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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 3/2023

13-01-2022 | Alirocumab | Invited Review Article

Cholesterol Lowering Biotechnological Strategies: From Monoclonal Antibodies to Antisense Therapies. A Pre-Clinical Perspective Review

Authors: S. Bellosta, C. Rossi, A. S. Alieva, A. L. Catapano, A. Corsini, A. Baragetti

Published in: Cardiovascular Drugs and Therapy | Issue 3/2023

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Abstract

In recent years, the increase in available genetic information and a better understanding of the genetic bases of dyslipidemias has led to the identification of potential new avenues for therapies. Additionally, the development of new technologies has presented the key for developing novel therapeutic strategies targeting not only proteins (e.g., the monoclonal antibodies and vaccines) but also the transcripts (from antisense oligonucleotides (ASOs) to small interfering RNAs) or the genomic sequence (gene therapies). These pharmacological advances have led to successful therapeutic improvements, particularly in the cardiovascular arena because we are now able to treat rare, genetically driven, and previously untreatable conditions (e.g, familial hypertriglyceridemia or hyperchylomicronemia). In this review, the pre-clinical pharmacological development of the major biotechnological cholesterol lowering advances were discussed, describing facts, gaps, potential future steps forward, and therapeutic opportunities.
Literature
1.
Collaboration CTT. (CTT) efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.CrossRef
2.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. 2015;372:2387–2397.
3.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. 2018;380:11–22.
4.
Packard C, Chapman MJ, Sibartie M, Laufs U, Masana L. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart. 2021;107:1369–75.PubMedCrossRef
5.
Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I-related receptor FcRn. Annu Rev Immunol. 2000;18:739–66.PubMedCrossRef
6.
Tabrizi MA, Tseng CML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.PubMedCrossRef
7.
Raghavan M, Bonagura VR, Morrison SL, Bjorkman PJ. Analysis of the pH dependence of the neonatal fc receptor/immunoglobulin G interaction using antibody and receptor variants. Biochemistry. 1995;34:14649–57.PubMedCrossRef
8.
Foltz IN, Karow M, Wasserman SM. Evolution and emergence of therapeutic monoclonal antibodies what cardiologists need to know. Circulation. 2013;127:2222–30.PubMedCrossRef
9.
Regeneron Alirocumab (SRA236553/REGN727). Investigator brochure. 2014.
10.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107.PubMedCrossRef
11.
Guedeney P, Giustino G, Sorrentino S, Claessen BE, Camaj A, Kalkman DN, et al. Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J. 2019.
12.
Kühnast S, Van Der Hoorn JWA, Pieterman EJ, Van Den Hoek AM, Sasiela WJ, Gusarova V, Peyman A, Schäfer HL, Schwahn U, Jukema JW, et al. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res. 2014;55:2103–12.PubMedPubMedCentralCrossRef
13.
Pouwer MG, Pieterman EJ, Worms N, Keijzer N, Jukema JW, Gromada J, Gusarova V, Princen HMG. Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice. J Lipid Res. 2020;61:365–75.PubMedCrossRef
14.
Shen Y, Li H, Zhao L, Li G, Chen B, Guo Q, et al. Increased half-life and enhanced potency of fc-modified human PCSK9 monoclonal antibodies in primates. PLoS One. 2017;12.
15.
Kasichayanula S, Grover A, Emery MG, Gibbs MA, Somaratne R, Wasserman SM, Gibbs JP. Clinical pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin Pharmacokinet. 2018;57:769–79.PubMedPubMedCentralCrossRef
16.
Chan JCY, Piper DE, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci. 2009;106:9820–5.PubMedPubMedCentralCrossRef
17.
Qi Z, Hu L, Zhang J, Yang W, Liu X, Jia D, et al. PCSK9 enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation. 2020.
18.
Wu Y, Xu MJ, Cao Z, Yang C, Wang J, Wang B, et al. Heterozygous ldlr-deficient hamster as a model to evaluate the efficacy of PCSK9 antibody in hyperlipidemia and atherosclerosis. Int J Mol Sci. 2019;20:5936.
