Therapies to treat Duchenne muscular dystrophy may sooner progress toward clinical trials thanks to a more realistic mouse model that mimics the human disease better than existing models. The new framework is detailed in a Nationwide Children’s Hospital study that appears in Science Translational Medicine.
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. This life-threatening, muscle-wasting disease leads to patients’ inability to walk and often leads to death from cardiac or pulmonary complications.
Existing animal models of DMD, including the most commonly used “mdx mouse,” are not entirely applicable to human conditions. “Although mdx mice display a number of aspects of DMD disease biology that make them useful for translational studies, the progression and severity of muscular dystrophy in mdx mice does not completely parallel the human disease,” said Paul T. Martin, PhD
, principal investigator in the Center for Gene Therapy
at The Research Institute at Nationwide Children’s Hospital and the study’s lead author.
A key difference between mice and humans relates to the gene CMAH, which impacts glycans (sugar chains) present on the cell surface. Cmah is expressed in most mammals, but the gene is mutated in humans; therefore, humans fail to produce a particular sugar molecule, Neu5Gc.
Dr. Martin and colleagues hypothesized that this evolutionary difference might play a role in why DMD appears much less severe in mice than in humans. To test whether CMAH gene function affects disease pathology, the team introduced a mutation, similar to that in humans, into the CMAH gene in mdx mice. This mutation altered mouse muscle glycosylation, specifically by getting rid Neu5Gc in the mice. In turn, these mice developed symptoms of muscular dystrophy earlier and more severely than the mdx mice, making their disease progression more like that in humans.
Dr. Martin says that this new model, which is more akin to humans, should facilitate the testing of DMD therapeutics. “Having a model that can better mimic the more severe aspects of DMD, including increased mortality, increased cardiac and respiratory muscle weakness, and increased deficits in ambulation should facilitate translational work on these important aspects of the disease,” said Dr. Martin.
This study also raises the possibility of modulating diet as a potential therapy for DMD.
The findings imply that a diet rich in Neu5Gc may stimulate negative immune responses in diseased muscle tissue that take up the sugar. “This could speed the wasting of skeletal muscle in DMD, the process that ultimately causes muscle failure and mortality in patients,” said Dr. Martin. Avoiding Neu5Gc, which is found significantly in red meats and dairy products, may help to reduce this immune response and thereby alleviate symptoms.
Chandrasekharan K, Yoon JH, Xu Y, Devries S, Camboni M, Janssen PM, Varki A, Martin PT. A Human-Specific Deletion in Mouse Cmah Increases Disease Severity in the mdx Model of Duchenne Muscular Dystrophy
. Sci Transl Med.
2010 Jul 28;2(42):42ra54.