Agnieszka Polak, Klara Ferenc, Karolina Zapletal-Pudełko, Grzegorz Machnik, Bogusław Okopień

Nucleic acid-based therapies in modulating gene expression in cardiovascular diseases. The key role of inhibiting PCSK9 gene expression

 

2026-09-09

Background. Atherosclerotic cardiovascular diseases remain the leading cause of global mortality, with hypercholesterolemia acting as their key, modifiable risk factor. The PCSK9 protein plays a critical, negative role in regulating cholesterol homeostasis by inducing the intracellular, lysosomal degradation of low-density lipoprotein receptors on the surface of hepatocytes. Given the limitations of traditional pharmacotherapy, such as widespread statin intolerance, inadequate response to ezetimibe, and the phenomenon of persistent residual risk, the development of innovative therapeutic strategies has become a priority. Targeting the PCSK9 pathway with nucleic acid-based drugs currently represents one of the most promising and rapidly evolving areas of modern molecular cardiology and pharmacogenomics.

Objective. The primary objective of this review paper is to comprehensively analyze, systematize, and critically evaluate the evolution of molecular methods targeting the PCSK9 pathway using nucleic acids. The study aims to compare clinically approved RNA interference technologies and antisense oligonucleotides with novel approaches based on genome editing (such as the CRISPR/Cas9 system and base editors) and epigenetic modifications. A specific goal is to demonstrate the unique pharmacological and biological potential of peptide nucleic acids as an innovative, highly specific alternative to classical nucleic acid analogues in the precision therapy of hypercholesterolemia.

Material and Methods. This paper is a narrative review of the literature regarding targeted PCSK9 therapies. The literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library from January to June 2026. The analysis included key original research, clinical trials, and meta-analyses from the last decade. The search strategy utilized relevant keywords (e.g., “PCSK9”, “nucleic acid therapy”, “CRISPR/Cas9”, “PNA”), excluding case reports, conference abstracts, and popular science articles.

Use of artificial intelligence tools. Figures [2–4] were prepared by the authors with the assistance of the artificial intelligence tool ChatGPT, GPT-5.5 Thinking model, and OpenAI, to generate schematic illustrations. The scientific concept and content of the figures were developed by the authors, and the generated images were subsequently reviewed and modified to ensure scientific accuracy. The figures are schematic. The authors take full responsibility for the final content of the figures.

Results. Analysis of the literature reveals a clear evolution in therapeutic strategies. Clinically approved RNA-based methods allow for effective, reversible reduction of PCSK9 protein levels with a favorable safety profile; however, they require regular maintenance dosing. In contrast, gene editing technologies (CRISPR/Cas9) demonstrate the potential for permanent PCSK9 deactivation in preclinical models, though their development is hindered by concerns regarding the irreversibility of edits, off-target mutagenesis, and immunogenicity. Against this background, peptide nucleic acids (PNAs) present an interesting experimental alternative. Due to their pseudopeptide structure, PNAs exhibit resistance to enzymatic degradation and high affinity for target sequences, inhibiting PCSK9 expression at both transcriptional and translational levels. Nevertheless, the translational potential of PNAs remains limited by challenges in intracellular delivery, the risk of non-specific interactions, and potential cytotoxicity arising from intracellular accumulation.

Conclusions. Advancements in nucleic acid-based therapies significantly broaden the perspectives for treating cardiovascular diseases. While approved RNA-based methods offer effective but transient control of the lipid profile, gene editing technologies and PNA inhibitors demonstrate the potential for long-term reduction of LDL cholesterol levels. Although these innovative approaches hold promise for improving patient compliance in chronic pharmacotherapy, their early, investigational stage of development must be emphasized. The prospect of utilizing the unique properties of PNAs and genome editing tools in precision medicine will depend on overcoming key translational barriers, including the optimization of intracellular delivery systems, as well as the elimination of potential cytotoxicity and long-term off-target effects.

Keywords: PCSK9, nucleic acid therapeutics, siRNA, antisense oligonucleotides, hypercholesterolemia.

© Farm Pol, 2026, 82(3): 129–140