For an overview of DMD research strategies and the latest research news, see Research. On Sept. On Feb. Skip to main content. Search MDA. Search Donate. What causes DMD? What is the life expectancy in DMD?
What is the status of DMD research? Parsippany, NJ. Ryder, S. DMD was one of the first diseases of which the genetic cause and the missing protein was discovered. Surgery was performed to release contractures of correct the deformity of spine and feet. Alternatively, patient-derived cells could be edited ex vivo and then transplanted back. However, this route is suboptimal owing to the inability to efficiently deliver cells to the musculature. Rather than delivering a functional copy of the micro- dystrophin gene, efforts are also ongoing to deliver cDNA of genes that encode proteins that can improve muscle mass such as follistatin or target disease mechanisms such as SERCA2a This approach has the advantage that it applies to all muscular dystrophies.
However, it will likely have a more limited impact on disease progression as the primary cause of the disease is not addressed. As previously mentioned, three ASOs are now approved for DMD, although the approval was based on low levels of dystrophin restoration rather than on a confirmation of functional effects.
ASOs are mutation-specific approaches and different dystrophin proteins will be formed after skipping different exons for different mutations. In fact, skipping the same exon can lead to the formation of different dystrophins; for example, the deletion of exons 47—50, 48—50, 49—50 and 52 can be restored by exon 51 skipping.
However, the dystrophins produced after exon 51 skipping will vary. Similarly, a deletion of exon 52 can be restored by either exon 51 or exon 53 skipping, resulting in two different dystrophins.
Although in-frame dystrophins are partially functional if they have an ABD and a CR-rich domain, their functionality depends on the connections between spectrin-like repeats ; for example, the connection between spectrin-like repeats can be close to normal, normal or disjointed and some disjointed connections impede the binding of proteins such as nNOS , Techniques to improve ASO efficiency and uptake by skeletal muscle and heart are being explored such as different chemical modifications, arginine-rich peptide conjugates or muscle-homing conjugates.
In parallel, multiexon skipping is being explored as an option to treat larger groups of patients. Here, the focus is on exon 45—55 skipping as patients with BMD and deletion of exons 45—55 generally have a very mild phenotype In addition, the delivery of antisense genes using AAV vectors is being explored.
This approach is a combination of gene therapy and exon skipping and has shown promising results in animal models A clinical trial to assess exon 2 skipping is ongoing in patients with DMD with exon 2 duplications based on promising preclinical results In addition to ataluren, which has been approved by the EMA, gentamicin has stop codon readthrough capacity and has been evaluated as a treatment for DMD However, due to its safety profile, long-term treatment is not an option.
Various other chemical compounds have been screened to identify a readthrough drug with a better safety profile. Utrophin — a ubiquitous protein that is enriched at neuromuscular junctions — shares a high level of homology with dystrophin and can recruit most of the proteins involved in the DAPC. In developing muscles, utrophin is expressed in the same regions of muscle fibres as dystrophin but utrophin production is downregulated in muscle when dystrophin expression commences.
Utrophin is often upregulated in patients with DMD and animal models that lack dystrophin and further upregulation of utrophin in mouse models ameliorated the pathology of DMD , High-throughput screening identified ezutromid as a potential compound to upregulate utrophin expression in muscle; however, this compound showed very limited bioavailability and no therapeutic effect was observed in a placebo-controlled trial in patients with DMD Based on these data, the clinical development of ezutromid has been abolished.
However, ezutromid was found to upregulate utrophin by acting as an aryl hydrocarbon receptor antagonist and other aryl hydrocarbon receptor antagonists were also found to upregulate utrophin ; accordingly, other compounds may be able to upregulate utrophin.
Therapeutic approaches that target the secondary consequences of dystrophin loss are under development for DMD. For example, as the chronic use of glucocorticosteroids is accompanied by many adverse effects, alternative steroids that have a better safety profile are being explored such as vamorolone , Vamorolone seems to be well tolerated in patients and adverse effects are seen at doses that exceed those used for prednisone and deflazacort This compound is now being tested in placebo-controlled trials.
