title: Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy.
abstract: In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4(+)CD49d(hi) T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease.
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UPR de Neurobiologie, 94704 Maisons-Alfort, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
authors.affiliation: Université Pierre et Marie Curie-Paris 06 UM76, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris, France. Institute of Pediatrics/Federal University of Rio de Janeiro (IPPMG/UFRJ), Rio de Janeiro 21941-912, Brazil. Laboratory of Thymus Research, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Pinto-Mariz
authors.affiliation: Université Pierre et Marie Curie-Paris 06 UM76, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris, France.
authors.forename: Erica
authors.initials: E
authors.lastname: Yada
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Unité D'Épidémiologie clinique et de Biostatistique, 94704 Maisons-Alfort, France. CNRS UMR 7179, MNHN, Brunoy 91800, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Desquilbet
authors.affiliation: Laboratory of Thymus Research, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: Savino
authors.affiliation: Department of Clinical Research, National Cancer Institute (INCA), Rio de Janeiro 20230-130, Brazil.
authors.forename: Suse Dayse
authors.initials: SD
authors.lastname: Silva-Barbosa
authors.affiliation: Université Pierre et Marie Curie-Paris 06 IFR 65 Saint-Antoine, Paris 75005, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.affiliation: Université Pierre et Marie Curie-Paris 06 UM76, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Université Pierre et Marie Curie-Paris 06 UM76, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, UPR de Neurobiologie, 94704 Maisons-Alfort, France. sblot@vet-alfort.fr gillian.butler-browne@upmc.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.affiliation: Université Pierre et Marie Curie-Paris 06 UM76, INSERM U974, CNRS UMR 7215, Institut de Myologie, Paris, France. sblot@vet-alfort.fr gillian.butler-browne@upmc.fr.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D004195:Disease Models, Animal; D004285:Dogs; D016130:Immunophenotyping; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers
keywords: Accelerometry; CD49d; DMD; Dog; Dystrophin; GRMD; Gait analysis; Lymphocyte; Predictive biomarker