I-6Pharmacological strategies for MuscularDystrophies. Review of the literatureand personal data

Although Duchenne Muscular Dystrophy (DMD) has been described 175 years ago, therapies for DMD remain supportive rather than curative. Gene- and cell-based therapies designed to replace the missing gene and/or dystrophin protein have achieved varying and controversial degrees of success. Three different therapeutic approaches are currently under study: 1. Gene therapy; 2. Cellular therapy; 3. Pharmacological therapy. The latter will be examined into the three fundamental aspects: 1. Utrophin over-expression; 2. Dystrophin re-expression; 3. Reversal of dystrophic phenotype. Utrophin over-expression. Recent developments in understanding the regulatory pathways that govern utrophin expression, stimulated studies using activators of these pathways to alleviate the dystrophic symptoms in DMD animal models. Drugs used to this aim are: Interleukin 6, Agrin, Heregulin, Calcineurin. All these drugs are able to induce overexpression of the sarcolemmal utrophin in vitro and in neonatal mdx skeletal muscles. The results of these preclinical studies are promising and stimulate to implement appropriate utrophin-based drug therapies for DMD patients. Dystrophin re-expression can be achieved by drug therapy – aminoglycosides, antisense strategy and chimeraplasty – or by cell therapy – myoblasts and stem cells – or by gene therapy. Aminoglycosides have been proven to cause an extensive misreading of the RNA code, allowing the insertion of alternative amino acids at the site of the mutated codon. Although it is now considered a therapeutic strategy for DMD caused by point-mutations, unfortunately it is applicable to only 1% of DMD patients. Reversal of dystrophic phenotype can be achieved by the use of corticosteroids. The two main classes of steroids used are prednisone or prednisolone and deflazacort (DFZ). They are probably equally effective in stabilizing muscle strength but may have different side-effect profiles. The exact mechanism by which steroids slow the dystrophic process is yet under investigation. Corticosteroids have been found to stabilize or improve muscle strength in boys with DMD and to have beneficial effects on the different aspects of DMD, such as walking time prolongation, development of scoliosis, development of respiratory insufficiency and development of cardiac involvement. A systematic review of the Cochrane database and the personal experience on more than 200 DMD patients treated with DFZ for 20 years, let us to conclude that long term steroid therapy is able to prolong ambulation by 2 to 5 years, reduce the need for spinal stabilization surgery, improve cardiopulmonary function, delay the need for non invasive nasal ventilation and finally increase survival and quality of life of patients with Duchenne muscular dystrophy.