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.
Highlights
Duchenne muscular dystrophy (DMD) is a recessive X-linked devastating muscle disease due to dystrophin-deficiency, affecting 1 newborn male in 3500, and for which to date no curative treatment exists
This study has shown that the association of cyclosporine A and prednisolone as an immunosuppressive therapy does have an effect on the GRMD disease course and at many levels
The motor scores were much lower than any previously quoted values in GRMD dogs, and primary alterations in gait were at least partially corrected by the treatment
Summary
Duchenne muscular dystrophy (DMD) is a recessive X-linked devastating muscle disease due to dystrophin-deficiency, affecting 1 newborn male in 3500, and for which to date no curative treatment exists. Many studies aiming to assess the efficacy of gene, cell or pharmacological strategies have been conducted in dog models of DMD [4,5,6,7]. During these studies, several of the investigators have been obliged to use immunomodulator treatments to avoid the immune response against the viral vector, donor cells and/or the product of a transgene [5,7,8,9,10,11,12]. The drugs used were cyclosporine alone, or associated with mycophenolate mofetil, anti-thymocyte globulin or corticosteroids
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