19.
Amgen Evolocumab (AMG 145). Investigator brochure. 2014.
20.
Khoshnejad M, Patel A, Wojtak K, Kudchodkar SB, Humeau L, Lyssenko NN, Rader DJ, Muthumani K, Weiner DB. Development of novel DNA-encoded PCSK9 monoclonal antibodies as lipid-lowering therapeutics. Mol Ther. 2019;27:188–99.PubMedCrossRef
21.
22.
Desai U, Lee EC, Chung K, Gao C, Gay J, Key B, Hansen G, Machajewski D, Platt KA, Sands AT, et al. Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc Natl Acad Sci U S A. 2007;104:11766–71.PubMedPubMedCentralCrossRef
23.
Harada-Shiba M, Ali S, Gipe DA, Gasparino E, Son V, Zhang Y, Pordy R, Catapano AL. A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis. 2020;314:33–40.PubMedCrossRef
24.
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan K-C, Gipe DA, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 2020;383:711–20.PubMedCrossRef
25.
Gusarova V, Alexa CA, Wang Y, Rafique A, Kim JH, Buckler D, Mintah IJ, Shihanian LM, Cohen JC, Hobbs HH, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308–17.PubMedPubMedCentralCrossRef
26.
Lee EC, Desai U, Gololobov G, Hong S, Feng X, Yu XC, Gay J, Wilganowski N, Gao C, Du LL, et al. Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of lipoprotein lipase (LPL). J Biol Chem. 2009;284:13735–45.PubMedPubMedCentralCrossRef
27.
Fattori E, Cappelletti M, Lo Surdo P, Calzetta A, Bendtsen C, Ni YG, Pandit S, Sitlani A, Mesiti G, Carfí A, et al. Immunization against proprotein convertase subtilisin-like/kexin type 9 lowers plasma LDL-cholesterol levels in mice. J Lipid Res. 2012;53:1654–61.PubMedPubMedCentralCrossRef
28.
Galabova G, Brunner S, Winsauer G, Juno C, Wanko B, Mairhofer A, Luhrs P, Schneeberger A, von Bonin A, Mattner F, et al. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One. 2014;9:e114469.PubMedPubMedCentralCrossRef
29.
Landlinger C, Pouwer MG, Juno C, van der Hoorn JWA, Pieterman EJ, Jukema JW, Staffler G, Princen HMG, Galabova G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Hear J. 2017;38:2499–507.CrossRef
30.
Kawakami R, Nozato Y, Nakagami H, Ikeda Y, Shimamura M, Yoshida S, et al. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/ kexin type 9 (PCSK9) epitope in mice. PLoS One. 2018;13:e0191895.
31.
Ji H, Wu G, Li Y, Wang K, Xue X, You S, et al. Self-albumin camouflage of carrier protein prevents nontarget antibody production for enhanced LDL-C immunotherapy. Adv Healthc Mater. 2020;9:e1901203.
32.
Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 2015;33:5747–55.PubMedPubMedCentralCrossRef
33.
34.
Wu D, Zhou Y, Pan Y, Li C, Wang Y, Chen F, et al. Vaccine against PCSK9 improved renal fibrosis by regulating fatty acid β-oxidation. J Am Heart Assoc. 2020;9:e014358.
35.
Wu D, Pan Y, Yang S, Li C, Zhou Y, Wang Y, et al. PCSK9Qβ-003 vaccine attenuates atherosclerosis in Apolipoprotein E-deficient mice. Cardiovasc Drugs Ther. 2020;35:141–151.
36.
Momtazi-Borojeni AA, Jaafari MR, Badiee A, Banach M, Sahebkar A. Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med. 2019;17:223.PubMedPubMedCentralCrossRef
37.
Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, Cowan CA, Rader DJ, Musunuru K. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115:488–92.PubMedPubMedCentralCrossRef
38.
Unger T, Peleg Y. Recombinant protein expression in the baculovirus-infected insect cell system. Methods Mol Biol. 2012;800:187–99.
39.
Silva Lima B, Videira MA. Toxicology and biodistribution: the clinical value of animal biodistribution studies. Mol Ther - Methods Clin Dev. 2018;8:183–97.PubMedPubMedCentralCrossRef
40.
Ferreira V, Petry H, Salmon F. Immune responses to AAV-vectors, the Glybera example from bench to bedside. Front Immunol. 2014;5:82.
41.
Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, Eckert MR, Vogel J, Charpentier E. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature. 2011;471:602–7.PubMedPubMedCentralCrossRef
42.
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21.PubMedPubMedCentralCrossRef
