Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents

Abifadel, Marianne; Pakradouni, Jihane; Collin, Matthieu; Samson-Bouma, Marie-Elisabeth; Varret, Mathilde; Rabès, Jean-Pierre; Boileau, Cathérine

doi:10.1517/13543776.2010.518615

Cited by 29 publications

(13 citation statements)

References 68 publications

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“…Various strategies were proposed to inhibit the function and/or levels of PCSK9, including mRNA knockdown approaches 44,45 or passive immunization with the use of monoclonal antibodies that inhibit binding of PCSK9 to the LDLR. 46 All of these approaches are now being tested in clinical trials 47 (http://www.clinicaltrials.gov/ct2/ results?termϭPCSK9), and in 2012-2013 we should know their efficacy and safety profiles. With the rapid pace of discoveries in the field, it is hoped that within a few years lead molecules reducing the level or activity of PCSK9 will be uncovered and that these will find their way into the clinic to help patients suffering from dyslipidemia and atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice

Denis

Marcinkiewicz²,

Zaid³

et al. 2012

Circulation

201

165

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Background-The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low-density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in Ϸ7-fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis. Methods and Results-We investigated the role of PCSK9 in atherosclerosis in C57BL/6 wild-type (WT), apolipoprotein E-deficient, and LDL receptor-deficient mouse models. Circulating cholesterol levels, fast protein liquid chromatography profiles, aortic cholesteryl esters (CE), and plaque sizes were determined. Intima-media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (knockout [KO]), normal (WT), or high (transgenic [Tg]) levels of PCSK9 were fed a 12-month Western diet. KO mice accumulated 4-fold less aortic CE than WT mice, whereas Tg mice exhibited high CE and severe aortic lesions. Next we generated apolipoprotein E-deficient mice, known to spontaneously develop lesions, that expressed null (KO/e), normal (WT/e), or high (Tg/e) levels of PCSK9. After a 6-month regular diet, KO/e mice showed a 39% reduction compared with WT/e mice in aortic CE accumulation, whereas Tg/e mice showed a 137% increase. Finally, LDL receptor-deficient mice expressing no (KO/L), normal (WT/L), or high (Tg/L) levels of PCSK9 were fed a Western diet for 3 months. KO/L and Tg/L mice exhibited levels of plasma cholesterol and CE accumulation similar to those of WT/L mice, suggesting that PCSK9 modulates atherosclerosis mainly via the LDL receptor. Conclusions-Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is proatherogenic, whereas its absence is protective. (Circulation. 2012;125:894-901.)Key Words: atherosclerosis Ⅲ cardiovascular diseases Ⅲ cholesterol Ⅲ lipoproteins Ⅲ proprotein convertases A therosclerosis is a progressive degenerative pathology of large arteries that leads to ischemic heart diseases, which are expected to remain one of the leading causes of mortality until at least 2030. 1 The different stages of atherosclerotic plaque development have been reviewed extensively. [2][3][4][5] In brief, high levels of circulating atherogenic lipoproteins favor the accumulation of oxidized low-density lipoproteins (LDLs) in the subendothelial space. The latter are taken up by invading macrophages that, if they cannot efflux excess cholesterol to high-density lipoprotein, become foam cells. Foamy cells then release cytokines that recruit more macrophages into the building plaque. After formation of a necrotic core, plaques may ultimately become unstable; their fibrous cap can rupture and cause the formation of thrombus that can lead to death. Although inflammation is an important contributor to atherosclerosis, accumulation of oxidized LDLs in the subendothelial compartment is a key triggering event in atherosclerosis...

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Section: Discussionmentioning

confidence: 99%

Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice

Denis

Marcinkiewicz²,

Zaid³

et al. 2012

Circulation

201

165

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“…This discovery has culminated in the development of a PCSK9-binding antibody that mimics the epidermal growth factor (EGF)A domain of the LDLR, which in vivo serves to effectively remove PCSK9's ability to bind and promote LDLR degradation and significantly reduce LDL-C by 20-50% in monkeys and 40% in "humanized" mice ( 324 ). The mechanics of PCSK9/LDLR binding and intracellular degradation have been reviewed quite recently (325)(326)(327) and are not covered in depth here. Instead, we focus on correlations between PCSK9, de novo cholesterol biosynthesis, and LDL-C levels in humans ( 328,329 ), as well as the growing consensus that PCSK9 participates in VLDL production/net secretion ( 330 ).…”

Section: Returning Internalized Ldlr To the Plasma Membranementioning

confidence: 99%

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Calandra

Tarugi

Speedy

et al. 2011

Journal of Lipid Research

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This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra-and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C). The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle-and oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c membrane transporter systems ( NPC1L1 , ABCG5/8 ); the incorporation of dietary sterols ( MTP ) and of de novo synthesized lipids ( HMGCR, TRIB1 ) into apoB-containing lipoproteins ( APOB ) and their release into the circulation ( ANGPTL3, SARA2, SORT1 ); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants ( LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL ).The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classifi cation of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

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“…Various therapeutic approaches for inhibiting PCSK9 have been reported, including gene silencing by siRNA or antisense oligonucleotides and disruption of the PCSK9-LDLR interaction by antibodies (18). Two monoclonal antibodies with LDL-C-lowering activity in mice and non-human primates (19,20) were reported to have unexplained short half-lives of ϳ2.5 (19) and 3.2 days (20) in non-human primates at 3 mg/kg.…”

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confidence: 99%

Increasing Serum Half-life and Extending Cholesterol Lowering in Vivo by Engineering Antibody with pH-sensitive Binding to PCSK9

Chaparro‐Riggers

Hong

DeVay

et al. 2012

Journal of Biological Chemistry

155

166

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Background: An antagonistic anti-PCSK9 antibody exhibits target-mediated clearance, resulting in a dose-dependent PK. Results: Engineering of an antibody with pH-sensitive binding to PCSK9 decreases target-mediated clearance, resulting in increased PK and efficacy in vivo. Conclusion: pH-sensitive anti-PCSK9 antibodies are excellent candidates for therapeutic development. Significance: pH-sensitive antibodies may enable less frequent or lower dosing of antibodies hampered by target-mediated clearance and high antigen load.

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Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents

Abstract: Clinical trials have been launched using RNA interference approaches to reduce PCSK9 expression or specific antibodies targeting and inhibiting PCSK9 interaction with the LDL receptor. They constitute very promising approaches to reducing cholesterol levels and coronary heart disease.

Cited by 29 publications

References 68 publications

Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice

Gene Inactivation of Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Atherosclerosis in Mice

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Increasing Serum Half-life and Extending Cholesterol Lowering in Vivo by Engineering Antibody with pH-sensitive Binding to PCSK9

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