Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3)

Ginsberg, Henry N.; Goldberg, Ira J.

doi:10.1161/atvbaha.122.317966

Cited by 43 publications

(29 citation statements)

References 68 publications

(109 reference statements)

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“…ASO targeting ANGPTL3 mRNA reduces lipid levels and decreases ASCVD progression in mice 145 . Importantly, patients with ANGPTL3 deficiency did not have hepatic steatosis 146 . The data from the above studies emphasize the importance of ANGPTL3 genetic variation in regulating lipid metabolism in humans and support the idea that genetic inactivation or low levels of ANGPTL3 are essential in lowering lipids and reducing the risk of ASCVD.…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 55%

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 55%

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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“…Here we observed increased abundance of the EV marker CD9 and decreased abundance of apolipoprotein C-III (APOC3) ( Figure 3B ). APOC3 is a lipoprotein lipase inhibitor [14] that its downregulation thus permits lipoprotein lipase-mediated fatty acid release to meet the energetic demands of the exercise.…”

Section: Main Textmentioning

confidence: 99%

A fast and sensitive size-exclusion chromatography method for plasma extracellular vesicle proteomic analysis

Ludovico,

Powell,

Many

et al. 2024

Preprint

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Extracellular vesicles (EVs) carry diverse biomolecules derived from their parental cells, making their components excellent biomarker candidates. However, purifying EVs is a major hurdle in biomarker discovery since current methods require large amounts of samples, are time-consuming and typically have poor reproducibility. Here we describe a simple, fast, and sensitive EV fractionation method using size exclusion chromatography (SEC) on a fast protein liquid chromatography (FPLC) system. Our method uses a Superose 6 Increase 5/150, which has a bed volume of 2.9 mL. The FPLC system and small column size enable reproducible separation of only 50 microliters of human plasma in 15 minutes. To demonstrate the utility of our method, we used longitudinal samples from a group of individuals who underwent intense exercise. A total of 838 proteins were identified, of which, 261 were previously characterized as EV proteins, including classical markers, such as cluster of differentiation (CD)9 and CD81. Quantitative analysis showed low technical variability with correlation coefficients greater than 0.9 between replicates. The analysis captured differences in relevant EV proteins involved in response to physical activity. Our method enables fast and sensitive fractionation of plasma EVs with low variability, which will facilitate biomarker studies in large clinical cohorts.

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“…Currently, icosapent ethyl is the only drug that is approved by the FDA and all major cardiovascular and diabetes management guidelines globally for additional risk reduction in people with ASCVD, or diabetes with multiple risk factors, who have persistent HTG 150–499 mg/dl, after LDL-C goals are met [4,41,42]. In view of the results of the PROMINENT trial discussed above, it is clear that the future studies should explore ways to increase clearance of Rem-C by agents that antagonize the action of LPL-inhibitory apoproteins, such as Apo-C-III, ANGPTL 3, and ANGPTL 4 in particular, based on the results from several studies in subjects with loss-of-function mutations [7 ▪▪ ,43 ▪▪ ,44 ▪▪ ]. Clinical trials with several such drugs are currently in progress [43 ▪▪ ,44 ▪▪ ,45].…”

Section: Management Of Remnant Cholesterol: Current and Future Prospectsmentioning

confidence: 99%

“…In view of the results of the PROMINENT trial discussed above, it is clear that the future studies should explore ways to increase clearance of Rem-C by agents that antagonize the action of LPL-inhibitory apoproteins, such as Apo-C-III, ANGPTL 3, and ANGPTL 4 in particular, based on the results from several studies in subjects with loss-of-function mutations [7 ▪▪ ,43 ▪▪ ,44 ▪▪ ]. Clinical trials with several such drugs are currently in progress [43 ▪▪ ,44 ▪▪ ,45]. A monoclonal antibody to ANGPTL3, evinacumab, lowers both LDL-C and TG.…”

Section: Management Of Remnant Cholesterol: Current and Future Prospectsmentioning

confidence: 99%

Triglyceride-rich lipoproteins, remnant-cholesterol, and atherosclerotic cardiovascular disease

Ganda¹

2023

Current Opinion in Lipidology

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Purpose of reviewDespite indisputable role of LDL-C lowering, a considerable residual risk for atherosclerotic cardiovascular disease (ASCVD) persists. The precise mechanism(s) underlying this phenomenon remain unclear. Triglyceride-rich lipoproteins (TRL) appear to be one of the main mediators, based on the genetic and epidemiologic data. However, whether this is caused by direct effects of Triglycerides or other components of TRL remains uncertain. The cholesterol component of TRL remnants (Rem-C) has been proposed as a more pertinent mediator of the increased risk associated with high triglycerides. Recent findingsSeveral long-term observational studies have shown a significant relationship between Rem-C and ASCVD events, compared with other triglyceride-related parameters. Recent trials have shown that lowering of triglyceride levels by various agents, including fibrates and omega-3 fatty acids, in statin-treated subjects, did not explain the reduction in ASCVD events. In a large clinical trial with pemafibrate, a highly selective PPAR-a agonist, in type 2 diabetes and elevated triglycerides, the reduction in triglycerides was accompanied by a significant increase in LDL-C and Apo-B levels, despite a reduction in Rem-C, and no effect on ASCVD events.

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Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3)

Cited by 43 publications

References 68 publications

Drug development advances in human genetics‐based targets

Drug development advances in human genetics‐based targets

A fast and sensitive size-exclusion chromatography method for plasma extracellular vesicle proteomic analysis

Triglyceride-rich lipoproteins, remnant-cholesterol, and atherosclerotic cardiovascular disease

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