Gene Editing Technologies for Coronary Artery Disease (CAD) Treatment (As of May 2025)
The treatment of coronary artery disease (CAD) has entered an era of precision intervention through gene editing. Below is a systematic review of current gene-editing technologies applied to CAD, covering mechanisms, therapeutic targets, clinical progress, and challenges:
1. CRISPR-Cas9 System
Core Mechanism:
Targeted DNA double-strand cleavage via CRISPR-Cas9, combined with non-homologous end joining (NHEJ) or homology-directed repair (HDR), enables gene knockout or insertion.
CAD Applications:
- Lipid Metabolism Targeting:
- PCSK9 Gene: Knockout in the liver reduces LDL-C levels, inhibiting atherosclerotic plaque formation. For example, Verve Therapeutics’ VERVE-101 uses base editing (ABE) to permanently suppress PCSK9, achieving >55% LDL-C reduction and 40% plaque regression in a single dose.
- ANGPTL3 Gene: Knockout lowers both triglycerides and LDL-C, addressing multi-factorial lipid disorders.
- Anti-Inflammatory & Plaque Stabilization: Targeting inflammatory pathway genes (e.g., NF-κB) or chemokine receptors (e.g., CCR2) inhibits monocyte migration to plaques and stabilizes fibrous caps.
Clinical Progress:
- In Vivo Editing: Intellia Therapeutics’ NTLA-2002 (targeting KLKB1 via LNP-delivered CRISPR-Cas9) is in Phase III trials for thrombosis risk reduction.
- Stent Integration: Drug-eluting stents coated with CRISPR/dCas9 systems activate VEGF-A and eNOS genes to enhance endothelialization and reduce restenosis.
2. Base Editing (BE)
Core Mechanism:
Single-base substitutions (C→T or A→G) via deaminase enzymes without DNA double-strand breaks.
CAD Applications:
- Pathogenic Variant Correction: Adenine base editors (ABEs) repair LDLR mutations to restore LDL receptor function and improve cholesterol metabolism.
- Epigenetic Regulation: dCas9-DNMT3A fusion proteins methylate pro-inflammatory gene promoters (e.g., IL-6) to suppress atherosclerosis-related inflammation.
Clinical Progress:
- VERVE-101 completed Phase I trials, showing sustained LDL-C reduction without severe hepatotoxicity; expansion to familial hypercholesterolemia patients is planned.
3. Prime Editing
Core Mechanism:
Reverse transcriptase fused with Cas9 nickase (nCas9) writes new sequences using pegRNA templates, enabling replacements, insertions, or deletions.
CAD Applications:
- Complex Mutation Repair: Corrects multi-nucleotide mutations (e.g., APOB splice site defects) beyond traditional CRISPR capabilities.
Challenges:
- Low delivery efficiency requires optimization of LNPs or AAVs for myocardial or endothelial targeting.
4. RNA Editing
Core Mechanism:
Modifies RNA sequences via ADAR enzymes or CRISPR-Cas13 for temporary gene expression regulation, avoiding permanent genomic changes.
CAD Applications:
- Dynamic Inflammation Control: Editing TNF-α or IL-1β mRNA transiently suppresses plaque inflammation, reducing acute cardiovascular events.
Advantage:
- Reversibility lowers off-target risks, ideal for chronic disease management requiring phased interventions.
5. Epigenome Editing
Core Mechanism:
dCas9 fused with epigenetic modifiers (e.g., DNMT3A, HDAC) regulates promoter methylation or acetylation to alter gene expression.
CAD Applications:
- Plaque Stabilization: Methylating NF-κB promoters in macrophages inhibits inflammatory cytokine release, delaying plaque rupture.
- Vascular Regeneration: Activating VEGF-A transcription in endothelial cells improves microcirculation in ischemic myocardium.
6. TALENs & ZFNs
Core Mechanism:
Engineered proteins (TALENs or zinc finger nucleases) target specific DNA sequences for cleavage.
CAD Applications:
- Rare Mutation Correction: Targets APOE variants (e.g., APOE4) to reduce early-onset CAD risk.
Limitations:
- High design complexity; largely replaced by CRISPR but retained for niche applications (e.g., AAV payload constraints).
Clinical Challenges & Future Directions
1. Delivery System Optimization:
- Tissue-Specific Vectors: AAV9 achieves ~60% cardiac targeting; novel variants (e.g., AAV6) or magnetic nanoparticles enhance coronary delivery.
- Transient Expression: Photoactivatable Cas9 (paCas9) or self-inactivating systems minimize long-term off-target risks.
2. Multi-Omics & AI Integration:
- Single-cell sequencing and spatial transcriptomics guide patient-specific editing (e.g., targeting plaque macrophage subtypes).
- AI platforms (e.g., Recursion BioMIA) predict optimal targets and optimize delivery routes.
3. Ethics & Accessibility:
- Real-time germline editing monitoring via WHO-CARPA platforms prevents misuse.
- Low-cost manufacturing (e.g., lyophilized formulations) reduces gene therapy costs from 10,000to500/dose, improving access in low-income regions.
Conclusion
Gene editing is reshaping CAD treatment by targeting lipid metabolism, inflammation, and vascular regeneration. CRISPR-Cas9 and base editing are clinically validated, while prime editing and RNA editing offer novel approaches for complex interventions. Despite challenges in delivery precision, safety, and cost, AI and multi-omics integration may enable a shift from single-gene correction to multi-pathway regulation within five years, advancing CAD care from disease management to curative repair.
Data sourced from public references. Contact: chuanchuan810@gmail.com.
