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Advances in lipid-lowering therapy through gene-silencing technologies

Key Points

  • Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins can cause acute pancreatitis in some individuals

  • Small molecule and antibody-based drugs such as statins, ezetimibe, and PCSK9 inhibitors efficiently reduce LDL-cholesterol levels and lower the risk of cardiovascular disease

  • In addition, these drugs can modestly reduce remnant lipoproteins, triglyceride-rich lipoproteins, and/or lipoprotein(a) levels

  • These lipoproteins can be reduced using novel gene-silencing approaches (antisense oligonucleotide inhibition and small interfering RNA technology) by targeting proteins that have an important role in lipoprotein production or removal

  • Using gene-silencing approaches, plasma levels of LDL, remnant lipoproteins, lipoprotein(a), and triglyceride-rich lipoproteins can be reduced by 50–90% when treatment is administered 2–12 times yearly

  • Evidence of long-term safety and cardiovascular disease reduction is needed before the widespread use of gene-silencing therapies; however, these drugs might have a role in patients with rare diseases

Abstract

New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9). Using this technology, plasma levels of these lipoproteins can be reduced by 50–90% with 2–12 injections per year; such dramatic reductions are likely to reduce the incidence of cardiovascular disease or acute pancreatitis in at-risk patients. The reported adverse effects of these new therapies include injection-site reactions, flu-like symptoms, and low blood platelet counts. However, newer-generation drugs are more efficiently delivered to liver cells, requiring lower drug doses, which leads to fewer adverse effects. Although these findings are promising, robust evidence of cardiovascular disease reduction and long-term safety is needed before these gene-silencing technologies can have widespread implementation. Before the availability of such evidence, these drugs might have roles in patients with unmet medical needs through orphan indications.

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Figure 1: Approaches to reduce LDL-cholesterol levels.
Figure 2: Apolipoprotein B-containing lipoproteins that cause cardiovascular disease.
Figure 3: Role of the apolipoprotein B-containing lipoproteins in atherosclerotic plaque initiation, progression, rupture, and regression.
Figure 4: Lipoprotein classes and risk of myocardial infarction.
Figure 5: siRNA-based versus antisense oligonucleotide-based approaches.
Figure 6: Efficacy of different approaches to lipid lowering.

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All the authors contributed to researching data for the article, discussion of its content, writing the article, and reviewing and editing the manuscript before submission.

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Correspondence to Børge G. Nordestgaard.

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B.G.N. is a consultant for Amgen, AstraZeneca, Denka Seiken, Dezima Pharma, Ionis Pharmaceuticals, Kowa, Merck, Regeneron Pharmaceuticals, and Sanofi. S.J.N. has received research funding from Amgen, Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, Eli Lilly, InfraReDx, LipoScience, Novartis, Regeneron Pharmaceuticals, Resverlogix, Roche, Sanofi, and The Medicines Company, and is a consultant for Anthera Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion Therapeutics, Merck, Omthera Pharmaceuticals, Regeneron Pharmaceuticals, Resverlogix, Sanofi, and Takeda. K.K.R. has received research funding from Amgen, Merck, Pfizer, Regeneron, and Sanofi, and is a consultant for AbbVie, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis Therapeutics, Cipla, Eli Lilly, Esperion, Ionis Pharmaceuticals, Kowa, Merck, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and The Medicines Company. The other authors declare no competing interests.

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Nordestgaard, B., Nicholls, S., Langsted, A. et al. Advances in lipid-lowering therapy through gene-silencing technologies. Nat Rev Cardiol 15, 261–272 (2018). https://doi.org/10.1038/nrcardio.2018.3

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