May 15, 2026 —
Tenaya Therapeutics presented interim data from the ongoing RIDGE-1 Phase 1b/2 trial of TN-401, an investigational AAV9-based gene therapy for PKP2-associated arrhythmogenic right ventricular cardiomyopathy, also known as ARVC or ACM. The data were presented as a late-breaker at ASGCT 2026 and showed meaningful reductions in arrhythmia burden, favorable tolerability, and biopsy-based evidence of TN-401 activity in heart muscle cells.
PKP2 mutations are the most common genetic cause of ARVC, occurring in approximately 40% of the overall ARVC population. In PKP2-associated ARVC, insufficient plakophilin-2 protein disrupts the desmosomal complex that helps maintain physical connections and electrical signaling between heart muscle cells. As the desmosomal structure deteriorates, cardiac muscle can be replaced by fibrofatty tissue, leading to unstable electrical signaling and potentially life-threatening ventricular arrhythmias. Current treatments, including anti-arrhythmic drugs, implantable cardioverter-defibrillators, and ablation, can help manage symptoms and arrhythmia risk but do not address the underlying genetic cause.
TN-401 is designed to deliver a functional PKP2 gene using an AAV9 vector through a one-time intravenous infusion. AAV9 was selected for its clinical experience and ability to target cardiac muscle cells. The therapy has received FDA Orphan Drug and Fast Track designations, as well as PRIME designation from the European Medicines Agency, reflecting its potential to address a serious unmet need in PKP2-associated ARVC.
The interim RIDGE-1 analysis included six adult patients treated at either 3E13 vg/kg or 6E13 vg/kg, with follow-up ranging from 20 to 52 weeks as of the April 2026 data cutoff. All six patients showed meaningful reductions in daily premature ventricular contractions, with a mean reduction of 64% overall. Cohort 1 showed a mean PVC reduction of 60%, while Cohort 2 showed a mean reduction of 67%. Two patients with high baseline non-sustained ventricular tachycardia counts also experienced substantial decreases, including one patient whose NSVT burden dropped from 78 counts per 24 hours to zero and remained stable at week 52.
Biopsy data from five patients provided evidence that TN-401 was transduced in cardiac muscle cells and expressed at the DNA and mRNA levels. TN-401 DNA was detected in heart tissue as early as eight weeks after dosing, and TN-401 mRNA expression was observed across the first five patients with available biopsy data. PKP2 protein measurements showed changes ranging from -4% to +15%, though interpretation is complicated by the variable composition of diseased ARVC cardiac tissue.
TN-401 was generally well tolerated at both dose levels. All patients successfully tapered off immunosuppressive therapy, and no dose-limiting toxicities were reported. The most frequent treatment-attributed adverse events were transient troponin and/or transaminase elevations. No clinical thrombotic microangiopathy, TN-401-related ventricular arrhythmias, or other cardiotoxicities were reported. The independent Data Safety Monitoring Board endorsed continuation of the expansion portion of the study as planned.
Overall, the RIDGE-1 interim results provide early clinical evidence supporting TN-401’s potential as a one-time genetic medicine for PKP2-associated ARVC. While longer follow-up and additional patients will be needed to determine durability, dose selection, and clinical impact, the observed reductions in arrhythmia burden and biopsy evidence of cardiac gene transfer mark an important step for AAV-based cardiac gene therapy.
