Effects of an immunosuppressive treatment in the GRMD dog model of Duchenne muscular dystrophy

PLoS One. 2012;7(11):e48478. doi: 10.1371/journal.pone.0048478. Epub 2012 Nov 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Accelerometry
  • Animals
  • Biomechanical Phenomena / drug effects
  • Creatine Kinase / blood
  • Cyclosporine / pharmacology
  • Cyclosporine / therapeutic use
  • Disease Models, Animal
  • Dogs
  • Follow-Up Studies
  • Gait / drug effects
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Motor Activity / drug effects
  • Muscular Dystrophy, Animal / blood
  • Muscular Dystrophy, Animal / complications
  • Muscular Dystrophy, Animal / drug therapy*
  • Muscular Dystrophy, Animal / physiopathology
  • Muscular Dystrophy, Duchenne / blood
  • Muscular Dystrophy, Duchenne / complications
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / physiopathology
  • Principal Component Analysis
  • Tetany / blood
  • Tetany / complications
  • Tetany / physiopathology

Substances

  • Immunosuppressive Agents
  • Cyclosporine
  • Creatine Kinase

Grant support

This work has been funded by the Association Française contre les Myopathies (AFM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.