Duchenne Muscular Disease

Duchenne muscular dystrophy(DMD) one of the most severe forms of inherited muscular dystrophies. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. Mutations in the dystrophin gene lead to progressive muscle fiber degeneration and weakness. This weakness may present initially with difficulty in ambulation but progressively advances to such an extent that affected patients are unable to carry out activities of daily living and become wheelchair bound. Cardiac and orthopaedic complications are common, and death usually occurs in the twenties due to respiratory muscle weakness or cardiomyopathy. Current therapy is centred on treatment with glucocorticoids and physiotherapy to prevent orthopaedic complications. [1] Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.