43.
Zalatan JG, Lee ME, Almeida R, Gilbert LA, Whitehead EH, La Russa M, Tsai JC, Weissman JS, Dueber JE, Qi LS, et al. Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell. 2015;160:339–50.PubMedCrossRef
44.
45.
Zheng J, Huynh HD, Umikawa M, Silvany R, Zhang CC. Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood. 2011;117:470–9.PubMedPubMedCentralCrossRef
46.
Chadwick AC, Wang X, Musunuru K. In Vivo Base editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol. 2017;37:1741–7.PubMedPubMedCentralCrossRef
47.
Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, Wang K, Iyer S, Dutta C, Clendaniel V, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593:429–34.PubMedCrossRef
48.
D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M. CAR-T cells: the long and winding road to solid tumors review-article. Cell Death Dis. 2018;9.
49.
Henry SP, Narayanan P, Shen L, Bhanot S, Younis HS, Burel SA. Assessment of the effects of 2′-methoxyethyl antisense oligonucleotides on platelet count in cynomolgus nonhuman primates. Nucleic Acid Ther. 2017;27:197–208.PubMedCrossRef
50.
Flierl U, Nero TL, Lim B, Arthur JF, Yao Y, Jung SM, Gitz E, Pollitt AY, Zaldivia MTK, Jandrot-Perrus M, et al. Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators. J Exp Med. 2015;212:129–37.PubMedPubMedCentralCrossRef
51.
Lundberg Slingsby MH, Couldwell G, Vijey P, Terkovich BE, Noetzli L, Okazaki R, Thon JN, Henry SP, Narayanan P, Italiano JE. Investigating potential mechanism(s) by which ASO-based drugs cause thrombocytopenia. Blood. 2018;132:3747.CrossRef
52.
Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, Wijngaard P, Horton JD, Taubel J, Brooks A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376:41–51.PubMedCrossRef
53.
Nair JK, Willoughby JLS, Chan A, Charisse K, Alam MR, Wang Q, Hoekstra M, Kandasamy P, Kel’in AV, Milstein S, et al. Multivalent N -Acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958–61.PubMedCrossRef
54.
Warden BA, Duell PB. Inclisiran: a novel agent for lowering Apolipoprotein B–containing lipoproteins. J Cardiovasc Pharmacol. 2021;78:e157–74.PubMedCrossRef
55.
Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U. Targeting RNA with antisense oligonucleotides and small interfering RNA in dyslipidemias. J Am Coll Cardiol. 2020;76:563–79.PubMedCrossRef
56.
57.
Khvorova A. Oligonucleotide therapeutics — a new class of cholesterol-lowering drugs. N Engl J Med. 2017;376:4–7.PubMedCrossRef
58.
Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–8.PubMedCrossRef
59.
Ray KK, Stoekenbroek RM, Kallend D, Nishikido T, Leiter LA, Landmesser U, Wright RS, Wijngaard PLJ, Kastelein JJP. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA Cardiol. 2019;4:1067–75.PubMedPubMedCentralCrossRef
60.
61.
Wright RS, Collins MG, Stoekenbroek RM, Robson R, Wijngaard PLJ, Landmesser U, Leiter LA, Kastelein JJP, Ray KK, Kallend D. Effects of renal impairment on the pharmacokinetics, efficacy, and safety of Inclisiran: an analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc. 2020;95:77–89.PubMedCrossRef
62.
Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008;105:11915–20.PubMedPubMedCentralCrossRef
63.
Banerjee Y, Pantea Stoian A, Cicero AFG, Fogacci F, Nikolic D, Sachinidis A, et al. Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia. Expert Opin Drug Saf. 2021.
64.
Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507–19.PubMedCrossRef
65.
Ray KK, Corral P, Morales E, Nicholls SJ. Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options. Lancet. 2019;394:697–708.PubMedCrossRef
66.
Landmesser U, Haghikia A, Leiter LA, Wright RS, Kallend D, Wijngaard P, et al. Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1. Cardiovasc Res. 2020.
67.
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–40.PubMedCrossRef
68.
Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22:823–33.PubMedCrossRef
69.
Dolgin E. Lp(a)-lowering drugs bolster cardiovascular pipeline. Nat Rev Drug Discov. 2020;19:154–5.PubMedCrossRef
70.
