Experimental Physiology Exp Physiol 96.11 pp 1101–1113 1101 Joan Mott Prize Lecture Joan Mott Prize Lecture Progress in therapy for Duchenne muscular dystrophy Rebecca J. Fairclough ∗ , Akshay Bareja ∗ and Kay E. Davies MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, UK Duchenne muscular dystrophy is a devastating muscular dystrophy of childhood. Mutations in the dystrophin gene destroy the link between the internal muscle filaments and the extracellular matrix, resulting in severe muscle weakness and progressive muscle wasting. There is currently no cure and, whilst palliative treatment has improved, affected boys are normally confined to a wheelchair by 12 years of age and die from respiratory or cardiac complications in their twenties or thirties. Therapies currently being developed include mutation-specific treatments, DNA- and cell-based therapies, and drugs which aim to modulate cellular pathways or gene expression. This review aims to provide an overview of the different therapeutic approaches aimed at reconstructing the dystrophin-associated protein complex, including restoration of dystrophin expression and upregulation of the functional homologue, utrophin. (Received 31 May 2011; accepted after revision 25 July 2011; first published online 31 July 2011) Corresponding author K. E. Davies: Oxford University, Physiology Anatomy and Genetics, Hertford College, Oxford OX1 3PT, UK. Email: [email protected] Duchenne muscular dystrophy (DMD) is an X-linked genetic disease that afflicts one in every 3500 males (Emery, 1993). It is caused by the absence of the protein dystrophin (Koenig et al. 1987). Duchenne muscular dystrophy patients are generally boys who exhibit early symptoms (around 3–5 years of age) of abnormal gait, calf muscle pseudohypertrophy (Emery, 1993) and the characteristic Gowers’ sign (weakness of the proximal muscles, particularly those of the lower limb; Gowers, 1892). Respiratory complications, including sleep-disordered breathing and apnoea, arise during the teenage years and result in headaches, nausea, fatigue and poor appetite (Emery, 1993; Cox & Kunkel, 1997). Patients are usually wheelchair bound by 12 years of age (Emery, 1993). Dilated cardiomyopathy of varying severity is evident from abnormal ECGs in most patients by 18 years of age, and is currently responsible for the death of approximately 10–40% of all DMD patients (Baxter, 2006). The development of scoliosis is coincident with permanent wheelchair use, rapidly progressing during puberty and adversely affecting respiratory function (Emery & Muntoni, 2003). Many patients die of respiratory failure in their twenties (Emery & Muntoni, 2003). Becker muscular This is based on the 2010 Joan Mott Prize Lecture, which was given by Kay Davies at Physiology 2010 in Manchester, 2 July 2010. ∗ R.J.F. and A.B. contributed equally to this work. dystrophy (BMD) is a milder disease caused by the reduced expression of dystrophin or expression of a partially functional protein. Some BMD patients present with only cardiomyopathy and remain ambulant into their fifties or sixties (Yazaki et al. 1999). There is currently no cure for DMD. Prednisolone has been shown to increase the ambulatory period for some patients (Connolly et al. 2002), but more effective interventions are desperately needed. Dystrophin and the dystrophin-associated protein complex (DAPC) Dystrophin is a 427 kDa protein that is comprised of the following four domains: the N-terminal domain (which binds actin); the rod domain (which consists of 26 spectrin-like repeats); a cysteine-rich domain; and a C- terminal domain (Koenig et al. 1988). Skeletal muscle is made up of thousands of muscle fibres (myofibres), each of which is surrounded by a plasma membrane (sarcolemma) and an overlying basal lamina. Dystrophin is expressed in skeletal muscle at the sarcolemma and is enriched at the myotendinous junction (the junction of muscle fibres and tendons) and the neuromuscular junction (the junction of a motor neuron with a muscle fibre; Khurana et al. 1991). Dystrophin binds to filamentous (F)-actin (a constituent member of the cytoskeleton) via its N-terminus and a cluster of C 2011 The Authors. Journal compilation C 2011 The Physiological Society DOI: 10.1113/expphysiol.2010.053025
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