ArticleCirculation. Genomic and precision medicine2024
AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans.
Article in Circulation. Genomic and precision medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 42 citations in OpenAlex.
- Therapeutic upregulation of gene expression in inherited cardiomyopathies from current approaches to future directions.Nature cardiovascular research · 2026Review
- Emerging Technologies in Cardiovascular Disease Modeling: Bridging Basic Science and Clinical Translation.Cells · 2026Review
- Arrhythmogenic right ventricular cardiomyopathy.European heart journal · 2026Review
- Periostin-CCL3 Feedforward Signaling Loop Promotes Cardiac Fibrosis and Cardiomyocyte Necroptosis in Arrhythmogenic Cardiomyopathy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lipid Metabolism as a Therapeutic Target in Arrhythmogenic Cardiomyopathy: Emerging Therapeutic Implications of Lipid-Lowering Therapy.Reviews in cardiovascular medicine · 2026Review
- Biologics for cardiovascular diseases: from bench to bedside.Signal transduction and targeted therapy · 2026Review
- Prioritizing Discovery and Advancements in Arrhythmia Therapies: NIH/NHLBI Workshop.JACC. Clinical electrophysiology · 2026Review
- Genotype-specific digital twins for arrhythmia ablation targeting in arrhythmogenic right ventricular cardiomyopathy.Communications medicine · 2026Article
- Gene Therapy for Cardiovascular and Cerebrovascular Disease: Mechanisms, Translational Barriers, and the Road Ahead.Biomedicines · 2026Review
- Cardiomyocyte-Specific Plakophilin-2 Loss Is Sufficient to Induce Aging and Senescence of Nonmyocytes: Relevance to Arrhythmogenic Cardiomyopathy.Journal of the American Heart Association · 2026Article
- RNA-Based Therapies for Treating Monogenic Cardiomyopathies.The Canadian journal of cardiology · 2026Review
- Connexin-43 Restoration Alleviates Desmosomal Arrhythmogenic Cardiomyopathy.Circulation. Heart failure · 2026Article
- Disease models and AAV therapies ofMolecular therapy. Advances · 2026Review
- High-throughput evaluation of cardiac-specific promoters for adeno-associated virus mediated cardiac gene therapy.Gene therapy · 2026Article
- Cardiac troponin T promoters lead the way: optimizing cardiac specificity in AAV-mediated gene therapy.Gene therapy · 2026Article
- Gene Therapy for Inherited Cardiac Arrhythmias.Journal of cardiovascular translational research · 2025Review
- Maintenance of Energy Metabolism Is an Integral Part of Plakophilin-2 and Desmosome Functions.JACC. Basic to translational science · 2025Article
- Genotype-specific Digital Twins for Arrhythmia Ablation Targeting in Arrhythmogenic Right Ventricular Cardiomyopathy.Research square · 2025Article
- Correlative imaging integrates electrophysiology with three-dimensional murine heart reconstruction to reveal electrical coupling between cell types.Nature cardiovascular research · 2025Article
- Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy: Mechanisms and Therapeutic Perspectives.Biomolecules · 2025Review
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14 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundPathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human
methodsExperiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography.
resultsConsistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset.
conclusionsThese preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.
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