Gene editing for inherited cardiac conditions: A new frontier in cardiology

Authors, Journal, Affiliations, Type, DOI

• Toufik Abdul-Rahman, Poulami Roy, Neil Garg, Abubakar Nazir, Kahan S Mehta, Neel A Doshi, Shamaila Hassnain, Renitha Reddi, Sai Gautham Kanagala, Patrick Ashinze, Carl J Lavie, Rahul Gupta (corresponding, Yale New Haven)
• Trends in Cardiovascular Medicine, 2025 (Article in Press)
• Multi-institutional: Ukraine, India, USA, Pakistan, Ireland, Nigeria
• Type: Narrative review
• DOI: https://doi.org/10.1016/j.tcm.2025.11.002

Overview

A broad narrative review of gene editing technologies applied to inherited cardiac conditions (ICCs), covering CRISPR-Cas9, base editing, and prime editing; delivery modalities (AAV vectors, extracellular vesicles, lipid nanoparticles); epigenome editing; and AI integration. Disease-specific applications are reviewed for HCM, Marfan syndrome, HPAH, DMD cardiomyopathy, calmodulinopathy-LQTS, familial hypercholesterolaemia, and PRKAG2 cardiac syndrome. A key clinical contribution is a structured risk-benefit framework for prioritising gene editing candidacy: WPW (catheter ablation >90% success — gene editing inappropriate) versus PRKAG2 syndrome (multisystem monogenic disease not curable by ablation — gene editing appropriate). Most evidence remains preclinical in murine models.

Keywords

Gene editing; CRISPR-Cas9; precision medicine; inherited cardiac conditions; artificial intelligence

Key Takeaways

Introduction

• ICCs affect ~3% of the population, often autosomal dominant (50% transmission risk); frequently underdiagnosed due to asymptomatic early stages
• CRISPR-Cas9 most prominent for HCM, DCM, muscular dystrophy cardiomyopathy, and amyloidosis
• Germline editing could theoretically eliminate heritable mutations entirely, but carries profound ethical and safety constraints

Gene Editing Techniques

• ZFN (Zinc finger nucleases): First nuclease technology with widespread use; artificial endonuclease combining finger protein with restriction enzyme capacity; used in drosophila, rats, mammalian somatic cells
• TALEN: Diverse organism applicability; induces chromosomal double-strand site breaks for effective genomic modification
• CRISPR-Cas9: Most accepted/utilised; 18–20 nucleotide sgRNA guides Cas9 to target site; recognises protospacer adjacent motif (PAM); DSBs repaired via NHEJ or HDR; for autosomal dominant conditions, NHEJ creates frameshift indels eliminating the dominant allele
• Base editing: Cas9 nickase + deaminase; single nucleotide changes without DSBs; restricted to specific base conversions; reduces toxicity risk
• Prime editing: Extensive genome editing without DSBs; promising for precise corrections of point mutations; requires optimised delivery

Gene Editing Delivery

• Ex vivo: Cells extracted → edited outside body → reinfused; precise control; unsuitable for non-regenerative tissues like myocardium
• In vivo: Therapeutic agent delivered directly into the body; AAV vectors (AAV9, AAVMYO for striated muscle), extracellular vesicles, lipid nanoparticles
• AAV limitations — key constraints for cardiac translation:
  • Packaging capacity 4.7–5.1 kb — insufficient for complete CRISPR/Cas9 complex + genetic control elements; workarounds: split vector and fragment AAV reassembly
  • AAV9 shows cardiac tropism in mice but human myocardium transduction efficiency not confirmed; anatomical differences, receptor variation, antibody production may reduce efficacy
  • Pre-existing immunity in humans constrains in vivo use
  • Mosaicism: heterogeneous editing across myocardium; >70% phenotypic correction required for cardiac function restoration in mouse models
  • Mosaicism risks: arrhythmia from heterogeneous electrophysiology, compensatory fibrosis, neoantigen immunogenicity
  • In DMD and ARVC, heterogeneous editing has led to myofiber necrosis and fibrosis
• AAVMYO: striated muscle-specific; reduces mosaicism by improving homogeneity of cardiac delivery

