Reflection 3: Disease Themes

Duchenne Muscular Dystrophy (DMD) is a severe muscular disorder caused by mutation in the DMD gene, resulting in acute muscle wasting and weakness caused by the almost complete absence of functional dystrophin protein . Dystrophin itself plays a key role in the healthy function of muscle, providing support and strength to muscle fibers. As such, DMD is an extremely fatal condition, with virtually all cases leading to an early death before the age of 30 or 40. DMD and the muscular dystrophy family of diseases have been known of for centuries, but much of the knowledge surrounding it has been uncovered only relatively recently. In compiling the extensive literature covering this disease, the following themes were apparent to me.

Theme 1: Identification and Distinction – Genetic, Clinical, and Historical

            The evolution of the clinical and genetic understanding of DMD over time is truly fascinating. DMD was noticed for the very first time in the nineteenth century. It was named posthumously after Dr. Duchenne de Boulogne of France (1806-1875), who worked with and extensively documented muscular dystrophy patients. This was and is slightly controversial apparently, as muscular dystrophy was first identified decades before Duchenne supposedly first published about it, and it is disputed whether he or another contemporary physician contributed more. Not much more is known about DMD or related diseases for the better part of a century until the 1970, 80s and 90s. In these three decades understanding progressed rapidly; the gene responsible was identified and the protein encoded by that gene, dystrophin, was characterized (along with its critically important healthy state function, associated proteins, and disease state dysfunction). In the year 2000, many of the mutations responsible for DMD was characterized on the dystrophin protein itself by Norwood et al.1 This new knowledge has also allowed scientists to specifically characterize and distinguish others in the disease family such as Becker Muscular Dystrophy and Limb Girdle Muscular Dystrophy.

Theme 2: Biomolecular and Cellular Pathology – Dystrophin and the DAPC

            Doctors and researchers had a relatively poor understanding of the underlying causes of Duchenne’s and other types of muscular dystrophy for most of the period since its discovery. Between the 1860s and 1980s, just about the only new discovery about the pathology of DMD was that it was X-linked recessive in the 1950s.2 The understanding of what goes wrong, and how, at the cellular and biochemical levels has increased vastly since dystrophin was first discovered in 1987, however.3 A series of papers by Ervasti et al. in the early to mid-1990s characterized the transmembrane dystrophin-associated protein complex (DAPC).4 In the absence of dystrophin, this complex was found to be partly or wholly missing as well. In 1993, Petrof et al. found further support that dystrophin and the DAPC play a role in sarcolemma stability and strength, demonstrating that dystrophin deficient muscles were more prone to sarcolemma tearing.5 Thus, the loss of dystrophin results in the weakening the sarcolemma and ultimately triggers a number of degenerative pathways such as fibrosis and diminished muscular regeneration.

Theme 3: Treatment – Dystrophin Restoration and Gene Therapy

            There are currently no treatments that effectively cure DMD. As such, treatment options primarily consist of symptom management, delaying disease progression and improving quality of life for as long as possible. However, advances in biomedical technology in recent decades have shown very promising results in rescuing dystrophin expression at a genetic level. Current biochemical research is focused largely on two methods: exon-skipping and gene therapy. DMD normally arises from a frameshift mutation that has a highly disruptive effect on the synthesis of the entire protein. Exon skipping is one strategy to get around this, by inhibiting certain exons and excluding them from splicing, thus “skipping” them.6 Skipping the damaged exon while remaining in frame results in a truncated, but still partially functional dystrophin protein that will usually not manifest symptoms as severe as seen in DMD. Additionally, researchers are beginning to explore potential gene therapies able to restore proper expression of dystrophin by correcting mutant gene expression. Research here has sought to use adenoviruses as vectors of gene replacement. More recently, researchers have also begun looking into the use of Crispr/Cas9 gene manipulation, a relatively new and extremely precise method of genomic editing that may eventually have the potential to cut out damaged sections of DNA, and replace it with the correct sequence.

1. Norwood, F.L., Sutherland-Smith, A.J., Keep, N.H., Kendrick-Jones, J. 2000. The Structure of the N-Terminal Actin-Binding Domain of Human Dystrophin and How Mutations in This Domain May Cause Duchenne or Becker Muscular Dystrophy.  Structure 8:481

2. Walton JN. 1955. On the inheritance of muscular dystrophy. Ann Hum Genet. 20(1):1-13.

3. Zhang Y et al. 2020. Enhanced CRISPR-Cas9 correction of Duchenne muscular dystrophy in mice by a self-complementary AAV delivery system. Sci Adv. 6(8): eaay6812.

4. Ervasti JM, Campbell KP. 1991. Membrane organization of the dystrophin-glycoprotein complex. Cell. 66:1121-1131.

5. Petrof et al. 1993. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 90(8): 3710-3714.

6. Mann CJ, Honeyman K, Cheng AJ, et al. 2001. Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc Natl Acad Sci U S A. 98(1):42–47

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