Finally, the large size of the mutated genes such as dystrophin (14 kb mRNA) in Duchenne Muscular Dystrophy (DMD) or dysferlin (6.2 kb mRNA) in limb–girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy, challenges classical gene replacement therapies. The gene discussed is DYSF; the disease is Duchenne muscular dystrophy.