Analysis of the Use of shRNA in Atherosclerosis Therapy: Current Status
- 1Laboratory of Molecular Genetic Modeling of Inflammaging, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- 2Institute for Atherosclerosis Research, 121609 Moscow, Russia
Abstract
Atherosclerosis remains the principal pathological substrate of myocardial infarction, ischemic stroke and peripheral artery disease, and its progression is driven by an interlocking set of processes, including hepatic and vascular lipid metabolism, chronic vascular inflammation, macrophage foam cell formation and vascular smooth muscle cell (VSMC) proliferation, none of which is fully controlled by currently approved pharmacotherapy. Short hairpin RNA (shRNA) technology, in which a DNA template encoding a stem-loop transcript is delivered to a cell and processed intracellularly into small interfering RNAs (siRNAs) that trigger sequence-specific mRNA degradation, offers a route to durable, vector-encoded gene silencing that is mechanistically distinct from transiently acting synthetic siRNA or antisense oligonucleotides and that, although non-permanent at the level of the target gene, is not readily reversible at the level of the vector, which cannot easily be withdrawn once administered. This review analyzes the current status of shRNA-based strategies for atherosclerosis therapy. We summarize the molecular mechanism and vector design principles of shRNA-mediated RNA interference (RNAi); critically examine preclinical studies in which shRNA delivered by lentiviral or adeno-associated viral (AAV) vectors has been used to silence hepatic lipid-metabolism genes (PCSK9, ApoB,), the endothelial gene ANGPTL2, inflammasome and inflammatory mediators (NLRP3, TACE/ADAM17), and genes driving VSMC proliferation in restenosis models (connexin 43); we explicitly distinguish this direct shRNA evidence from complementary target-validation studies that use antisense oligonucleotides (e.g., ANGPTL4), synthetic siRNA, genetic knockout, or antimiR approaches (e.g., lncRNA AK136714, CD36, miR-33, P2X7R); and discuss the principal delivery vectors, their tissue tropism, and the toxicity arising from saturation of the endogenous microRNA-processing machinery. We further place shRNA in the context of competing and complementary RNA-based and gene-editing modalities, including clinically approved synthetic siRNA drugs (inclisiran, patisiran) and CRISPR-based gene editing of PCSK9 and ANGPTL3, both of which have now yielded human phase 1 data, to clarify why, despite two decades of robust preclinical proof-of-concept, no shRNA construct has yet reached clinical use in atherosclerosis; we further compare this with the clinical trajectory of vector-encoded shRNA in other indications, in which anti-CCR5 and anti-HCV constructs have already been administered to patients in phase 1/2 trials, in order to establish that the limiting factor is not the hairpin itself but the risk–benefit case obtainable in a chronic, largely asymptomatic disease for which withdrawable and outcome-validated therapies already exist. We conclude that shRNA remains a mechanistically attractive but clinically immature modality whose translation will depend on vector engineering that limits off-target saturation of the RNAi pathway and achieves durable, cell type-restricted expression in the liver, endothelium, macrophages or vascular wall, and, equally, on the identification of an atherosclerosis indication—most plausibly a small, high-residual-risk or locally treatable population—in which durability outweighs the vector-level irreversibility, immunogenicity and manufacturing burden of a viral vector.
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BibTeX
@article{blagov2026analysis,
title = {{Analysis of the Use of shRNA in Atherosclerosis Therapy: Current Status}},
author = {Alexander V. Blagov and Anastasia O. Maksaeva and Tatiana I. Kovyanova},
journal = {Cells},
year = {2026},
month = nov,
doi = {10.3390/cells15212032},
url = {https://www.mdpi.com/2073-4409/15/21/2032},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Analysis of the Use of shRNA in Atherosclerosis Therapy: Current Status
AU - Alexander V. Blagov
AU - Anastasia O. Maksaeva
AU - Tatiana I. Kovyanova
PY - 2026
DA - 2026/11/07
JO - Cells
DO - 10.3390/cells15212032
UR - https://www.mdpi.com/2073-4409/15/21/2032
AB - Atherosclerosis remains the principal pathological substrate of myocardial infarction, ischemic stroke and peripheral artery disease, and its progression is driven by an interlocking set of processes, including hepatic and vascular lipid metabolism, chronic vascular inflammation, macrophage foam cell formation and vascular smooth muscle cell (VSMC) proliferation, none of which is fully controlled by currently approved pharmacotherapy. Short hairpin RNA (shRNA) technology, in which a DNA template encoding a stem-loop transcript is delivered to a cell and processed intracellularly into small interfering RNAs (siRNAs) that trigger sequence-specific mRNA degradation, offers a route to durable, vector-encoded gene silencing that is mechanistically distinct from transiently acting synthetic siRNA or antisense oligonucleotides and that, although non-permanent at the level of the target gene, is not readily reversible at the level of the vector, which cannot easily be withdrawn once administered. This review analyzes the current status of shRNA-based strategies for atherosclerosis therapy. We summarize the molecular mechanism and vector design principles of shRNA-mediated RNA interference (RNAi); critically examine preclinical studies in which shRNA delivered by lentiviral or adeno-associated viral (AAV) vectors has been used to silence hepatic lipid-metabolism genes (PCSK9, ApoB,), the endothelial gene ANGPTL2, inflammasome and inflammatory mediators (NLRP3, TACE/ADAM17), and genes driving VSMC proliferation in restenosis models (connexin 43); we explicitly distinguish this direct shRNA evidence from complementary target-validation studies that use antisense oligonucleotides (e.g., ANGPTL4), synthetic siRNA, genetic knockout, or antimiR approaches (e.g., lncRNA AK136714, CD36, miR-33, P2X7R); and discuss the principal delivery vectors, their tissue tropism, and the toxicity arising from saturation of the endogenous microRNA-processing machinery. We further place shRNA in the context of competing and complementary RNA-based and gene-editing modalities, including clinically approved synthetic siRNA drugs (inclisiran, patisiran) and CRISPR-based gene editing of PCSK9 and ANGPTL3, both of which have now yielded human phase 1 data, to clarify why, despite two decades of robust preclinical proof-of-concept, no shRNA construct has yet reached clinical use in atherosclerosis; we further compare this with the clinical trajectory of vector-encoded shRNA in other indications, in which anti-CCR5 and anti-HCV constructs have already been administered to patients in phase 1/2 trials, in order to establish that the limiting factor is not the hairpin itself but the risk–benefit case obtainable in a chronic, largely asymptomatic disease for which withdrawable and outcome-validated therapies already exist. We conclude that shRNA remains a mechanistically attractive but clinically immature modality whose translation will depend on vector engineering that limits off-target saturation of the RNAi pathway and achieves durable, cell type-restricted expression in the liver, endothelium, macrophages or vascular wall, and, equally, on the identification of an atherosclerosis indication—most plausibly a small, high-residual-risk or locally treatable population—in which durability outweighs the vector-level irreversibility, immunogenicity and manufacturing burden of a viral vector.
SN - 2073-4409
ER -