Several lines of evidence now attest that lipoprotein[a] (Lp[a]) is a significant risk factor for many cardiovascular disorders. This enigmatic lipoprotein, composed of a single copy of apolipoprotein B (apoB) and apolipoprotein[a] (apo [a]), expresses peculiar metabolism, virtually independent from lifestyle interventions. Several therapeutic options have hence been proposed for lowering elevated Lp[a] values, with or without concomitant effect on low density lipoprotein (LDL) particles, mostly encompassing statins, ezetimibe, nicotinic acid, lipoprotein apheresis, and anti-PCSK9 monoclonal antibodies. Since all these medical treatments have some technical and clinical drawbacks, a novel strategy is currently being proposed, based on the use of antisense apo[a] and/or apoB inhibitors. Although the role of these agents in hypercholesterolemic patients is now nearby entering clinical practice, the collection of information on Lp[a] is still underway. Preliminary evidence would suggest that apo[a] antisense therapy seems more appropriate in patients with isolated Lp[a] elevations, while apoB antisense therapy is perhaps more advisable in patients with isolated LDL elevations. In patients with concomitant elevations of Lp[a] and LDL, either combining the two apo[a] and apoB antisense therapies (a strategy which has never been tested), or the combination of well-known and relatively inexpensive drugs such as statins with antisense apo[a] inhibitors can be theoretically suggested. The results of an upcoming phase 3 study with antisense apo[a] inhibitors will hopefully provide definitive clues as to whether this approach may become the standard of care in patients with increased Lp[a] concentrations.

01 Apr 2017·Current Opinion in PharmacologyQ2 · MEDICINE

Dyslipidemia management update

Q2 · MEDICINE

Review

Author: Robidoux, Jacques ; Chang, Yingzi

Association of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) is well established. Reducing low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein-cholesterol (HDL-C) have been the therapeutic targets to reduce the risk of ASCVD. Cholesterol-lowering medications have been used to provide both primary and secondary prevention of ASCVD for many years by reducing the absorption and reabsorption, promoting excretion, or decreasing the synthesis of cholesterol. Within the past five years, several new classes of cholesterol-lowering drugs have been tested and approved for patients with hypercholesterolemia that are not well controlled by conventional therapy (ezetimibe, bile-acid sequestrants, and statins). These drugs include proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies, apolipoprotein A-100 (Apo B-100) antisense, and microsomal triglyceride transfer protein (MTP) inhibitor. Clinical trials revealed that adding PCSK9 antibodies to the preexisting statin therapy can further reduce LDL-C by 60%. ApoB antisense and MTP inhibitor are currently approved for patients with homozygous familial hypercholesterolemia. Several HDL-raising drugs have also been tested, but the results are not promising. Studies suggest that specifically raising reverse cholesterol transport rather than HDL-C level could be a novel therapeutic approach to reduce cardiovascular risk.

01 Apr 2017·American Journal of Physiology-Heart and Circulatory PhysiologyQ2 · MEDICINE

Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells

Q2 · MEDICINE

Article

Author: Wolf, Dennis ; Sette, Alessandro ; Miller, Jacqueline ; Mikulski, Zbigniew ; Tse, Kevin ; Ley, Klaus ; Gerhardt, Teresa ; Kimura, Takayuki ; Sidney, John ; McArdle, Sara

Although immunization with major histocompatibility complex (MHC) class II-restricted apolipoprotein B (ApoB) peptides has been shown to be atheroprotective, the mechanism is unclear. Here, we investigated CD4+ T cell populations in immunized atherosclerotic mice. Peptides (16-mers) from mouse ApoB, the core protein of low-density lipoprotein (LDL), were screened for binding to I-Ab by computer prediction and confirmed by radiolabeled peptide competition. Three new peptides, P101 (FGKQGFFPDSVNKALY, 5.5 nM IC50), P102 (TLYALSHAVNSYFDVD, 6.8 nM), and P103 (LYYKEDKTSLSASAAS, 95 nM), were tested in an atherosclerosis model ( Apoe−/− mice on Western diet). Immunization with each of the three peptides (1 time in complete Freund’s adjuvant subcuntaneously and 4 time in incomplete Freund’s adjuvant intraperitoneally) but not with adjuvant alone showed significantly reduced atherosclerotic plaques in the aortic root by serial sections and in the whole aorta by en face staining. There were no differences in body weight, LDL cholesterol, or triglycerides. Peritoneal leukocytes from ApoB peptide-immunized mice, but not control mice, secreted significant amounts of IL-10 (150 pg/ml). Flow cytometry showed that peptide immunization induced IL-10 in 10% of peritoneal CD4+ T cells, some of which also expressed chemokine (C-C motif) receptor 5 (CCR5). Vaccination with ApoB peptides expanded peritoneal FoxP3+ regulatory CD4+ T cells and more than tripled the number of CCR5+FoxP3+ cells. Similar trends were also seen in the draining mediastinal lymph nodes but not in the nondraining inguinal lymph nodes. We conclude that vaccination with MHC class II-restricted autologous ApoB peptides induces regulatory T cells (Tregs) and IL-10, suggesting a plausible mechanism for atheroprotection. NEW & NOTEWORTHY Vaccination against apolipoprotein B (ApoB), the protein of LDL, attracts attention as a novel approach to prevent atherosclerosis. We discovered major histocompatibility complex class II-restricted ApoB peptides, which reduce atherosclerosis and induce IL-10-producing CD4+ T cells and chemokine (C-C motif) receptor 5 expression on regulatory T cells, suggesting that immunization with ApoB peptides inhibits atherosclerosis by inducing anti-inflammatory cytokines.

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Indication	Highest Phase	Country/Location	Organization	Date
Heterozygous familial hypercholesterolemia	Preclinical	GB	Argonaute RNA Ltd.	10 Aug 2024
Homozygous familial hypercholesterolemia	Preclinical	GB	Argonaute RNA Ltd.	10 Aug 2024

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