Gene Editing and Epigenetics

• Epigenetic mechanisms in CVD: DNA methylation, histone modification, non-coding RNA
• HDAC inhibition: promising for load-induced heart disease; BRD4 proteins govern pathological cardiac remodelling in HF
• HDAC6 upregulated by Angiotensin II → deacetylates cystathionine γ-lyase (CSEγ) → reduced H₂S → hypertension and impaired endothelial function
• CRISPR/Cas9 enables epigenome editing by fusion with transactivators; more cost-effective than ZFN/TALEN approaches for programmable epigenomic targeting

Disease-Specific Gene Editing Evidence

HCM (MYBPC3)

• Ma et al. 2017: CRISPR-Cas9 corrected heterozygous MYBPC3 4 bp deletion in human preimplantation embryos; high efficiency; preferential repair using wild-type oocyte allele as HDR template; minimal off-target effects; further reproducibility required before clinical implementation

Marfan Syndrome (FBN1)

• Zeng et al. 2018: BE3 base editing of FBN1-T7498C pathogenic mutation; 89% correction efficiency; no off-target effects detected by high-throughput + whole-genome sequencing
• Li et al. 2021: CRISPR/Cas9 correction in patient-specific hiPSC (compound heterozygous FBN1 variant); maintained normal karyotype, pluripotency markers, and trilineage differentiation potential

Heritable PAH (BMPR2)

• BMPR2 mutations underlie 75% of HPAH cases
• Reynolds et al. 2012: adenoviral BMPR2 gene delivery to pulmonary vascular endothelium in rat PAH models; 38–48% reduction in pulmonary vascular resistance; 40% reduction in vascular smooth muscle area; ~29% reduction in TGF-β signalling; requires further safety/efficacy validation

DMD Cardiomyopathy (Dystrophin)

• Refaey et al. 2017: recombinant AAV delivering SaCas9 + gRNA to dystrophic mice; excised mutant exon 23; 40% dystrophin protein restoration in cardiac muscles; improved cardiac fibre architecture; reduced fibrosis; restored contractility

Calmodulinopathy-LQTS (CALM2)

• Limpitikul et al. 2017: CRISPR interference selectively suppresses mutant CALM2 gene sparing wild-type; normalised action potential duration and Ca²⁺/CaM-dependent L-type Ca²⁺ channel inactivation in iPSC-derived CMs; potential mutation-agnostic approach for calmodulinopathies

Familial Hypercholesterolaemia (LDLR)

• Zhao et al. 2020: in vivo AAV-CRISPR/Cas9 correction of LdlrE208X mutation; significant reductions in total cholesterol, triglycerides, and LDL; smaller atherosclerotic plaques and lower macrophage infiltration in aorta

PRKAG2 Cardiac Syndrome

• Mutations in γ2 subunit of AMP-activated protein kinase (PRKAG2); autosomal dominant; cardiac hypertrophy + pre-excitation (WPW) + glycogen storage + progressive conduction disease; not curable by ablation alone
• Xie et al. 2016: CRISPR reversed cardiac hypertrophy and glycogen storage in mouse model
• AAV9-CRISPR/Cas9-sgRNA single postnatal injection restored cardiac function in transgenic mice; CRISPR correction in iPSC-CMs normalised arrhythmic behaviour

AI + Gene Editing

• Patient stratification: AI identifies HCM subgroups by genetic mutation type, age of onset, and clinical outcomes to tailor gene editing approaches
• gRNA target optimisation: Hua et al. — AI-guided optimisation of CRISPR target sites improved editing efficiency and reduced off-target effects in cardiomyocytes
• Smart diagnostics: AI models detect LQTS and PLN-cardiomyopathy from ECG; ResNet CNN distinguishes genotype-positive from genotype-negative HCM using CMR (>85% accuracy); machine learning classifiers on MYBPC3/MYH7 variants achieve >85% accuracy for pathogenic vs benign discrimination
• Off-target safety: Lin et al. — AI accurately predicted off-target CRISPR sites, enabling safer gRNA design