However, although it was well tolerated , no efficacy was observed in a double-blind, randomized placebo-controlled trial and development of this drug was stopped. Compounds to improve muscle mass have also been evaluated for the treatment of DMD. Soluble myostatin receptors ActIIB resulted in improved muscle mass in healthy volunteers; however, longer-term treatment in patients with DMD was not feasible owing to adverse effects, including spontaneous bleeding , which was likely due to interference with activin signalling.
A more specific approach involved myostatin antibodies; however, results from two large placebo-controlled trials with two different myostatin antibodies did not find a therapeutic effect. In hindsight, this finding is not unexpected as myostatin levels are very low in patients with DMD, so further inhibition may not be possible.
Approaches to improve mitochondrial function in DMD have also been studied. These compounds are expected to reduce oxidative stress and fibrosis. One compound targeting mitochondrial function, idebenone, demonstrated a reduced decline in respiratory function in patients with DMD not using corticosteroids in a placebo-controlled trial ; however, studies in patients using corticosteroids were prematurely terminated as no therapeutic effects were found in the interim analysis NCT and NCT In addition, histone deacetylase inhibition has been explored as a method to improve regeneration and reduce inflammation in patients with DMD.
Givinostat was tested in a small open-label study, where treatment reduced fibrosis in all patients based on muscle biopsies taken before and after the clinical trial Mercuri, E.
Muscular dystrophies. Lancet , — Comprehensive overview of the clinical and genetic aspects of muscular dystrophies. Google Scholar. Aartsma-Rus, A. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule.
Muscle Nerve 34 , — CAS Google Scholar. Monaco, A. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2 , 90—95 Natl Acad. USA , — Mendell, J. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ryder, S. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review.
Orphanet J. Rare Dis. Mah, J. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Bladen, C. Kieny, P. Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper centre between and Ferrier, P. Chelly, J. Satre, V. Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome. Takeshita, E. Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.
Ishizaki, M. Female dystrophinopathy: review of current literature. Holloway, S. Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland. Heart 94 , — Systematic analysis of different mutation types and locations of mutations in patients around the world. Magri, F. Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up.
Garcia, S. Kesari, A. Nakamura, A. Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. Deletion of exons encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. Nevin, N. Duchenne muscular dystrophy in a female with a translocation involving Xp Chen, W.
Acta , 35—38 Yu, H. A de novo mutation in dystrophin causing muscular dystrophy in a female patient. Caskey, C. Sporadic occurrence of Duchenne muscular dystrophy: evidence for new mutation.
Haldane, J. The rate of spontaneous mutation of a human gene. Helderman-van den Enden, A. Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy. Dreyfus, J. Serum enzymes in the physiopathology of muscle.
Moser, H. Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Koenig, M. Cell 50 , — Hoffman, E. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51 , — This paper reports the discovery of the dystrophin protein and its absence in DMD. Dystrophin gene transcribed from different promoters in neuronal and glial cells. Nature , 64—65 Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters.
Doorenweerd, N. Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy. A novel dystrophin isoform is required for normal retinal electrophysiology. Lidov, H. Dp a novel kDa CNS transcript from the dystrophin locus. Byers, T. An alternative dystrophin transcript specific to peripheral nerve. Hugnot, J. Distal transcript of the dystrophin gene initiated from an alternative first exon and encoding a kDa protein widely distributed in nonmuscle tissues.
USA 89 , — Tinsley, J. Apo-dystrophin a 2. Gao, Q. The dystrophin complex: structure, function, and implications for therapy. Ervasti, J. Biology of the striated muscle dystrophin-glycoprotein complex. Zhao, J. Dystrophin contains multiple independent membrane-binding domains. Amann, K. A cluster of basic repeats in the dystrophin rod domain binds F-actin through an electrostatic interaction. Prins, K. Dystrophin is a microtubule-associated protein. Cell Biol. Nelson, D. Rapid, redox-mediated mechanical susceptibility of the cortical microtubule lattice in skeletal muscle.
