Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) Lp (a) is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp (a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp (a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. However, effective therapies to specifically reduce plasma Lp (a) levels are lacking. Recent animal and human studies have shown that Lp (a) can be specifically targeted with second generation antisense oligonucleotides (ASOs) that inhibit apo (a) mRNA translation. In apo (a) transgenic mice, an apo (a) ASO reduced plasma apo (a) /Lp (a) levels and their associated oxidized phospholipid (OxPL) levels by 86 and 93%, respectively. In cynomolgus monkeys, a second generation apo (a) ASO, ISIS-APO (a) Rx, significantly reduced hepatic apo (a) mRNA expression and plasma Lp (a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO (a) Rx ASO reduced Lp (a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO (a) Rx represents the first specific and potent drug in clinical development to lower Lp (a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis. Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) Lp (a) is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp (a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp (a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. However, effective therapies to specifically reduce plasma Lp (a) levels are lacking. Recent animal and human studies have shown that Lp (a) can be specifically targeted with second generation antisense oligonucleotides (ASOs) that inhibit apo (a) mRNA translation. In apo (a) transgenic mice, an apo (a) ASO reduced plasma apo (a) /Lp (a) levels and their associated oxidized phospholipid (OxPL) levels by 86 and 93%, respectively. In cynomolgus monkeys, a second generation apo (a) ASO, ISIS-APO (a) Rx, significantly reduced hepatic apo (a) mRNA expression and plasma Lp (a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO (a) Rx ASO reduced Lp (a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO (a) Rx represents the first specific and potent drug in clinical development to lower Lp (a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis. ERRATUMJournal of Lipid ResearchVol. 57Issue 12PreviewThe authors of “Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans” (J. Lipid Res. 2016. 57: 340–351) have advised the Journal that there was an error in the legend to Table 1. The corrected table legend should read “ISIS-APO (a) Rx complementary binding sites within the human apo (a) transcript (GenBank accession NM₀05577. 2) at position 3901-3920. ISIS-APO (a) Rx was designed to perfectly match only the exon 24-25 splice site (indicated with bold type) but may also bind at 11 other apo (a) exon splice sites containing one to three mismatched nucleotides (indicated by underlined letters). ” Additionally, on page 343 under the “Identification of a Second Generation Antisense Drug to Human apo (a) ” section, “ISISAPO (a) Rx also has the potential to bind to 11 alternative sites within the transcript containing one to four mismatched nucleotides” should read “ISISAPO (a) Rx also has the potential to bind to 11 alternative sites within the transcript containing one to three mismatched nucleotides. ” Full-Text PDF Open Access Lipoprotein (a) Lp (a) is a highly polymorphic lipoprotein found in human plasma in levels ranging from 250 mg/dl. Lp (a) consists of an LDL-like particle and apo (a), which are covalently bound via a disulfide bond between Cys4326 of apoB-100 and Cys4057 of apo (a) located in kringle IV (KIV) type 9 (KIV9). The apo (a) comprises 10 KIV subunits, of which KIV2 is present in variable identically sized repeats, kringle V (KV), and an inactive protease domain. The apo (a) protein shows a high degree of homology (75–100%) to plasminogen at both the nucleotide and the amino acid level (1Kronenberg F. Utermann G. Lipoprotein (a): resurrected by genetics. J. Intern. Med. 2013; 273: 6-30Crossref PubMed Scopus (336) Google Scholar). However, the apo (a) gene transcript is much larger due to the repetitive KIV2 domain (3 to >40 repeats) in the LPA gene. The majority of apo (a) mRNA is expressed in the liver, with minor amounts present in the testes, brain, adrenals, lung, and pituitary. Lp (a) levels are primarily genetically determined by the LPA alleles present within an individual (2McLean J. W. Tomlinson J. E. Kuang W. J. Eaton D. L. Chen E. Y. Fless G. M. Scanu A. M. Lawn R. M. cDNA sequence of human apolipoprotein (a) is homologous to plasminogen. Nature. 