Pig models for Duchenne muscular dystrophy – from disease mechanisms to validation of new diagnostic and therapeutic concepts.

• Various tailored pig models for Duchenne muscular dystrophy (DMD) were generated. • Porcine DMD models resemble human DMD pathology in an accelerated mode. • Proteomics unraveled molecular derangements in skeletal muscle and myocardium. • Multispectral optoacoustic tomography (MSOT) was validated for detection of muscle fibrosis. • Dystrophin was restored by CRISPR/Cas9-mediated deletion of exon 51 in DMD Δ52 pigs. Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal muscles and heart. Animal models are essential for preclinical evaluation of novel diagnostic procedures and treatment strategies. Gene targeting/editing offers the possibility of developing tailored pig models for monogenic diseases. The first porcine DMD model was generated by deletion of DMD exon 52 (DMD Δ52) in cultured kidney cells, which were used for somatic cell nuclear transfer to produce DMD Δ52 offspring. The animals resembled clinical, biochemical, and pathological hallmarks of DMD, but died before sexual maturity, thus preventing their propagation by breeding. This limitation was overcome by the generation of female heterozygous DMD Δ52 carrier pigs, which allowed the establishment of a large breeding colony. In this overview, we summarize how porcine DMD models have been used for dissecting disease mechanisms, for validating multispectral optoacoustic tomography as an imaging modality for monitoring fibrosis, and for preclinical testing of a CRISPR/Cas9 based approach to restore an intact DMD reading frame. Particular advantages of porcine DMD models include their targeted design and the rapid disease progression with early cardiac involvement, facilitating translational studies in reasonable time frames. [ABSTRACT FROM AUTHOR]