Risk-Benefit Framework for Gene Editing in ICCs

A clinical decision framework comparing gene editing to existing standard of care:

• WPW syndrome: catheter ablation achieves 90–95% long-term success with <2% complications → gene editing clinically disproportionate given risks (off-target effects, immunogenicity, irreversibility)
• PRKAG2 cardiac syndrome: ablation cannot address the multisystem progressive monogenic disease → gene editing appropriate; represents a paradigm case for when gene editing should be prioritised
• Homozygous FH: despite advanced lipid therapies, PCSK9/ANGPTL3 gene editing trials show durable lipid reduction; appropriate candidate
• TTR amyloidosis: beyond stabilisers and RNA interference, gene editing enabling lasting TTR silencing is a meaningful advance
• CPVT: gene editing targets root RYR2 genetic defect more directly than pharmacological suppression or ICD
• Framework criteria for gene editing candidacy: disease severity, availability and effectiveness of existing therapies, monogenic vs polygenic architecture, somatic delivery feasibility, durability and reversibility of therapeutic effects

Ethical Considerations

• Germline editing: autonomy of future individuals whose traits were altered without consent; heritable consequences unpredictable
• Equity: high initial costs → access only to financially privileged; exacerbates health disparities
• Definitional: distinguishing treatment from enhancement; defining "normal vs disability"
• Regulatory frameworks required to govern responsible use

Limitations of the document

• Predominantly murine model evidence; limited human efficacy data for cardiac applications
• AAV packaging constraints (4.7–5.1 kb) not yet solved for large cardiac genes (SCN5A, RYR2, TTN)
• Mosaicism remains a fundamental challenge in vivo
• Narrative review methodology with English-only inclusion — publication bias likely
• Broad heterogeneous ICC spectrum limits uniform conclusions
• Many cited AI studies are small or hypothetical; limited clinical validation
• No specific clinical trial outcomes reported (most trials still preclinical or early phase)

Key Concepts Mentioned

• concepts/CRISPR-Cas9-in-Channelopathies — expanded with PRKAG2, calmodulinopathy, DMD applications; risk-benefit framework; base editing/prime editing
• concepts/AAV-Gene-Delivery — AAVMYO tropism; mosaicism >70% threshold; human translation constraints
• concepts/Gene-Silencing-Therapy — epigenome editing; CRISPRi for CALM2 suppression
• concepts/iPSC-Derived-Cardiomyocytes — Marfan, calmodulinopathy applications
• concepts/Biological-Pacemaker — gene therapy context
• concepts/Pharmacological-Provocation-Testing — PRKAG2/WPW distinction

Key Entities Mentioned

• entities/HCM — MYBPC3 CRISPR embryo editing (Ma 2017)
• entities/DCM — gene editing candidate; DMD cardiomyopathy
• entities/CPVT — gene editing candidate for RYR2 root defect
• entities/Long-QT-Syndrome — calmodulinopathy CRISPRi; CALM2
• entities/MYBPC3 — CRISPR correction in preimplantation embryos
• entities/RYR2 — gene editing target in CPVT
• entities/PKP2 — ARVC; mosaicism concern in heterogeneous editing
• entities/ATTR-Amyloidosis — TTR gene editing candidate
• entities/Familial-Hypercholesterolemia — LDLR/PCSK9/ANGPTL3 editing
• entities/Pulmonary-Hypertension — BMPR2 gene delivery in HPAH

Wiki Pages Updated

• wiki/sources/gene-editing-cv-tcm-2025 (created)
• wiki/sourceindex (updated)
• wiki/wikiindex (updated)