1987; 330: 132-137Crossref PubMed Scopus (1594) Google Scholar, 3Boerwinkle E. Leffert C. C. Lin J. Lackner C. Chiesa G. Hobbs H. H. Apolipoprotein (a) gene accounts for greater than 90% of the variation in plasma lipoprotein (a) concentrations. J. Clin. Invest. 1992; 90: 52-60Crossref PubMed Scopus (821) Google Scholar). Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that Lp (a) is an independent causal risk factor for CVD, including myocardial infarction, stroke, and peripheral arterial disease, as well as calcific aortic valve stenosis (4Erqou S. Kaptoge S. Perry P. L. Di Angelantonio E. Thompson A. White I. R. Marcovina S. M. Collins R. Thompson S. G. Danesh J. Lipoprotein (a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009; 302: 412-423Crossref PubMed Scopus (1156) Google Scholar, 5Clarke R. Peden J. F. Hopewell J. C. Kyriakou T. Goel A. Heath S. C. Parish S. Barlera S. Franzosi M. G. Rust S. PROCARDIS Consortium et al. Genetic variants associated with Lp (a) lipoprotein level and coronary disease. N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1031) Google Scholar, 6Thanassoulis G. Campbell C. Y. Owens D. S. Smith J. G. Smith A. V. Peloso G. M. Kerr K. F. Pechlivanis S. Budoff M. J. Harris T. B. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 2013; 368: 503-512Crossref PubMed Scopus (626) Google Scholar, 7Kamstrup P. R. Benn M. Tybjaerg-Hansen A. Nordestgaard B. G. Extreme lipoprotein (a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation. 2008; 117: 176-184Crossref PubMed Scopus (350) Google Scholar, 8Kamstrup P. R. Tybjaerg-Hansen A. Nordestgaard B. G. Elevated lipoprotein (a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 2014; 63: 470-477Crossref PubMed Scopus (351) Google Scholar, 9Capoulade R. Chan K. L. Yeang C. Mathieu P. Bossé Y. Dumesnil J. G. Tam J. W. Teo K. K. Mahmut A. Yang X. et al. Oxidized phospholipids, lipoprotein (a), and progression of calcific aortic valve stenosis. J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (239) Google Scholar). While extensive epidemiological data suggest that elevated plasma Lp (a) levels are pro-atherogenic (10Dubé J. B. Boffa M. B. Hegele R. A. Koschinsky M. L. Lipoprotein (a): more interesting than ever after 50 years. Curr. Opin. Lipidol. 2012; 23: 133-140Crossref PubMed Scopus (95) Google Scholar), the molecular mechanisms by which it contributes to the atherosclerotic process remain enigmatic. There is evidence that apo (a) potentiates atherothrombosis through its LDL moiety and by additional apo (a) -driven mechanisms, including impairing fibrinolysis, mediating pro-inflammatory effects, activating endothelial cells, recruiting monocytes to the vessel wall, accelerating macrophage foam cell formation, and transporting pro-inflammatory oxidized phospholipids (OxPLs) (1Kronenberg F. Utermann G. Lipoprotein (a): resurrected by genetics. J. Intern. Med. 2013; 273: 6-30Crossref PubMed Scopus (336) Google Scholar, 11Bergmark C. Dewan A. Orsoni A. Merki E. Miller E. R. Shin M. J. Binder C. J. Horkko S. Krauss R. M. Chapman M. J. et al. A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma. J. Lipid Res. 2008; 49: 2230-2239Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 12Merki E. Graham M. A. G. Yang X. Miller E. R. R. P. et plasma levels of (a) and lipoprotein (a) in transgenic Am. Coll. 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Lipid Res. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). to the evidence that Lp (a) contributes to CVD, a for potent and specific of apo (a) was the to inhibition of antisense have as a in Lp (a) levels in the clinical the from and and have shown in specific of in and to their of by binding complementary mRNA via is In the of of the apo (a) transcript plasminogen transcript levels Second generation are nucleotides in containing at the and and and nucleotides in the with a to R. Drug of antisense up to their Opin. Google Scholar, in antisense Med. PubMed Scopus Google Scholar, S. S. G. Graham M. J. Yang Marcovina S. M. et therapy a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). These