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<p>Plakophilin-2 (PKP2) mutations cause fatal genetic heart disease and arrhythmogenic cardiomyopathy (ACM) with primary effects on the right ventricle (RV). Adeno-associated virus (AAV)-PKP2 gene therapy shows promise as a therapeutic strategy but lacks long-term data and guidelines on minimal effective doses in animal studies for treating RV deficits, arrhythmia burden, and improving survival when administered during disease settings, which are most relevant to clinical trials. Using AAVrh10, known for its preferential cardiac gene expression at lower doses, we show minimal doses required for efficacy for AAVrh10.PKP2 (LX2020) to rescue cardiac (molecular and especially RV) deficits, arrhythmia burden and survival in PKP2 ACM mice, suggesting its potential to reverse late-stage pathology. Safety assessments in non-human primates revealed no adverse events. These data support LX2020 as a viable treatment for PKP2 ACM patients.</p>

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Preclinical efficacy and safety of AAVrh10-based plakophilin-2 gene therapy (LX2020) as a treatment for arrhythmogenic cardiomyopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月3日

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  • Jing Zhang,
  • Erika Joana Gutierrez-Lara,
  • Aryanne Do,
  • Lena Nguyen,
  • Anju Nair,
  • Nithya Selvan,
  • Tim Fenn,
  • Eric Adler,
  • Richie Khanna,
  • Farah Sheikh

摘要

Plakophilin-2 (PKP2) mutations cause fatal genetic heart disease and arrhythmogenic cardiomyopathy (ACM) with primary effects on the right ventricle (RV). Adeno-associated virus (AAV)-PKP2 gene therapy shows promise as a therapeutic strategy but lacks long-term data and guidelines on minimal effective doses in animal studies for treating RV deficits, arrhythmia burden, and improving survival when administered during disease settings, which are most relevant to clinical trials. Using AAVrh10, known for its preferential cardiac gene expression at lower doses, we show minimal doses required for efficacy for AAVrh10.PKP2 (LX2020) to rescue cardiac (molecular and especially RV) deficits, arrhythmia burden and survival in PKP2 ACM mice, suggesting its potential to reverse late-stage pathology. Safety assessments in non-human primates revealed no adverse events. These data support LX2020 as a viable treatment for PKP2 ACM patients.