Muscular dystrophies and stem cells: a therapeutic challenge

Correspondence to : E Gussoni, Division of Genetics, Children’s Hospital, 320 Longwood Ave, Boston, MA 02115, USA Introduction The muscular dystrophies are a diverse group of inherited disorders with common skeletal muscle pathological changes, characterized by progressive weakness and wasting due to muscle-cell necrosis [1,2]. Typical histological features include myofiber degeneration–regeneration, which lead to gradual destruction of skeletal muscle and replacement by connective tissue and fat. The X-linked Duchenne muscular dystrophy (DMD) represents the most frequent and severe form of muscular dystrophy, affecting 1 in 3500 live male births. Although the dystrophic process in DMD patients’ skeletal muscle is present at birth, the first motor difficulties do not appear until age 3–5 years. The disease leads to progressive loss of motor functions, wheelchair dependence by age 10–12 years and death in the third decade from respiratory and/or cardiac failures. In 1986–87, identification of the DMD gene and its encoded protein (dystrophin) opened new avenues of research [3–5]. Dystrophin is localized at the cytoplasmic side of the sarcolemma of skeletal and cardiac muscle [6], and is associated with a protein complex composed of trans-membrane (sarcoglycans, dystroglycans) and intracellular (dystrobrevins, syntrophins) proteins [7–10]. This dystrophin-associated protein complex (DAPC) provides a physical link between the actin cytoskeleton and the extracellular matrix, and one of its presumed functions is to stabilize the muscle-cell membrane during contraction– relaxation [7–10]. Since the discovery of the dystrophin gene, nearly 30 other forms of muscular dystrophy have been identified, many of them caused by mutations in members of the DAPC. For example, the limb-girdle muscular dystrophies (LGMD) LGMD2C-F result from mutations in one of four sarcoglycans [11,12]. Many of the histopathological changes observed in DMD are also seen in other forms of muscular dystrophy, implying that there are common pathways of muscle breakdown and regeneration among the different forms of dystrophy. Slowing or repairing these pathways may lead to effective disease treatment. In recent years, new mouse models have been generated for several forms of muscular dystrophy, including LGMDs [13]. These models not only have been very useful for the identification of common mechanisms underlying muscular dystrophy, but are also great tools for testing therapeutic approaches. In addition to these models, the naturally occurring muscular dystrophy models mdx (with a stop codon mutation in dystrophin exon 23) [14,15] and dy (with laminin a 2 chain deficiency) [16] are some of the most widely used models. Despite the progress made in understanding the molecular basis of muscular dystrophies, no efficient treatment is yet available for these devastating diseases [9,17,18]. Promising progress has been made in gene replacement [19,20] and pharmacological-based therapies, including utrophin up-regulation [21–23], corticosteroids [24–30] and aminoglycoside antibiotics [31,32]. However, this review will focus on recent efforts in the field of cell-based therapy.