{
  "abstract": "Background Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages.Methods Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function.Results Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function.Discussion and conclusion Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.",
  "authors": [
    {
      "affiliations": [
        "Clinical Data Science GmbH, Basel, Switzerland"
      ],
      "name": "Christian Rummey"
    },
    {
      "affiliations": [
        "University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ian A Blair"
    },
    {
      "affiliations": [
        "Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Clementina Mesaros"
    },
    {
      "affiliations": [
        "University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Teerapat Rojsajjakul"
    },
    {
      "affiliations": [
        "University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA",
        "The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Yina Dong"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, Georgia, USA"
      ],
      "name": "George Wilmot"
    },
    {
      "affiliations": [
        "Neurology, University of South Florida, Tampa, Florida, USA"
      ],
      "name": "Theresa Zesiewicz"
    },
    {
      "affiliations": [
        "The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA"
      ],
      "name": "Kathy Mathews"
    },
    {
      "affiliations": [
        "Ohio State University, Columbus, Ohio, USA"
      ],
      "name": "Joseph C Hoyle"
    },
    {
      "affiliations": [
        "University of Colorado, Denver, Colorado, USA"
      ],
      "name": "Lauren Seeberger"
    },
    {
      "affiliations": [
        "Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Victoria, Australia",
        "Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia"
      ],
      "name": "Louise A Corben"
    },
    {
      "affiliations": [
        "Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Parkville, Victoria, Australia",
        "Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia"
      ],
      "name": "Martin Bruce Delatycki"
    },
    {
      "affiliations": [
        "Pediatrics, St Jude Children’s Research Hospital, Memphis, Tennessee, USA"
      ],
      "name": "Richard S Finkel"
    },
    {
      "affiliations": [
        "Neurology, Auckland City Hospital, Auckland, New Zealand"
      ],
      "name": "Richard H Roxburgh"
    },
    {
      "affiliations": [
        "Service de Neurologie, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, Quebec, Canada"
      ],
      "name": "Antoine Duquette"
    },
    {
      "affiliations": [
        "Divisions of Neurology and Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Grace Yoon"
    },
    {
      "affiliations": [
        "University of Chicago, Chicago, Illinois, USA"
      ],
      "name": "Christopher M Gomez"
    },
    {
      "affiliations": [
        "Department of Neurology and Fixel Institute for Neurological Disorders, University of Florida College of Medicine, Gainesville, Florida, USA"
      ],
      "name": "S H Subramony"
    },
    {
      "affiliations": [
        "Neurology, UCLA, Los Angeles, California, USA"
      ],
      "name": "Susan Perlman"
    },
    {
      "affiliations": [
        "University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA",
        "The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Shana Mccormack"
    },
    {
      "affiliations": [
        "Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "David R Lynch"
    }
  ],
  "title": "Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia",
  "uid": "44d1e066-1508-5c25-955c-2d85aa90db62"
}