Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in relevant animal models. Because clinical features in dogs are more severe than those in mdx mice, in keeping with the DMD phenotype, preclinical studies in the canine models might be more predictive of disease pathogenesis and treatment efficacy.
Here, we developed a novel canine DMD model (Beagle, DmdE51*) with a 4-bp deletion in Dmd at exon 51 introduced using CRISPR/Cas9 (Beijing Sinogene Biotechnology Co., Ltd.). In principle, this indel leads to a frameshift mutation and a downstream premature stop codon in exon 51. The Dmd gene mutation in this DMD canine model located in the hotspot region may better reflect the pathological features and disease progression of DMD patients. In phenotypes analysis, DmdE51* canine model revealed typical DMD features, including shortened lifespan (7-8 months age), stiff limbs, salivation, dysphagia, loss of dystrophin protein expression and a significant increase in serum CK levels (about 149-fold compared to WT).
Collectively, unlike the dystrophin-deficient mdx mouse, which remains relatively normal clinically, DMD dogs develop progressive, fatal disease strikingly similar to the human condition, which provides a valuable DMD animal model for human DMD gene and cell therapy evaluation and setting the stage for clinical trials in DMD. In addition, Beagles are classified as small size dogs, which helps reduce the amount of gene therapy products needed and lowers the costs of early drug evaluations.