A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

Suchowerska, Alexandra K.; Stokman, Geurt; Palmer, James T.; Coghlan, Phillip A.; Pieterman, Elsbet J.; Keijzer, Nanda; Lambert, Gilles; Chemello, Kévin; Jaafar, Ali K; Parmar, Jasneet; Yan, Liping; Tong, Yingtao; Mei, Lin; Princen, H.M.G.; Bonnar, J.; Evison, Benny J.

doi:10.1016/j.jlr.2022.100293

Cited by 13 publications

(5 citation statements)

References 63 publications

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“…Nyrada Inc. recently published a series of small molecule compounds, targeting the PCSK9-LDLR binding site. 42,43 One compound, NYX-1492, exhibited a strong in vivo pharmacokinetic profile following oral and IV administration, with a high maximum serum concentration and relatively long half-life (supplementary material Fig. S4).…”

Section: Resultsmentioning

confidence: 99%

PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system

Lee,

Shores,

Breithaupt

et al. 2023

APL Bioengineering

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Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P−) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P− equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.

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Section: Resultsmentioning

confidence: 99%

PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system

Lee,

Shores,

Breithaupt

et al. 2023

APL Bioengineering

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“…[11][12][13][14] Small-molecule inhibitors of PCSK9 are also under development and showing promise. 15 The current widespread use of these PCSK9 biologics is limited by their cost and side effects that can result in poor patient compliance. 14 These issues have motivated some scientists and pharmaceutical manufacturers 16 to propose targeting the PCSK9 locus for the treatment of familial hypercholesterolemia by somatic gene editing (excluding individuals homozygous for LDL receptor loss-of-function alleles).…”

Section: Highlightsmentioning

confidence: 99%

Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution

Kozan,

Farber

2024

ATVB

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The tremendous burden of lipid metabolism diseases, coupled with recent developments in human somatic gene editing, has motivated researchers to propose population-wide somatic gene editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) within the livers of otherwise healthy humans. The best-characterized molecular function of PCSK9 is its ability to regulate plasma LDL (low-density lipoprotein) levels through promoting LDL receptor degradation. Individuals with loss-of-function PCSK9 variants have lower levels of plasma LDL and reduced cardiovascular disease. Gain-of-function variants of PCSK9 are strongly associated with familial hypercholesterolemia. A new therapeutic strategy delivers CRISPR/Cas9 specifically to liver cells to edit the wild-type alleles of PCSK9 with the goal of producing a loss-of-function allele. This direct somatic gene editing approach is being pursued despite the availability of FDA-approved PCSK9 inhibitors that lower plasma LDL levels. Here, we discuss other characterized functions of PCSK9 including its role in infection and host immunity. We explore important factors that may have contributed to the evolutionary selection of PCSK9 in several vertebrates, including humans. Until such time that more fully understand the multiple biological roles of PCSK9, the ethics of permanently editing the gene locus in healthy, wild-type populations remains highly questionable.

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“…A promising area of research is the inhibition of PCSK9, a protein that plays a key role in regulating cholesterol levels in the body. PCSK9 works by binding to LDL receptors (LDLr) on the surface of liver cells, causing the receptors to be internalized and degraded (Suchowerska et al, 2022). Fig.…”

Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

High density lipoprotein as a therapeutic target: Focus on its functionality

ROSSO,

DAVICO,

CHIAPPE

et al. 2023

BIOCELL

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Cardiovascular diseases (CVDs) are the leading cause of death globally. CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular disease and rheumatic heart disease among other conditions. There are multiple independent risk factors for CVD, including hypertension, age, smoking, insulin resistance, elevated low-density lipoprotein cholesterol (LDL-C) levels, and triglyceride levels. LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk. High density lipoprotein (HDL) constitutes the only lipoprotein fraction with atheroprotective functions. Early HDL-targeted therapies have focused on increasing HDL-C levels. However, clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction. A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition, leading to loss of functionality. As a result, targeting HDL-C levels would be insufficient to achieve CVD risk reduction, making HDL functionality a more desirable focus for HDL-directed therapies. There are several drugs which show the potential to improve HDL functionality. These drugs include molecules already approved for human use, such as statins and niacin, and particularly, compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations. These therapies show promising potential to improve HDL functionality specifically. Future therapeutic strategies should incorporate HDL functionality as a main target of interest.

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A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

Cited by 13 publications

References 63 publications

PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system

PCSK9 activation promotes early atherosclerosis in a vascular microphysiological system

Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution

High density lipoprotein as a therapeutic target: Focus on its functionality

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