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A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept In vivo Studies (excluding Non-Human Primates)

Preclinical Efficacy of AAVrh.74-PKP2a (RP-A601): Gene Therapy for PKP2-Associated Arrhythmogenic Cardiomyopathy

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts 1
Location: Room 515 AB
Start Time: 5/19/2023 8:15
End Time: 5/19/2023 8:30

Arrhythmogenic cardiomyopathy (ACM) is a progressive, inherited, autosomal dominant disorder, which manifests most commonly in young adults with an estimated 50,000 cases in the US & EU. This devastating disease is characterized by extensive cardiomyocyte loss, myocardial fibrofatty infiltration, frequent ventricular arrhythmias, significant risk of sudden cardiac death (SCD) and systolic dysfunction. Pathogenic loss-of-function variants of the PKP2 gene, which encodes for the desmosomal protein Plakophilin 2 (PKP2), constitute the largest proportion of known genetic causes of ACM (PKP2-ACM). PKP2-ACM consequences are severe and life-limiting. Although PKP2-ACM patients may receive an implantable cardioverter-defibrillator (ICD) to mitigate the risk of SCD, these are not curative, and breakthrough life-threatening arrythmias may persist with ongoing risk of death. Cardiac transplantation is a salvage option in end-stage disease. A substantial unmet medical need exists for transformative therapies that target the underlying PKP2 genetic deficit. Understanding the genetic mechanism of PKP2-ACM affords the opportunity to develop potential precision therapies. To that end, RP-A601 (AAVrh.74-PKP2a) is a recombinant adeno-associated viral vector containing the coding sequence of human plakophilin-2a, the dominant cardiac isoform, under development as a potential therapeutic for PKP2-ACM patients.
The well-characterized cardiomyocyte-specific, PKP2 conditional knockout mouse model of ACM (PKP2-cKO) replicates many of the clinical hallmarks of PKP2-ACM including severe right ventricular dilation, reduced ejection fraction, arrhythmia, myocardial fibrosis and heart failure. A series of studies evaluated intravenous administration of AAVrh.74-PKP2 in the PKP2-cKO mouse model and established efficacy in mitigating the ACM disease phenotype across a range of doses and timepoints. AAVrh.74-PKP2a-mediated PKP2 expression at an efficacious dose resulted in 100% survival up to 5 months (longest time point evaluated; vs 100% mortality by day 50 in PKP2-cKO controls) and diminished right ventricular dilation to wild type levels, with robust functional benefit in multiple additional measures including LVEF, FS and RV-VTI. Furthermore, at an efficacious dose, an 85% reduction in isoproterenol-induced arrythmia in PKP2-cKO animals was observed. Notably, consistent and dramatic benefit was observed even when AAVrh.74-PKP2a was administered after disease onset. Multiple studies therefore established the efficacy of AAVrh.74-PKP2 in arresting the progression of the ACM phenotype in a relevant PKP2-ACM mouse model. Additional IND-enabling mouse and nonhuman primate studies have been completed that characterized the safety of AAVrh.74-PKP2. Nonclinical data to date support the further evaluation of the therapeutic potential of RP-A601 in a first-in-human clinical trial.

Bitha Narayanan1, Chantal J. M. Van Opbergen2, Mingliang Zhang2, Chester B. Sacramento1, Katie M. Stiles1, Vartika Mishra1, Esther Frenk1, David Ricks1, Jonathan Schwartz1, Gopal Parthasarathy1, Raj Prabhakar1, Paul Yarabe1, Mario Delmar2, Marina Cerrone2, Christopher D. Herzog1

1Rocket Pharmaceuticals, Inc., Cranbury, NJ,2NYU Grossman School of Medicine, New York, NY
 C.D. Herzog: None.

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