Abstract Body: Arrhythmogenic cardiomyopathy (ACM) is a fatal inherited cardiac disease caused by mutations in desmosomal anchoring genes, with plakophilin-2 (PKP2) being the most frequently mutated gene (70%). While AAV9-PKP2 gene therapy shows promise in mitigating ACM-related deficits in mice, high dose toxicity and organ failure of AAV9 in human clinical trials raises safety concerns. Prior studies showed AAVrh.10 exhibiting preferential cardiac gene expression at lower doses that could potentially be safer. We hypothesized that AAVrh.10.PKP2 (LX2020) could restore PKP2 to scaffold the desmosomal complex and ameliorate cardiac deficits with long-term efficacy at relatively lower doses and safety in non-human primates (NHP). We employed LX2020 to assess its efficacy in severe (PKP2 homozygous (Hom)) and mild (PKP2 heterozygous (Het)) adult ACM diseased mice, as well as safety in NHP at doses from 2E13 to 1E14 vg/kg and up to 12 weeks post-administration. A dose-dependent increase in hPKP2 expression was seen in all models, with rescue of desmosomal/gap junction protein deficits at 2E13 and 6E13 vg/kg doses in PKP2-Het and PKP2-Hom mouse hearts. Long term LX2020 efficacy was observed at the same doses in PKP2-Hom mice with dose-dependent improvements in cardiac function, arrhythmia reduction and histological improvements, such that LX2020 treated PKP2-Hom hearts resembled wild-type hearts, indicating a potential for reversal of late-stage pathology. The extended lifespan was striking with 100% of PKP2-Hom mice surviving using 2E13 vg/kg, completely averting premature death. Safety assessments in NHP also revealed no adverse events up to the highest dose of 1E14 vg/kg. These data support advancing LX2020 as a potentially viable treatment for PKP2 ACM patients, based on safety and long-term efficacy in rescuing desmosomal and cardiac deficits in ACM models at lower doses reported in the field.