediated proteolysis”, respectively. Finally the study identified the relationship between the hub genes and COPD in CTD. Conclusions The present study uncovered different molecular mechanisms in COPD patients based on sex. Additionally, distinct pathways and hub genes including NRAS, RAC1, APOE, APOC3, CDK2 and UBE2N were identified in the two genders of COPD patients. Further studies are needed to explore individualized treatment for COPD based on the findings.

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Section: Discussionmentioning

confidence: 99%

Identification of Molecular Mechanisms Underlying Sex-Associated Differences in the Chronic Obstructive Pulmonary Disease through Bioinformatics Analysis

Chen¹,

Hou²,

Han³

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Volanesorsen (ISIS 304801/ISIS-APOCIII Rx /IONIS-APOCIII Rx , Waylivra®, Akcea/Ionis) is a 20-nucleotide second generation 2’-O-methoxyethyl chimeric antisense inhibitor of apoC3 mRNA developed for the very rare condition of FCS, as well as potentially for other forms of hypertriglyceridaemia and familial partial lipodystrophy. 69 It was approved in the EU in May 2019 for the treatment of adult patients with FCS based on positive results from the multinational, Phase 3 APPROACH and COMPASS studies. 70 It was not approved by the US FDA in 2018, mainly because of the high incidence of thrombocytopaenia.…”

Section: Apoc3mentioning

confidence: 99%

Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors

Tomlinson,

Wu,

Zhong

et al. 2024

J Lipid Atheroscler

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Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.

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“…FCS can determine some complications such as lipemia retinalis, acute pancreatitis, xanthomas, and diabetes. To treat this syndrome, it is possible to inhibit the expression of APOC3, because it is an inhibitor of LPL, in order to improve the activity of LPL [ 33 ]. “Volanesorsen” is the first drug based on a second-generation ASO, containing 2′-O-methoxyethyl modification, that applies this mechanism: in fact, it has as target the APOC3′s mRNA.…”

Section: Transcript-targeted Therapies For Genetic Diseasesmentioning

confidence: 99%

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets

Barresi

Musmeci

Rinaldi

et al. 2022

IJMS

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The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.

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Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia – spotlight on volanesorsen

Cited by 12 publications

References 43 publications

Identification of Molecular Mechanisms Underlying Sex-Associated Differences in the Chronic Obstructive Pulmonary Disease through Bioinformatics Analysis

Identification of Molecular Mechanisms Underlying Sex-Associated Differences in the Chronic Obstructive Pulmonary Disease through Bioinformatics Analysis

Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets

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