Author + information
- Received April 3, 2020
- Revision received April 29, 2020
- Accepted May 10, 2020
- Published online July 27, 2020.
- Julius L. Katzmann, MDa,∗ (, )@UKL_Leipzig,
- Chris J. Packard, DScb,
- M. John Chapman, PhD, DScc,d,
- Isabell Katzmann, MDe and
- Ulrich Laufs, MDa
- aDepartment of Cardiology, University Hospital Leipzig, Leipzig, Germany
- bInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
- cEndocrinology-Metabolism Division, Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France
- dNational Institute for Health and Medical Research (INSERM), Paris, France
- eDepartment of Internal Medicine, Zeisigwaldkliniken Bethanien Chemnitz, Chemnitz, Germany
- ↵∗Address for correspondence:
Dr. Julius L. Katzmann, Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, 04103 Leipzig, Germany.
• RNA targeting is a novel therapeutic approach in cardiovascular prevention.
• Liver-specific drug delivery is enhanced by N-acetylgalactosamine conjugation.
• Specific targeting of PCSK9, apoCIII, apo(a), and ANGPTL3 mRNA is described.
• Effects on clinical outcomes and safety are under assessment in ongoing trials.
There is an unmet clinical need to reduce residual cardiovascular risk attributable to apolipoprotein B-containing lipoproteins, particularly low-density lipoprotein and remnant particles. Pharmacological targeting of messenger RNA represents an emerging, innovative approach. Two major classes of agents have been developed—antisense oligonucleotides and small interfering RNA. Early problems with their use have been overcome by conjugation with N-acetylgalactosamine, an adduct that targets their delivery to the primary site of action in the liver. Using these agents to inhibit the translation of key regulatory proteins such as PCSK9, apolipoprotein CIII, apolipoprotein(a), and angiopoietin-like 3 has been shown to be effective in attenuating dyslipidemic states. Cardiovascular outcome trials with N-acetylgalactosamine–conjugated RNA-targeting drugs are ongoing. The advantages of these agents include long dosing intervals of up to 6 months and the potential to regulate the abundance of any disease-related protein. Long-term safety has yet to be demonstrated in large-scale clinical trials.
Dr. Packard has received research funding from Merck; and has received honoraria from Amgen, Daiichi-Sankyo, Dal-Cor, and Merck. Dr. Chapman has received research funding from Amgen, CSL, Kowa, and Pfizer; and has served on the Advisory Board and/or Speakers Bureau for Amarin, AstraZeneca, Kowa, Merck, Sanofi, Regeneron, and Servier. Dr. Laufs has received honoraria for lectures from Amgen and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received April 3, 2020.
- Revision received April 29, 2020.
- Accepted May 10, 2020.
- 2020 American College of Cardiology Foundation
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