Some recent news articles have reported a new beagle model carrying a mutation in the dystrophin gene that has severe functional impact on skeletal and heart muscle. Professor Richard Piercy, at the Royal Veterinary College (United Kingdom), previously discovered an exon 50 splice site mutation in dystrophin in a line of dogs bred from a Cavalier King Charles Spaniel and a Bichon Fries (download publication). This model is appropriate to testing exon 51 skipping strategies, and Prof. Piercy has successfully done that in cells from these dogs.
To move the exon 50 splice site mutation onto a more consistent genetic background, lacking other genetic problems seen in the Cavalier King Charles Spaniel, Prof. Piercy has now crossed this mutation into beagles and is breeding this line of dogs to characterize their natural history and begin to use them in Duchenne drug testing.
I spoke with Dr. Joe Kornegay, a Professor of Veterinary Medicine and Biomedical Sciences at Texas A&M University, who has long worked with the Golden Retriever Muscular Dystrophy (GRMD) model of Duchenne. Dr. Kornegay is collaborating with Dr. Piercy and says that the GRMD, like the UK beagle model, has a splice site mutation, but the GRMD mutation is in intron 6/exon 7. Both GRMD and UK beagle models then have their mutations in areas of the genome that are “hot spots” for human dystrophin mutations, and both mutations are out of frame, meaning that no functional dystrophin is produced. The UK beagle model appears to be more severe than the GRMD, since the beagles have to be euthanized by 18 months. But both models provide sufficient window of opportunity for efficacy testing of candidate therapeutics, in order to provide preclinical proof of concept that would justify clinical trials in Duchenne boys.
The UK beagle model, once its natural history is characterized by Prof. Piercy and colleagues, is likely to become a valuable tool in the arsenal to discover and develop new drugs to combat Duchenne.