AAV-PKP2 gene therapy administered to neonatal and adult mice with a PKP2 mutation restored protein levels, prevented pathological deficits, and ensured 100% survival up to 6 months.
Does AAV-PKP2 gene therapy improve survival and prevent or rescue pathological deficits in a mouse model of ARVC with a PKP2 mutation?
AAV-PKP2 gene therapy successfully prevents and rescues the ARVC phenotype and prevents sudden death in a mouse model harboring a human PKP2 splice site mutation.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a fatal genetic heart disease characterized by cardiac arrhythmias, in which fibrofatty deposition leads to heart failure, with no effective treatments. Plakophilin 2 (PKP2) is the most frequently mutated gene in ARVC, and although altered RNA splicing has been implicated, there are no models to study its effect and therapeutics. Here, we generate a mouse model harboring a PKP2 mutation (IVS10-1G>C) affecting RNA splicing, recapitulating ARVC features and sudden death starting at 4 weeks. Administering AAV-PKP2 gene therapy (adeno-associated viral therapy to drive cardiac expression of PKP2) to neonatal mice restored PKP2 protein levels, completely preventing cardiac desmosomal and pathological deficits associated with ARVC, ensuring 100% survival of mice up to 6 months. Late-stage AAV-PKP2 administration rescued desmosomal protein deficits and reduced pathological deficits including improved cardiac function in adult mice, resulting in 100% survival up to 4 months. We suggest that AAV-PKP2 gene therapy holds promise for circumventing ARVC associated with PKP2 mutations, including splice site mutations.
Bradford et al. (Thu,) conducted a other in Arrhythmogenic right ventricular cardiomyopathy (ARVC). AAV-PKP2 gene therapy was evaluated on Survival. AAV-PKP2 gene therapy administered to neonatal and adult mice with a PKP2 mutation restored protein levels, prevented pathological deficits, and ensured 100% survival up to 6 months.
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