Melquist S, Wakefield D, Hamilton H, et al. Abstract 17167: Targeting apolipoprotein(a) with a novel RNAi delivery platform as a prophylactic treatment to reduce risk of cardiovascular events in individuals with elevated lipoprotein (a). Circulation. 2016;134:A17167
71.
Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, Fu W, Mullick AE, Lee R, Willeit P, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol. 2011;57:1611–21.PubMedCrossRef
72.
Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif J-C, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382:244–55.PubMedCrossRef
73.
Yu RZ, Grundy JS, Geary RS. Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin Drug Metab Toxicol. 2013;9:169–82.PubMedCrossRef
74.
Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis. 1990;10:240–5.PubMedCrossRef
75.
Rouy D, Grailhe P, Nigon F, Chapman J, Angles-Cano E. Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator: in vitro studies in a plasma milieu. In proceedings of the arteriosclerosis and thrombosis. Arterioscler Thromb. 1991;11:629–38.PubMedCrossRef
76.
Palabrica TM, Liu AC, Aronovitz MJ, Furie B, Lawn RM, Furie BC. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. Nat Med. 1995;1:256–9.PubMedCrossRef
77.
Biemond BJ, Friederich PW, Koschinsky ML, Levi M, Sangrar W, Xia J, Büller HR, Ten Cate JW. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo. Circulation. 1997;96:1612–5.PubMedCrossRef
78.
Boffa MB, Marar TT, Yeang C, Viney NJ, Xia S, Witztum JL, Koschinsky ML, Tsimikas S. Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J Lipid Res. 2019;60:2082–9.PubMedPubMedCentralCrossRef
79.
Helgadottir A, Gretarsdottir S, Thorleifsson G, Holm H, Patel RS, Gudnason T, Jones GT, Van Rij AM, Eapen DJ, Baas AF, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60:722–9.PubMedCrossRef
80.
Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. Arterioscler Thromb Vasc Biol. 2012;32:1732–41.PubMedCrossRef
81.
Boffa MB, Koschinsky ML. Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease. Nat Rev Cardiol. 2019;16:305–18.PubMedCrossRef
82.
Adam RC, Mintah IJ, Alexa-Braun CA, Shihanian LM, Lee JS, Banerjee P, Hamon SC, Kim HI, Cohen JC, Hobbs HH, et al. Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res. 2020;61:1271–86.PubMedPubMedCentralCrossRef
83.
Wu L, Soundarapandian MM, Castoreno AB, Millar JS, Rader DJ. LDL-cholesterol reduction by ANGPTL3 inhibition in mice is dependent on endothelial lipase. Circ Res. 2020;127:1112–4.PubMedPubMedCentralCrossRef
84.
Graham MJ, Lee RG, Brandt TA, Tai L-J, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377:222–32.PubMedCrossRef
85.
Graham MJ, Lee RG, Bell TA, Fu W, Mullick AE, Alexander VJ, Singleton W, Viney N, Geary R, Su J, et al. Antisense oligonucleotide inhibition of apolipoprotein c-iii reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112:1479–90.PubMedCrossRef
86.
Alexander VJ, Xia S, Hurh E, Hughes SG, O’Dea L, Geary RS, Witztum JL, Tsimikas S. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019;40:2785–96.PubMedPubMedCentralCrossRef
87.
Post N, Yu R, Greenlee S, Gaus H, Hurh E, Matson J, Wang Y. Metabolism and disposition of volanesorsen, a 29-O-(2 methoxyethyl) antisense oligonucleotide, across species. Drug Metab Dispos. 2019;47:1164–73.PubMedCrossRef
88.
Alexander VJ, Digenio A, Xia S, Hurh E, Hughes S, Geary RS, et al. Inhibition pf apolipoprotein CIII with GalNac conjugated antisense drug potently lowers fasting serum apolipoprotein CIII and triglycerides levels in healthy volunteers with elevated triglycerides. JACC. 2018;71:A1724.
Metadata
Title
Cholesterol Lowering Biotechnological Strategies: From Monoclonal Antibodies to Antisense Therapies. A Pre-Clinical Perspective Review
Authors
S. Bellosta
C. Rossi
A. S. Alieva
A. L. Catapano
A. Corsini
A. Baragetti
Publication date
13-01-2022
Publisher
Springer US
Keyword
Alirocumab
Published in
Cardiovascular Drugs and Therapy / Issue 3/2023
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07293-w

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