At the 3E13 vg/kg dose in Tenaya Therapeutics’ RIDGE-1 Phase 1b/2 study, three adults with PKP2-associated ARVC showed early signals across safety, transduction, and electrophysiology. No dose-limiting toxicities were observed; adverse events were mostly mild and manageable, with one asymptomatic Grade 1 troponin elevation categorized as serious due to monitoring. No thrombotic microangiopathy or cardiotoxicities were reported, and all patients tapered off immunosuppression. Endomyocardial biopsies at Week 8 confirmed cardiac transduction in two patients (3.4 and 5.0 vg/dg), mRNA expression in all three (approximately 1.4×10^4 to 2.9×10^5 copies/µg RNA), and mean PKP2 protein increases of about 10% from baseline in two patients. Arrhythmia burden improved in the two patients with more than six months’ follow-up: PVC counts fell 46% by Week 40 in one patient and 89% by Week 32 in another; NSVTs in the latter dropped from 78 per 24 hours at baseline to zero by Week 32. No clinically meaningful change was expected or observed yet in the third patient given shorter follow-up. Tenaya also completed enrollment at the 6E13 vg/kg dose with no new treatment-related serious adverse events reported to date.
The company’s update marks the first human data readout for TN-401, an AAV9-based, one-time IV gene replacement therapy designed to restore PKP2 in cardiomyocytes. RIDGE-1 is enrolling up to 15 adults at increased arrhythmic risk, all with ICDs, in the U.S. and UK. The program is built to demonstrate a mechanistic chain of evidence—vector DNA in tissue, RNA expression, protein restoration, and downstream electrophysiologic effects—alongside a tolerability profile that has been a key stumbling block for high-dose systemic AAVs.
Strategically, Tenaya is making an early case that ARVC may be tractable with a lower AAV dose and a defined, taperable immunosuppression window, aiming to sidestep prior safety headwinds seen elsewhere in cardiac gene therapy. The 10% protein increase is modest in absolute terms but, paired with consistent mRNA expression and clinically relevant reductions in PVCs and NSVTs, suggests biological activity. The tension is dose selection versus safety: higher exposure could amplify protein restoration and clinical effect but risks reopening the safety envelope for complement activation, liver injury, or myocarditis-like events that have complicated the modality. The small n and variability—illustrated by strong mRNA in the third patient without a measurable protein delta at first biopsy—underscore sampling and assay noise that can distort early decisions.
For sites, this program is operationally intensive: serial endomyocardial biopsies, ICD interrogations or prolonged ambulatory monitoring for arrhythmia endpoints, and immunosuppression initiation and tapering protocols. CROs and vendors will need tight workflows for cardiac device data capture, centralized LC-MS protein quantification, and adjudication of electrophysiologic measures. Sponsors and manufacturers will watch vector supply and release testing, given the dose range spans a two-fold difference with implications for batch utilization and cost per patient. Regulators will be weighing whether reductions in PVCs and NSVTs, linked to mechanistic biomarkers, can serve as acceptable surrogates in a rare arrhythmogenic disorder dominated by device-based standard of care.
Next, attention turns to durability at 12 months, reproducibility of protein restoration in the second biopsy for the third patient, and safety at the 6E13 dose. A clear, dose-responsive relationship across DNA/RNA/protein and sustained reductions in arrhythmia burden will be critical for dose selection and any discussion of an accelerated pathway. Watch for immunogenicity signals after immunosuppression taper, ICD shock incidence over time, and how the sponsor frames pivotal endpoints—hard arrhythmic events versus composite electrophysiologic measures—given feasibility in a small population. Consistency, not magnitude alone, will determine whether TN-401 can navigate the evidentiary bar for cardiac gene therapy after a period of modality-specific caution.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
