Abstract 13599: LX2020, an Adeno Associated Viral-Based Plakophilin 2 Gene Therapy Stabilizes Cardiac Disease Phenotype in a Severe Mouse Model of Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) increases risk of sudden cardiac death (SCD) and can progress to heart failure. Clinical studies have established 40-50% prevalence of mutations to desmosomal genes, with plakophilin-2 (PKP2) being the most frequent. To date, no effective treatment exists for ARVC. LX2020 is a novel AAV gene therapy that restores cardiac expression of human PKP2. A proof-of-concept study with LX2020 was conducted in a severe novel PKP2 mutant mouse model that exhibits all classic phenotypes of ARVC. Hypothesis: LX2020 mediated PKP2 expression is sufficient to scaffold the desmosomal cell-cell complex to promote survival as well as preserving cardiac electrical and mechanical function. Methods: A total of N=16 PKP2 Hom mice were randomized for vehicle/formula control (VC), low dose (LD) and high dose (HD). LX2020 was administered at postnatal day 2 and mice were analyzed 4-weeks post administration. Endpoints included survival, EKG, cardiac MRI and desmosomal levels of PKP2, desmoplakin (DSP), desmoglein-2 (DSG2), plakoglobin (JUP), along with fascia-adherens (N-Cad), and gap junction (CX43), using western blot analyses. Results: LX2020 showed dose dependent improvements in ARVC related deficits in PKP2 mice, including survival. HD resulted in 100% survival of PKP2 mutant mice, while LD resulted in 60% survival, when compared to 50% survival with VC. ECG data revealed suppression of ectopic beats in 100% of PKP2 mutant mice at HD and 75% suppression at LD when compared to 60% with VC. MRI HD improved left and right ejection fraction, as well as reduced right and left end-diastolic and systolic volumes, when compared to VC. LD showed a mild impact on left ventricular end-diastolic and end-systolic volumes like HD. Mechanistically, while LD showed limited increase in cardiac PKP2 expression, HD showed substantial cardiac PKP2 expression. Significantly increased levels of other desmosomal proteins, especially DSP and DSG2, were seen suggesting scaffolding functions to PKP2. Conclusions: These data indicate that the restoration of cardiac PKP2 expression can halt or slow ARVC disease progression, making LX2020 a promising gene therapy candidate for treating PKP2 mutation patients.