Preclinical efficacy and safety of AAVrh10-based plakophilin-2 gene therapy (LX2020) as a treatment for arrhythmogenic cardiomyopathy
Year: 2025
Type: article
Abstract: 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.
Source: npj Regenerative Medicine
Institution: University of California San Diego
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: Uncovering New Functions of CSN6 in Cardiac Desmosomal Biology and Disease, G3033040839, University of California San Diego Neuroscience Microscopy Imaging Core, G639426234, G6902260743, G9000255603, Understanding Early Drivers and Therapeutic Targets for Severe Forms of Arrhythmogenic Cardiomyopathy
OpenAlex ID: W4409148376