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

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  Fig. 1. Efficacy of AAVrh10.PKP2 (LX2020) in PKP2 ACM models. a Schemata of groups and doses administered to PKP2 Hom mice. 4 treatment conditions (Low dose, Mid dose, High dose and Vehicle) were administrated to PKP2 Hom mice retro-orbitally at approximately 3 weeks of age (n = 12 per group, mixed sex). Protein expression, arrhythmias, cardiac function (MRI), cardiac histopathology, and survival were analyzed after 12 weeks post-injection. Representative western blot (b) and quantitation (c) in WT, PKP2 Hom dosing groups. Two-way ANOVA with Tukey’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n = 9 for WT and n = 12 for each dosing group. Molecular weight (kDa) labeled on the right side of the gel. d The number of mice that displayed PVCs (gray bars) or normal rhythm (white bars) in different dosing groups compared with WT. e Quantification of the left (LV) and right (RV) ventricle end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) using MRI in WT and PKP2 Hom mice. n = 9 for WT, n = 1 for Veh, n = 3 for no treatment, n = 4 for low dose, n = 10 for mid and high dose. Two-way ANOVA with Tukey’s multiple comparison test. *P…

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  Fig. 2. Safety profile analysis of AAVrh10.PKP2 (LX2020) in non-human primates. a Schemata of dosing groups in NHPs (cynomolgus monkeys) following IV administration. N = 3–4 for each group, mixed sex. All NHPs were euthanized after 12 weeks, and clinical pathological assays, immunology, cardiac function, protein expression, and vector distribution were evaluated. b and (c) Representative M-Mode echocardiography images and statistical analysis of cardiac function from all NHP dosing groups at 12 weeks showed no significant difference. d Cardiac electrocardiogram showed no significant difference between NHP dosing groups at different time points. e Table of safety evaluations indicate that there is no abnormalities found in NHP dosing groups. f Biodistribution of LX2020 across the NHP hearts as quantified by vector copy number (VCN) analysis. g Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) analysis of PKP2 mRNA levels within different compartments of NHP hearts following treatment with AAV-rh10 PKP2. h Biodistribution of LX2020 across the NHP livers as quantified by VCN (left) and PKP2 protein expression analysis (right). f–h Two-way ANOVA with Tukey’s multiple…