are up to more potent than ASO due to their mRNA via the moiety S. S. G. Graham M. J. Yang Marcovina S. M. et therapy a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, R. and cell of antisense Drug 2015; PubMed Scopus Google Scholar, and and of a antisense of 2015; PubMed Scopus Google Scholar), their an and their that These also have an due to reduced pro-inflammatory of second generation antisense Opin. Drug 2013; PubMed Scopus Google Scholar, of a second generation antisense of J. Clin. 2013; PubMed Scopus Google Scholar, S. G. Graham M. J. R. M. et in the Engl. J. Med. 2014; PubMed Scopus Google Scholar, C. S. A. P. antisense for of Engl. J. Med. 2015; PubMed Scopus Google Scholar, S. G. Graham M. J. et inhibition of in patients with Engl. J. Med. 2015; PubMed Scopus Google Scholar). ASO are by and the can be with with of R. and cell of antisense Drug 2015; PubMed Scopus Google Scholar). Additionally, as are may be in via and Antisense and Opin. Drug 2009; PubMed Scopus Google Scholar). The of have in and in of second generation antisense Opin. Drug 2013; PubMed Scopus Google Scholar). the liver, and the drug is to the lung, and are to in ranging from 10 to In are from by lower molecular that are by In the first antisense study in a human apo (a) containing and was designed to specifically target KIV of the apo (a) mRNA plasminogen transcript levels R. S. A. Y. Lawn R. J. et for oligonucleotides apolipoprotein (a) inhibit apolipoprotein (a) but plasminogen gene PubMed Scopus Google Scholar). human cell the apo (a) an apo (a) expression containing the the the first repeats, and of the kringle of apo (a) by the was with a of and the apo (a) the apo (a) was shown to reduce protein by in plasminogen protein was While the of of the apo (a) to have in studies more a second generation ASO to apoB-100 and for clinical in the for LDL in patients with S. S. The clinical and Am. Coll. Cardiol. 2014; 63: PubMed Scopus Google Scholar), has shown to lower Lp (a) levels in E. Graham M. J. Miller E. R. R. M. S. Antisense to human lipoprotein (a) levels and oxidized phospholipids on human in lipoprotein (a) transgenic 2008; PubMed Scopus Google and in M. J. S. et an for of LDL in patients with a Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. R. G. S. of in patients with 2012; PubMed Scopus Google Scholar, R. C. C. D. L. M. inhibition with in of a to and as therapy in patients with coronary 2012; PubMed Scopus Google Scholar, S. M. an in patients with at high a Am. Coll. Cardiol. 2013; PubMed Scopus Google Scholar). In four phase in patients on therapy and to for reduced plasma Lp (a) levels by was in the E. S. an antisense to lipoprotein (a) in with of phase 2015; PubMed Scopus Google Scholar). in the only present between in Lp (a) and and Lp (a) and mechanisms of Lp (a) to of that are by plasma study in by Merki et E. Graham M. J. Miller E. R. R. M. S. Antisense to human lipoprotein (a) levels and oxidized phospholipids on human in lipoprotein (a) transgenic 2008; PubMed Scopus Google that one potential of Lp (a) reduction by may be through hepatic of apo (a) is to an Lp (a) both human human LPA to Lp (a) apo (a) a bond with with reduced hepatic and plasma levels of to levels and reduced and Lp (a) levels by However, the to amounts of apo (a) to as with that apoB-100 is a factor in Lp (a) particle generation in LPA transgenic In a Merki et E. Graham M. A. G. Yang X. Miller E. R. R. P. et plasma levels of (a) and lipoprotein (a) in transgenic Am. Coll. Cardiol. 57: PubMed Scopus Google a second generation ASO, in the LPA transgenic a human LPA cDNA with KIV that has high Lp (a) levels C. Dewan A. Orsoni A. Merki E. Miller E. R. Shin M. J. Binder C. J. Horkko S. Krauss R. M. Chapman M. J. et al. A novel function of lipoprotein a as a preferential carrier of oxidized phospholipids in human plasma. J. 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The for consists of the hepatic and 1. both human and the human LPA LPA transgenic the human apo (a) gene containing KIV in a that the apo (a) and transgenic for in hepatic apo (a) mRNA significantly reduced Lp (a) by in and reduced apo (a) levels by in mice, in mice, and in The potent was in apo (a) with KIV2 containing the LPA and in the mice, also significantly reduced on by of clinical studies have that the of apo (a) with high Lp (a) are strong of CVD evidence that the of pro-inflammatory are of risk by Lp (a) S. J. M. M. F. C. J. S. et al. Oxidized phospholipids, lipoprotein (a), and from the PubMed Scopus Google Scholar, S. Miller E. R. J. A. et lipoprotein (a), and risk of and coronary Am. Coll. Cardiol. PubMed Scopus Google Scholar, S. P. J. P. M. A. S. and and of Am. Coll. Cardiol. 