Effects of an Immunosuppressive Treatment in the GRMD Dog Model of Duchenne Muscular Dystrophy

Abstract

The GRMD (Golden retriever muscular dystrophy) dog has been widely used in pre-clinical trials targeting DMD (Duchenne muscular dystrophy), using in many cases a concurrent immune-suppressive treatment. The aim of this study is to assess if such a treatment could have an effect on the disease course of these animals. Seven GRMD dogs were treated with an association of cyclosporine A (immunosuppressive dosage) and prednisolone (2 mg/kg/d) during 7 months, from 2 to 9 months of age. A multi-parametric evaluation was performed during this period which allowed us to demonstrate that this treatment had several significant effects on the disease progression. The gait quality as assessed by 3D-accelerometry was dramatically improved. This was consistent with the evolution of other parameters towards a significant improvement, such as the clinical motor score, the post-tetanic relaxation and the serum CK levels. In contrast the isometric force measurement as well as the histological evaluation argued in favor of a more severe disease progression. In view of the disease modifying effects which have been observed in this study it should be concluded that immunosuppressive treatments should be used with caution when carrying out pre-clinical studies in this canine model of DMD. They also highlight the importance of using a large range of multi-parametric evaluation tools to reliably draw any conclusion from trials involving dystrophin-deficient dogs, which reproduce the complexity of the human disease.

Gait characteristics in a canine model of X-linked myotubular myopathy

“…Indeed, gait speed is widely used as an outcome measure in clinical trials for muscular dystrophy [26–35]. Gait abnormalities have also been reported in canines with Duchenne muscular dystrophy and other myopathies [19, 27, 36–40]. Some measures of muscle strength and respiratory function have already been reported in the XLMTM dog [13, 41], but this is the first study of gait assessment in this large animal model and the first assessment of awake animals.…”

Immune-mediated pathology in Duchenne muscular dystrophy

“…In canine DMD, treatment with CysA and prednisone demonstrated a mixed outcome with improvement in some muscle characteristics but worsening of others. Improvements were observed in motor scores, gait analysis, and possibly contracture relief, but these were offset by the worsening of force measurements (although this may be due to possible measurement artifact) and worsening of histopathology (with an increase in calcified myofibers) (82). …”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…Glucocorticoids are the most commonly used drug in DMD patients. Several groups have tested prednisone in affected dogs (167)(168)(169). These studies revealed some beneficial effects, such as improvement in gait, increase of the extensor muscle force, and elevation of the integrin level.…”