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

Inès Barthélémy,Erica Yada,Gillian Butler-Browne,Fernanda Pinto-Mariz,Thomas Voit,Stéphane Blot,Suse Dayse Silva-Barbosa,Anne-Marie Faussat,Wilson Savino,Vincent Mouly,Loïc Desquilbet

doi:10.1242/dmm.016014

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+CD49dhi 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.

Highlights

Duchenne muscular dystrophy (DMD) is the most common genetic muscular dystrophy, affecting 1 in 3500-5000 male births
A population of 61 Golden Retriever muscular dystrophy (GRMD) dogs was evaluated at 2 months of age and was subsequently divided into two subgroups according to the occurrence of ambulation loss before 6 months of age
Beyond the possibility to significantly improve the preclinical phase of clinical studies, the fact that these predictive biomarkers are shared between dogs and humans reinforces the translational relevance of this canine model of DMD

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most common genetic muscular dystrophy, affecting 1 in 3500-5000 male births. A wide interindividual variability figures among the numerous similarities shared by canine and human diseases At first glance, this interindividual variability can be seen as a major obstacle in the evaluation of therapies at the preclinical stage (Banks and Chamberlain, 2008; Willmann et al, 2009), but this model could be relevant in discovering modulatory factors and modifier genes for this disease. This interindividual variability can be seen as a major obstacle in the evaluation of therapies at the preclinical stage (Banks and Chamberlain, 2008; Willmann et al, 2009), but this model could be relevant in discovering modulatory factors and modifier genes for this disease Taking advantage of this inter-individual heterogeneity to identify predictive markers of the clinical evolution could help to increase the robustness of preclinical trials on the one hand, and unveil mechanisms underlying variations in disease expression on the other hand

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