Duchenne muscular dystrophy (DMD) is an X-linked recessive lethal muscle wasting disorder that affects approximately 1 in 5,000 live human male births worldwide and for which there is no treatment that prevents the progressive muscle loss and associated cardiomyopathy.
Although this is a rare disease, it has a huge effect on the patients and family members and a high economic impact in terms of medical management and care with patients becoming wheelchair dependent by an average of 12 years old and requiring full time assistance by their mid to late teens. The RVC is working to develop new treatments for this condition.
In order to test the potential of different experimental treatments the lab uses the mdx mouse model of DMD. The use of animal models of the condition is essential in order to understand both the effectiveness of a therapy and potential harmful side-effects. The mdx mouse line is derived from a spontaneous mutation in the mouse DMD gene. The mice are good biochemical and muscle physiology models of DMD but, unlike man, they do not show any obvious clinical signs of the condition. Indeed, most observers cannot tell the difference between mdx and wild-type mice when looking at a cage of mice. Most experiments involve intravenous, sub-cutaneous or oral administration of the experimental treatment followed by physiological assessment of muscle function under terminal anaesthesia and extensive post-mortem analyses. Thus the mice experience little pain or suffering.
The RVC is currently working on a number of different therapeutic approaches. In one study we are examining the potential effectiveness of individual or combinations of drugs that are already approved for use in man but for other diseases. In another study we are continuing to test the next generation of exon-skipping antisense reagents in collaboration with groups from Oxford and Cambridge (e.g. Godfrey et al., 2015). The antisense reagents are used to modify the splicing of the primary RNA transcript into the mRNA. Most Duchenne mutations cause a disruption of the open reading frame in the mRNA of the DMD gene and thus do not produce the protein (dystrophin). By masking binding sites for the spliceosome proteins, specific exons can be excluded and this can restore the open reading frame resulting in an internally deleted but functional version of dystrophin.
Godfrey C, Muses S, McClorey G, Wells KE, Coursindel T, Terry RL, Betts C, Hammond S, O'Donovan L, Hildyard J, El Andaloussi S, Gait MJ, Wood MJ, Wells DJ. (2015) How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. Hum Mol Genet. 24(15):4225-37.