A new dawn for managing dyslipidemias: The era of rna-based therapies

Macchi, Chiara; Sirtori, Cesare R.; Corsini, Alberto; Santos, Raúl D.; Watts, Gerald F.; Ruscica, Massimiliano

doi:10.1016/j.phrs.2019.104413

Cited by 77 publications

(66 citation statements)

References 135 publications

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“…In view of the apparent increase of Lp(a) synthesis in carriers of elevated Lp(a), and consequent reductions by PCSK9 antagonists, the potential of biosynthetic drug treatments appears to be best targeted to synthesis. In particular, the use of appropriate antisense oligonucleotides (ASOs) appears to be most suitable [ 150 ]. The first developed APO-(a)Rx by IONIS was a second generation 2-O-(2-metoxyethyl) (2-MOE)-modified ASO with improved potency, duration and tolerability.…”

Section: Antisense Antinuocleotidementioning

confidence: 99%

“…Instead, contrasting conclusions have been reached in the case of statins, while ezetimibe monotherapy provided a modest 7% reduction [ 155 ]. Relative to mipomersen, although the potential benefit in reducing Lp(a) was between 20% and 50% [ 156 ], the manufacturing of the compound was discontinued (2018) and the product is not clinically available [ 150 ]. Interestingly, although not approved for clinical use [ 157 ], inhibitors of cholesteryl ester transfer protein lowered Lp(a) in a range between 25% and 40% [ 156 ].…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

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Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.

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Section: Antisense Antinuocleotidementioning

confidence: 99%

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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“…A series of Phase I to III trials of this drug and a related drug, AKCEA-APOCIII-L RX , have shown decreases of both apoC-III production and TAG concentrations in preclinical models and healthy volunteers (Graham et al 2013) and in patients with familial chylomicronemia syndrome (FCS) (Gaudet et al 2014(Gaudet et al , 2017 and those with hypertriglyceridaemia (Alexander et al 2019;Gaudet et al 2015;Ionna Gouni-Berthold et al 2018). Whilst conclusions from the Phase III trials were that the therapy was generally welltolerated (indeed, volanesorsen was recently approved in Europe for treatment of FCS (Macchi et al 2019)), there are two important limitations to these trials in terms of understanding the full effects of such an intervention. Firstly, these trials have not been able to evaluate either the efficacy or safety of targeting apoC-III in the longer term.…”

Section: Discussionmentioning

confidence: 99%

Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype

et al. 2020

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Introduction High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-IIItargeting drugs, volanesorsen, having recently progressed through Phase III trials. Objectives To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome. Methods In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype. Results 161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class. Conclusion Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.

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“…A more recent alternative to anti-PCSK9 antibodies is represented by Inclisiran, a short interfering RNA (siRNA) designed to target hepatic PCSK9 mRNA. However, this approach still has some drawbacks, such as the long pharmacokinetic profile, parenteral administration, and an as yet undefined safety profile [193]. Thus, cheaper, orally administrable, small-molecule drugs are greatly needed.…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring PCSK9 Inhibitors

et al. 2020

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Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.

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A new dawn for managing dyslipidemias: The era of rna-based therapies

Cited by 77 publications

References 135 publications

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype

Naturally Occurring PCSK9 Inhibitors

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