2012; PubMed Scopus Google Scholar, A. G. M. A. E. Miller et and of oxidized phospholipids and oxidized coronary and peripheral arterial in Am. Coll. 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In of the in the transgenic studies and the to an human clinical a high of second generation designed to complementary sites the human apo (a) transcript for their to reduce apo (a) mRNA expression in transgenic LPA ASO, as ISIS-APO (a) Rx, to it from the was that to the exon 24-25 splice site of the human apo (a) transcript (GenBank accession NM₀05577. 2) at position KIV2 are at the protein but are at the nucleotide which is the drug only to a splice with ISIS-APO (a) Rx also has the potential to bind to 11 alternative sites within the transcript containing one to four mismatched to the The concentration of ISIS-APO (a) Rx that an of the apo (a) mRNA in LPA transgenic was In cynomolgus the was In the for targeted to the apo (a) mRNA in both cell complementary binding sites within the human apo (a) on apo (a) mRNA on on Second complementary binding sites within the human apo (a) transcript (GenBank accession NM₀05577. 2) at position ISIS-APO (a) Rx was designed to perfectly match only the exon 24-25 splice site (indicated with bold type) but may also bind at 11 other apo (a) exon splice sites containing one to four mismatched nucleotides (indicated by underlined Open table in a ISIS-APO (a) Rx complementary binding sites within the human apo (a) transcript (GenBank accession NM₀05577. 2) at position ISIS-APO (a) Rx was designed to perfectly match only the exon 24-25 splice site (indicated with bold type) but may also bind at 11 other apo (a) exon splice sites containing one to four mismatched nucleotides (indicated by underlined the apo (a) transcript is expressed in in to studies in transgenic a kringle KIV apo (a) which expressed the human LPA G. The apolipoprotein (a) gene is by and in transgenic PubMed Scopus Google Scholar). of ISIS-APO (a) Rx to in apo (a) mRNA and apo (a) in plasma after of ASO at and 50 The effective for ISIS-APO (a) Rx apo (a) mRNA and plasma apo (a) and respectively, in transgenic While the ISIS-APO (a) Rx binding site in the a to the the potential effects of in cynomolgus up to for monkeys, in a to have a of plasma Lp (a) levels due to in the KIV2 to but of human apo (a) lipoprotein (a) concentration is by apolipoprotein (a) protein and the of hepatic apo (a) mRNA in a cynomolgus Full Text PDF PubMed Google Scholar). in both and data that cynomolgus highly variable hepatic mRNA expression levels lipoprotein (a) concentration is by apolipoprotein (a) protein and the of hepatic apo (a) mRNA in a cynomolgus Full Text PDF PubMed Google Scholar, concentration is with the of V in the apo (a) Clin. Invest. PubMed Scopus Google Scholar). from study that ISIS-APO (a) Rx significantly reduced hepatic apo (a) mRNA by to the due to of apo (a) and plasminogen nucleotide are three within the homologous binding plasminogen mRNA levels also There was in hepatic plasminogen mRNA to the after of ISIS-APO (a) Rx of ISIS-APO (a) Rx on apo (a) and plasminogen mRNA in cynomolgus are expressed as the of in for apo (a) and plasminogen mRNA are expressed as the of in for apo (a) and plasminogen mRNA and protein are expressed as a of and protein are expressed as a of and protein are expressed as a of and protein are expressed as a of from was to cynomolgus at of three in first by was are expressed as the of in for apo (a) and plasminogen mRNA and protein are expressed as a of from Open table in a ISIS-APO (a) Rx was to cynomolgus at of three in first by was In the effects of ISIS-APO (a) Rx inhibition as a function of in cynomolgus the and hepatic apo (a) mRNA was reduced to and respectively, of expression levels by of ISIS-APO (a) Rx plasma Lp (a) levels reduced by and at the and respectively, to levels plasma after there in at the In to the of apo (a) expression within the and ISIS-APO (a) Rx cynomolgus was to and in both and ISIS-APO (a) Rx The apo (a) with plasma apo (a) levels as in study both and for apo (a) in four with ISIS-APO (a) Rx, plasma apo (a) levels reduced to levels at the by of apo (a) protein in the in expression levels in of the plasma These that ISIS-APO (a) Rx is highly effective in plasma apo (a) levels in of individual variation in phase I in with Lp (a) concentration of was to the and of ISIS-APO (a) Rx S. S. G. Graham M. J. Yang Marcovina S. M. et therapy a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). of the and the to ISIS-APO (a) Rx by in the of the study to of ISIS-APO (a) Rx for a of a in the of the In the ISIS-APO (a) Rx in in plasma Lp (a) concentration of from in the in the and in the The in an individual was at after of plasma of ISIS-APO (a) Rx the and plasma concentration was by an plasma in the which with the of Lp (a) and and in the of associated with apoB-100 to and apo (a) to but in other in on plasminogen plasminogen in and from to the in the with was from S. S. G. Graham M. J. Yang Marcovina S. M. et therapy a phase 2015; Full Text Full Text PDF PubMed Scopus Google with In the an was between the of the expressed apo (a) and plasma Lp (a) and However, there was between the apo (a) and the from to in Lp (a) with the of of Lp (a) and on In the and at a strong was between Lp (a) and and Lp (a) and In ISIS-APO (a) Rx in potent of plasma Lp (a) and represents a potential drug to reduce the risk of CVD and calcific aortic valve stenosis in patients with elevated Lp (a) Recent data has that Lp (a) can be significantly by with to E. S. an antisense to lipoprotein (a) in with of phase 2015; PubMed Scopus Google Scholar), to type 9 C. S. of levels in the type 9 of potent Opin. Lipidol. 2015; PubMed Scopus Google Scholar, M. J. R. S. M. R. J. B. et and of a human to in patients on of patients in four phase Heart J. 2014; PubMed Scopus Google Scholar, M. J. G. M. R. S. M. et in lipoprotein (a) with a of more than patients in phase Am. Coll. 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Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 2013; 368: 503-512Crossref PubMed Scopus (626) Google Scholar, 8Kamstrup P. R. Tybjaerg-Hansen A. Nordestgaard B. G. Elevated lipoprotein (a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 2014; 63: 470-477Crossref PubMed Scopus (351) Google Scholar). has the of Lp (a) and which the of in the of progression of aortic stenosis in the of Elevated levels of both Lp (a) and aortic stenosis progression by the in aortic in second by as well as the for aortic valve and of R. Chan K. L. Yeang C. Mathieu P. Bossé Y. Dumesnil J. G. Tam J. W. Teo K. K. Mahmut A. Yang X. et al. Oxidized phospholipids, lipoprotein (a), and progression of calcific aortic valve stenosis. J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (239) Google Scholar). The of progression was in patients in the of Lp (a) aortic and These support the that Lp (a) aortic stenosis progression through its associated and a for of and therapies in aortic stenosis clinical can be to Lp (a) may reduce progression of aortic stenosis and the for aortic valve of Lp (a) and OxPL with the development and progression of calcific aortic valve stenosis. Elevated Lp (a) and OxPL plasma levels clinical progression of aortic valve with high Lp (a) and OxPL plasma levels have a significantly calcific aortic valve stenosis progression by aortic and larger valvular with with Lp (a) and OxPL plasma was from R. Chan K. L. Yeang C. Mathieu P. Bossé Y. Dumesnil J. G. Tam J. W. Teo K. K. Mahmut A. Yang X. et al. Oxidized phospholipids, lipoprotein (a), and progression of calcific aortic valve stenosis. J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (239) Google with Finally, the development of is to the of by as much as to for mRNA expressed in hepatic Graham M. J. J. R. A. A. C. M. et of antisense oligonucleotides to in Res. 2014; PubMed Scopus Google Scholar). is the for the and are and expressed on Y. C. The with acid PubMed Scopus Google Scholar, The between and PubMed Scopus Google Scholar). may to as antisense the of and of The authors for of the antisense human kringle IV kringle V LDL lipoprotein (a) second oxidized phospholipid oxidized phospholipid on lipoprotein