ArticleCommunications medicine2024
AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.
Article in Communications medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Arrhythmogenic cardiomyopathy diagnosis and management: a systematic review of clinical practice guidelines and recommendations with insights for future research.European heart journal. Quality of care & clinical outcomes · 2025Pooled it
- Single nucleus RNA sequencing identifies PLXNA4 upregulation in end-stage arrhythmogenic right ventricular cardiomyopathy.iScience · 2026Article
- Therapeutic upregulation of gene expression in inherited cardiomyopathies from current approaches to future directions.Nature cardiovascular research · 2026Review
- AAV Vector Toolkit for the Delivery and Expression of the Artificial microRNA in the Murine Heart.Biotech (Basel (Switzerland)) · 2026Article
- 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
- Review
- 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
- Connexin-43 Restoration Alleviates Desmosomal Arrhythmogenic Cardiomyopathy.Circulation. Heart failure · 2026Article
- Disease models and AAV therapies ofMolecular therapy. Advances · 2026Review
- 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
- Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy: Mechanisms and Therapeutic Perspectives.Biomolecules · 2025Review
- Tailored therapeutics for cardiomyopathies.Nature reviews. Cardiology · 2025Review
- Gene Therapy TargetingMedComm · 2025Article
- Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management.Journal of cardiovascular electrophysiology · 2025Review
- Exercise-induced dysregulation of the adrenergic response in a mouse model of PKP2-arrhythmogenic cardiomyopathy.Heart rhythm · 2025Article
- PNPLA2 gene therapy resolves myocardial lipid deposition in arrhythmogenic cardiomyopathy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Consequences of Right Heart Disease for Cardiac Electrophysiology and Arrhythmias: Cellular and Structural Mechanisms.CJC open · 2025Review
Corrections and comments
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Authors and funding
32 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression.
methodsOur goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2.
resultsWe show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology.
conclusionsWe identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.