Predictive markers of clinical outcome in the GRMD dog model of Duchenne Muscular Dystrophy

Abstract

Abstract In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last pre-clinical validation step is often carried out in the most relevant animal model of this human disease namely the GRMD (Golden retriever muscular dystrophy) dog. GRMD dogs mimic the human disease,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 its close resemblance to DMD patients. In order to improve the management of this inter-individual heterogeneity we have screened a combination of biomarkers in 61 two 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+CD49dHi T-lymphocytes, 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 pre-clinical 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 DMD boys, strengthening the relevance of GRMD dogs as pre-clinical models of this devastating muscle disease.