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Background MicroRNAs (miRNAs) are involved in the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), one of the regulators of low-density lipoprotein cholesterol (LDL-C) metabolism, and are directly involved in the atherosclerotic process. The aim of this study was to verify whether treatment with PCSK9 inhibitors (PCSK9i) and changes in the expression of miRNAs involved in PCSK9 metabolism are associated with arterial wall properties in stable post-myocardial infarction (MI) patients with insufficiently regulated LDL-C levels and significantly increased Lp(a) levels. Methods Ninety-five patients after MI were enrolled and randomized to a placebo ( N  = 31) or PCSK9i group ( N  = 64). The treatment group received subcutaneous alirocumab 150 mg or evolocumab 140 mg, every 2 weeks. Blood for biochemical and epigenetic analysis was taken and ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima–media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. The expression of the selected 5 miRNAs (miR-191-5p, miR-224-5p, miR-337-3p, miR-483-5p, and miR-552-3p) was quantified using quantitative polymerase chain reaction. Results A decrease in c-IMT was associated with a decrease in the expression of miR-337-3p ( ρ  = 0.329; p  = 0.010) and miR-483-5p ( ρ  = 0.324; p  = 0.012). We did not detect any associations between miRNA changes and FMD or PWV. Conclusions Our results suggest that changes in the selected miRNAs are associated with changes in the morphological properties of the arterial wall. We have shown that the decrease in miR-483-5p expression present a good indicator of the regression of morphological atherosclerotic change. The trial registration : The study is registered with CinicalTrials under the number NCT04613167, date of registration November 2nd, 2020. Approval for this study was obtained from the National Medical Ethics Committee of the Republic of Slovenia (reference number: KME 0120-357/2018/8).

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low‐density lipoprotein‐cholesterol (LDL‐C) by decreasing the expression of the LDL‐receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long‐acting LDL‐C lowering effect by exclusively inhibiting PCSK9 in pre‐clinical studies. Two randomized, double‐blind, placebo‐controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty‐four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15–450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non‐linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half‐life (t1/2) values of 4.5–6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL‐C levels by 30%–73% in healthy subjects, and repeated doses of ongericimab reduced LDL‐C levels by 67%–80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL‐C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long‐acting LDL‐C lowering effect with good safety and potential for clinical application.

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known. Objectives To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i. Methods Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane. Results A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001). Conclusions In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m2) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (−30 ± 20 mg/dL; p = 0.012), LDL cholesterol (−31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (−14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention.

Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12–26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.

PurposeThis post-hoc analysis examined whether age modified the efficacy and safety of alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH).MethodsData from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years). In the FH I and II trials, patients received 75 mg subcutaneously every 2 weeks (Q2W), with dose increase to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dl. In HIGH FH and LONG TERM, patients received 150 mg alirocumab Q2W.ResultsBaseline characteristics were similar between treatment groups across all age groups; the proportion of males decreased whereas the proportion of patients with coronary heart disease, diabetes, hypertension, and declining renal function increased with increasing age. Mean LDL-C reductions at week 24 were consistent across age groups (50.6–61.0% and 51.1–65.8% vs. placebo for the 75/150 and 150 mg alirocumab dose regimens, respectively; both non-significant interaction P-values). Treatment-emergent adverse events occurred in similar frequency in alirocumab- and placebo-treated patients regardless of age, except for injection-site reactions, which were more common in alirocumab than placebo but declined in frequency with age.ConclusionsAlirocumab treatment resulted in significant LDL-C reductions at weeks 12 and 24 and was generally well tolerated in patients with HeFH across all age groups studied.

Gene-editing technologies, which include the CRISPR–Cas nucleases 1 – 3 and CRISPR base editors 4 , 5 , have the potential to permanently modify disease-causing genes in patients 6 . The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys ( Macaca fascicularis ). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a ‘once-and-done’ approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide 7 ), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs. In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.

This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF‐05335810), a specifically engineered, pH‐sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low‐density lipoprotein cholesterol (LDL‐C) ≥ 80 mg/dl) 18–70 years old receiving statin therapy. Subjects were randomized to: single‐dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple‐dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half‐life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment‐related adverse events. RN317 lowered LDL‐C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single‐dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL‐C reductions of ∼50%, sustained over an 85‐day dosing interval.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model. Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery. Human disease mutations affect protein–protein interfaces in a three-dimensional structurally resolved interaction network. Predicted oncoPPIs in cancer correlate with survival and drug sensitivity, and affect growth in vitro, supporting their relevance to disease pathogenesis.