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Oral oligonucleotide therapy of LDL cholesterol

ESC Working Group on Coronary Pathophysiology & Microcirculation

Basic Science - Cardiac Diseases - Drugs, Drug Targets

Low-density lipoprotein is the central driver of the development of atherosclerotic plaques, which drive obstructive coronary artery disease and aortic aneurysm formation1.  Consequently, lowering LDL cholesterol is the mainstay of primary and secondary prevention of coronary artery disease and progression of aortic aneurism formation. Statin therapy has proven effective in attenuating the progression of atherosclerotic plaque development1, 2 and cardiovascular disease2. Further LDL lowering by inhibiting proprotein convertase subtilisin-kexin type 9 (PCSK9), which controls the breakdown of hepatic LDL receptors, has been shown to lower the incidence of cardiovascular disease even further3. The currently available and highly effective method of inhibiting PCSK9 is evolocumab, a monoclonal antibody that needs subcutaneous injections for delivery3.

In the May issue of Science Translational Medicine, Gennemark et al. from Astra Zeneca R&D present a second strategy for inhibiting PCSK9, oral treatment with an antisense oligonucleotide (ASO)4. The ASO is targeted to the liver using a N-acetylgalactosamine conjugate, and uptake from the bowel is enhanced by the transient permeation enhancer sodium caprate, which is clinically approved5. In extensive studies on the pharmacokinetics and pharmacodynamics of the ASO in mice, rats, dogs and monkeys, oral ASO treatment was shown to reduce hepatic PCSK9 levels by 80 percent, comparable to subcutaneous injections, resulting in a ˜50 percent reduction in plasma LDL cholesterol. These effects were cumulative and lasted for 2-3 weeks after administration, and common side effects of the treatment were emesis and diarrhea.

Although permeation enhancers have previously disappointed in oral insulin administration, the presented strategy of oral oligonucleotide delivery to the liver is a highly promising alternative to injection-based drug delivery6. The impact of this strategy may well extend beyond PCSK9 and the liver to epigenetic modification of the cardiovascular system, as Gennemark et al. also show effective delivery and efficacy of a GapMer against the long non-coding RNA Malat-1. LncRNAs are intriguing targets for attenuating cardiovascular ageing7, and tools to manipulate them in patients could revolutionize cardiovascular medicine.

This thorough methodological study in animal models should be interpreted with caution as models do not fully reflect heterogeneous patient phenotypes, there were common side effects and the study did not include a model of hypercholesterolemia. Nevertheless, the data presented warrant a proof-of-concept study of oral oligonucleotide therapy in man, and the availability of permeation enhancers for human use brings such a study within reach. Intriguingly, the same can now be said for patient-friendly PCSK9 inhibition and treating the epigenome in cardiovascular disease.


  1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen M-R, Tokgözoğlu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ and Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal. 2017;38:2459-2472.
  2. Ford I, Murray H, McCowan C and Packard CJ. Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study. Circulation. 2016;133:1073-80.
  3. Giugliano RP, Pedersen TR, Park J-G, De Ferrari GM, Gaciong ZA, Ceska R, Toth K, Gouni-Berthold I, Lopez-Miranda J, Schiele F, Mach F, Ott BR, Kanevsky E, Pineda AL, Somaratne R, Wasserman SM, Keech AC, Sever PS and Sabatine MS. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. The Lancet. 390:1962-1971.
  4. Gennemark P, Walter K, Clemmensen N, Rekić D, Nilsson CAM, Knöchel J, Hölttä M, Wernevik L, Rosengren B, Kakol-Palm D, Wang Y, Yu RZ, Geary RS, Riney SJ, Monia BP, Isaksson R, Jansson-Löfmark R, Rocha CSJ, Lindén D, Hurt-Camejo E, Crooke R, Tillman L, Rydén-Bergsten T, Carlsson B, Andersson U, Elebring M, Tivesten A and Davies N. An oral antisense oligonucleotide for PCSK9 inhibition. Science Translational Medicine. 2021;13:eabe9117.
  5. Twarog C, Fattah S, Heade J, Maher S, Fattal E and Brayden DJ. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C(10)). Pharmaceutics. 2019;11.
  6. Maher S, Brayden DJ, Casettari L and Illum L. Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics. 2019;11:41.
  7. Boon RA, Jae N, Holdt L and Dimmeler S. Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets? J Am Coll Cardiol. 2016;67:1214-26.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.