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Published on: November 1, 2024
New Approaches for Targeting PCSK9: Small-Interfering Ribonucleic Acid and Genome Editing
Reindert F Oostveen1, Amit V Khera2, Sekar Kathiresan2
1Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, The Netherlands (R.F.O., E.S.G.S., J.J.P.K.).
Abstract:
There is overwhelming clinical and genetic evidence supporting the concept that low-density-lipoprotein cholesterol should be as low as possible for as long as possible in patients at very high cardiovascular risk. Despite the wide availability of effective lipid-lowering therapies, the majority of patients still fail to reach guideline-based lipid goals. Advances in novel approaches targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) through small-interfering RNA and genome editing hold the potential to bridge this gap, by offering long-acting alternatives, which may overcome adherence and other challenges in the current chronic care model. In this review, we discuss the history of targeting PCSK9 with the use of mRNA and small-interfering ribonucleic acid. We also shed light on targeting PCSK9 with genome editing, including discussion of the VERVE-101 clustered regularly interspaced short palindromic repeats-base editing medicine currently being evaluated in a clinical trial and others in development.
Insights
Novel therapies targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) using RNA interference and genome editing offer promising long-acting solutions for patients with very high cardiovascular risk who struggle to meet lipid goals.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Low-density-lipoprotein cholesterol (LDL-C) reduction is critical for patients at very high cardiovascular risk.
- Current lipid-lowering therapies often fail to achieve guideline-recommended LDL-C goals.
- Adherence and chronic care challenges limit the effectiveness of existing treatments.
Purpose of the Study:
- To review the evolution of targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) for lipid management.
- To explore novel therapeutic strategies including mRNA, small-interfering RNA, and genome editing.
- To highlight the potential of these advanced approaches to improve patient outcomes.
Main Methods:
- Review of historical and current research on PCSK9 inhibition.
- Discussion of mRNA and small-interfering RNA (siRNA) based therapies.
- Exploration of genome editing technologies, including CRISPR-base editing.
Main Results:
- PCSK9 inhibition represents a significant advancement in cardiovascular risk reduction.
- RNA-based therapies offer sustained and effective LDL-C lowering.
- Genome editing, exemplified by VERVE-101, shows potential for durable PCSK9 targeting.
Conclusions:
- Targeting PCSK9 with novel modalities like siRNA and genome editing addresses unmet needs in cardiovascular risk management.
- These approaches may overcome limitations of current therapies, improving adherence and goal attainment.
- Future research and clinical trials are essential to realize the full potential of these innovative treatments.
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