{
  "abstract": "Background ARVC is a severe genetic cardiomyopathy with sudden cardiac death as the initial presentation in nearly 25% of patients. PKP2 mutations are the genetic cause in ~40% of ARVC cases and result in insufficient levels of critical desmosmal proteins needed to maintain the structural integrity of heart muscle cells. TN-401 is a gene replacement therapy designed to deliver a functional PKP2 gene into heart muscle cells using an AAV9 capsid with a single intravenous dose. AAV9 was selected as the gene therapy delivery capsid for TN-401 based on its extensive body of safety and transduction data, including clinical validation of delivery to the heart.In preclinical studies, TN-401 successfully delivered the healthy PKP2 gene was successfully delivered to heart cells where it produced the missing plakophilin 2 protein. TN-401 normalized heart rhythms, reversed disease progression and extended survival following a single dose.Objective To introduce the design of the RIDGE-1 Phase 1b clinical trial, which is a multi-center, open-label, first-in-human and dose escalation study of TN-401 being conducted in the U.S. and UK.Methods RIDGE-1 will assess the safety, tolerability and preliminary clinical efficacy of a one-time intravenous infusion of TN-401. The trial will seek to enroll up to fifteen adults who have been diagnosed with PKP2-associated ARVC, have an ICD, and are at increased risk for arrhythmias as determined by premature ventricular contraction count during screening.Participants will be enrolled in two dose cohorts. The first dose of TN-401 being assessed in the RIDGE-1 clinical trial is 3E13 vector genomes per kg body weight (vg/kg), a dose that was associated with near maximal efficacy in preclinical studies. Once three patients have been dosed at the 3E13 vg/kg dose level, a panel of independent safety reviewers will advise on plans to dose escalate and/or expand enrollment of the initial cohort dosing in parallel.Measures of transduction and PKP2 expression, arrhythmia burden, ICD activity, cardiac function, biomarkers, patient symptoms and quality of life will be assessed throughout 52-weeks plus an additional 4-year long-term follow up. Participant safety will be monitored closely and prophylactic immunosuppressive medication used for a limited time after administration of TN-401.Results The first RIDGE-1 patient was dosed with TN-401 at the University of California, San Francisco in November 2024. The trial is currently enrolling patients at six leading U.S. centers specializing in ARVC care and four sites in the UK are in the activation process.Conclusion If the results of RIDGE-1 show positive safety, tolerability and efficacy results in ARVC adults, Tenaya Therapeutics plans to assess TN-401 in a broader range of PKP2-associated ARVC patients.",
  "authors": [
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Natasha Paterson"
    },
    {
      "affiliations": [
        "Glasgow University Hospital, Glasgow, UK"
      ],
      "name": "Caroline Coats"
    },
    {
      "affiliations": [
        "University College London, NHS Foundation Trust, London, UK"
      ],
      "name": "Perry Elliott"
    },
    {
      "affiliations": [
        "St George’s University Hospitals, NHS Foundation Trust, London, UK"
      ],
      "name": "Elijah Behr"
    },
    {
      "affiliations": [
        "Royal Brompton and Harefield, NHS Foundation Trust, London, UK"
      ],
      "name": "Antonis Pantazis"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Jay Vora"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Jane Yang"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Kathy Ivey"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Michelle Corral"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Whit Tingley"
    },
    {
      "affiliations": [
        "Tenaya Therapeutics, Inc, South San Francisco, CA, USA"
      ],
      "name": "Matthew Pollman"
    }
  ],
  "title": "1-036 RIDGETM-1: a phase 1b interventional study to evaluate safety and efficacy of TN-401, an adeno-associated virus serotype 9 (AAV9) investigational gene therapy, in adults with PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC)",
  "uid": "8bca2ec1-d42c-5fa2-ae84-c546be083004"
}