Recent developments in Duchenne muscular dystrophy: facts and numbers

Muscular dystrophies are a clinically and genetically heterogeneous group of skeletal muscle-wasting diseases. Even for experts in the field of neuromuscular diseases, it is becoming increasingly difficult to distinguish and accurately diagnose all forms of muscular dystrophy on clinical grounds alone, as there is currently a still growing number of different genetic loci for muscular dystrophies. At present, therapy of muscular dystrophies is predominantly based on symptomatic treatment and supportive care. However, within the last years, promising new molecular therapies have been developed facilitating causative therapy in the near future. Duchenne muscular dystrophy (DMD) represents the most frequent hereditary childhood myopathy, leading to progressive muscle atrophy and weakness and premature death; interestingly, the underlying genetic defect in the dystrophin gene with an X-linked trait has been described more than 25 years ago. The worldwide incidence is estimated with 1:5000 male newborns. First symptoms are usually noted between age 3 and 5, while loss of ambulation occurs around age 12, along with scoliosis, contractures, respiratory and cardiac impairment requiring early ventilatory support and heart medication (Table 1). Life expectancy is reduced to 30–40 years of age although multidisciplinary symptomatic and surgical treatment has considerably improved survival within the last two decades. Becker muscular dystrophy (BMD) is the allelic phenotype of DMD with wider variability of clinical symptoms but usually milder impairment and slower progression with an estimated incidence of 1:20 000. The mutation in the dystrophin gene does not cause a reading frame interruption but a so called in frame mutation that leads to translation of different amounts of a truncated Dystrophin protein that can maintain a low protein function level within the muscle cells of these patients. Similar to leading the way towards genetic diagnostics back then, DMD today is within the main focus of new gene-based therapies. Over the last decades, the identification of the dystrophin gene has led to a deeper understanding of the muscle cell membrane and the proteins responsible for membrane stability. Animal models, mainly the mdx mouse and the golden retriever muscular dystrophy (GRMD) dog—with natural mutations or specifically developed by gene targeting— have strongly contributed to enhance knowledge on disease progression, underlying pathology and therapeutic development. Recently, a promising large animal model for studying disease mechanisms and for the development and evaluation of targeted therapies of Duchenne muscular dystrophy, the DMDpig, had been successfully established. Pigs are particularly suitable animal models for translational biomedical research as they reflect many anatomical and physiological characteristics of humans. This animal model reflects a frequent mutation of human DMD patients, a deletion of exon 52; therefore, the DMD pig represents a promising model for testing targeted genetic treatments. Two predominant therapeutic strategies can be differentiated—dystrophin-based therapies, e.g. stem cell therapy, virus-based gene therapy, exon skipping by antisense oligonucleotides or morpholinos, e.g. Eteplirsen/Exondys51®, approved in the US in 2016 for DMD with deletions amendable to exon 51 skipping, and stop codon read-through by Ataluren/Translarna®, which had been conditionally approved as the first drug in DMD in 2014 in Europe for treatment of nonsense-mutation DMD (nmDMD), and dystrophin-independent treatments such as utrophin modulation, alpha-7-integrin up-regulation, myostatin inhibition, follistatin gene therapy, along with other strategies for muscle growth. Unfortunately, until now, the large size of the dystrophin gene hinders direct replacement through viral gene therapy. ED ITOR IAL