Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy

Inès Barthélémy (1) , Fernanda Pinto-Mariz (2, 3, 4) , Erica Yada (2) , Loic Desquilbet (5, 6) , Wilson Savino (4) , Suse Dayse Silva-Barbosa (7) , Anne-Marie Faussat (8) , Vincent Mouly (2) , Thomas Voit (2) , Stéphane Blot (1) , Gillian Butler-Browne (2)

1 UPR de neurobiologie
2 Institut de Myologie
3 UFRJ - Universidade Federal do Rio de Janeiro [Brasil] = Federal University of Rio de Janeiro [Brazil] = Université fédérale de Rio de Janeiro [Brésil]
4 FIOCRUZ - Fundação Oswaldo Cruz / Oswaldo Cruz Foundation
5 ENVA - École nationale vétérinaire d'Alfort
6 Mécanismes adaptatifs : des organismes aux communautés
7 INCA Rio de Janeiro
8 Cancer, Inflammation, Hormones

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.

Mots clés: GRMD; DMD; Dystrophin; Dog; Predictive biomarker; Lymphocyte; CD49d; Gait analysis; Accelerometry

Domaines: Médecine humaine et pathologie

Inès Barthélémy, Fernanda Pinto-Mariz, Erica Yada, Loic Desquilbet, Wilson Savino, et al.. Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy. Disease Models & Mechanisms, 2014, 7 (11), pp.1253-1261. ⟨10.1242/dmm.016014⟩. ⟨hal-01316488⟩