Redox Biol. Stone, M. Specific interaction of the actin-binding domain of dystrophin with intermediate filaments containing keratin Cell 16 , — Bhosle, R. Interactions of intermediate filament protein synemin with dystrophin and utrophin.
Huang, X. Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan. Ayalon, G. An ankyrin-based mechanism for functional organization of dystrophin and dystroglycan.
Cell , — Rezniczek, G. Plectin 1f scaffolding at the sarcolemma of dystrophic mdx muscle fibers through multiple interactions with beta-dystroglycan. Yamashita, K. The 8th and 9th tandem spectrin-like repeats of utrophin cooperatively form a functional unit to interact with polarity-regulating kinase PAR-1b.
Lai, Y. Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. This paper showed, for the first time, the direct binding of dystrophin to nNOS. Anderson, J. Reynolds, J. Deregulated protein kinase A signaling and myospryn expression in muscular dystrophy. Constantin, B.
Dystrophin complex functions as a scaffold for signalling proteins. Acta , — Allen, D. Chang, N. The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment. Cell Stem Cell 22 , — Lumeng, C. Sarparanta, J. Muscle Res. Cell Motil. Sugita, S. A stoichiometric complex of neurexins and dystroglycan in brain.
Mokri, B. Duchenne dystrophy: electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber. Neurology 25 , — Assessing functional performance in the mdx mouse model. Stedman, H. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature , — Duan, D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy.
Comprehensive overview of microdystrophin gene therapy development, its opportunities and challenges. Bradley, W. Structural changes in the early stages of Duchenne muscular dystrophy. Psychiatry 35 , — Pearson, C. Histopathological features of muscle in the preclinical stages of muscular dystrophy.
Brain 85 , — Brenman, J. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82 , — Sander, M. Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy.
USA 97 , — Patel, A. Muscle 8 , 36 Kodippili, K. Dual AAV gene therapy for Duchenne muscular dystrophy with a 7-kb mini-dystrophin gene in the canine model.
Gene Ther. Prosser, B. X-ROS signaling: rapid mechano-chemo transduction in heart. Science , — Khairallah, R. Microtubules underlie dysfunction in Duchenne muscular dystrophy. Li, D. Nitrosative stress elicited by nNOSmu delocalization inhibits muscle force in dystrophin-null mice. Kim, J. Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.
Grounds, M. Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress. Models Mech. Rando, T. Dudley, R. Dynamic responses of the glutathione system to acute oxidative stress in dystrophic mouse mdx muscles.
Petrillo, S. Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway. Turner, P. Increased protein degradation results from elevated free calcium levels found in muscle from mdx mice. Millay, D. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy.
Phillips, M. Calcium antagonists for Duchenne muscular dystrophy. Cochrane Database Syst. Kyrychenko, S.
Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy. Bellinger, A. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Kushnir, A. Ryanodine receptor dysfunction in human disorders. Acta Mol.
Cell Res. The first signs and symptoms. If you notice the signs and symptoms below, use this guide to have a conversation with your doctor Common signs and symptoms of Duchenne you may notice:. Not walking until approximately 18 months of age. Walking on toes with legs apart, walking with the belly pointed out, or both.
Duchenne's effect on the brain Children with Duchenne are more likely to have conditions affecting the brain, such as mental health, learning, or seizure disorders. In children with Duchenne, the lack of dystrophin is believed to affect the ability of certain brain cells, called neurons, to connect properly and share information This can lead to challenges with important brain functions such as attention, memory, learning, speech, and intellectual ability.
The difference between Duchenne muscular dystrophy and Becker muscular dystrophy. Common questions about Duchenne. Learn More. Why dystrophin is so important.
The typical progression of Duchenne.
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