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Download references. The laboratory of A. Duchenne muscular dystrophy DMD research in the laboratory of A. DMD research in the laboratory of D.
DMD research in the laboratory of N. We thank N. Wasala University of Missouri and K. Zhang University of Missouri for their help in the preparation of Fig. You can also search for this author in PubMed Google Scholar. Introduction A. Correspondence to Annemieke Aartsma-Rus. The lab of D. As principal inventor of these patents, S. As co-inventor of some of these patents, A. Remuneration for these activities is paid to LUMC. Project funding is received from Sarepta Therapeutics. Nature Reviews Disease Primers thanks J.
Novak, who co-reviewed with T. Partridge, P. Clemens, H. Gordish-Dressman, M. Ryan, J. Tremblay, and the other, anonymous, reviewer s for their contribution to the peer review of this work. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions. Duchenne muscular dystrophy. Nat Rev Dis Primers 7, 13 Download citation. Accepted : 22 January Published : 18 February Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Journal of Cardiovascular Magnetic Resonance Gene Therapy Scientific Reports Journal of Molecular Neuroscience Advanced search. Skip to main content Thank you for visiting nature. Download PDF. Subjects Molecular medicine Neuromuscular disease. Abstract Duchenne muscular dystrophy is a severe, progressive, muscle-wasting disease that leads to difficulties with movement and, eventually, to the need for assisted ventilation and premature death.
Introduction Duchenne muscular dystrophy DMD is a severe, progressive, muscle-wasting disease. Full size image. Epidemiology Dystrophinopathies are X-linked recessive disorders affecting 1 in 5, to 1 in 6, live male births 5 , 6 , 7. Box 1 Muscle activity and DMD pathogenesis Duchenne muscular dystrophy DMD cannot be explained by a single mechanism ; indeed, overlapping yet distinctive pathogenetic processes are likely involved at different stages of the disease and account for different clinical presentations in various organ systems.
Diagnosis, screening and prevention Obtaining an accurate genetic diagnosis Guidelines for the genetic diagnosis of DMD should be followed Respiratory care Improved respiratory care for patients with DMD has considerably increased life expectancy 9 , Cardiac care Cardiac involvement in DMD is characterized by the development of a progressive dilated cardiomyopathy, resulting in congestive heart failure, cardiac insufficiency, conduction abnormalities, ventricular or supraventricular arrhythmia, and risk of sudden early death 9 , Orthopaedic management DMD is characterized by the development of limb muscle contractures a shortening of the muscles leading to deformity and scoliosis.
Endocrinological management Although corticosteroids are associated with improvements in DMD disease course and survival, they are also associated with treatment-related adverse effects that affect multiple systems.
Gastrointestinal management Symptoms of involvement of visceral smooth muscle, such as delayed gastric emptying and intestinal paresis, become more apparent in adults with DMD. Urological management Men with DMD can develop signs and symptoms of bladder and urinary tract dysfunction, such as small capacity, hyper-reflexive bladder and detrusor sphincter dyssynergia disturbance of muscle coordination resulting in urinary urgency, retention and hesitancy of stream.
Neurodevelopmental and neuropsychological management Specific attention should be paid to the management of neurodevelopmental and neuropsychological disorders in patients with DMD 34 , Glucocorticosteroid treatment The most recent guidelines strongly recommend the use of the glucocorticosteroids prednisone or deflazacort in boys with DMD when their motor development stops or starts to decline and to continue treatment throughout life Clinical trials and approved therapies Over the past two decades, several therapeutic approaches have focused on the different steps of DMD pathophysiology.
Small molecules targeting nonsense mutations Two randomized, double-blind, placebo-controlled trials of ataluren , , an orally bioavailable small molecule that induces ribosomal read-through of nonsense mutations, failed to achieve the 48 weeks primary endpoint of improved distance walked in the 6-minute walk test SMWT compared with patients who received placebo treatment. Taken from Yokota et al. Vamorolone suppression of inflammation. Taken from Conklin et al.
By late , Tony had identified potential conserved exons within the genomic walk and used one to identify the first partial cDNA RNA clone from human fetal skeletal muscle that detected multiple putative exons within the genomic walk [ 5 ]. There were a lot of laboratories working on DMD, and the race was on to both clone and sequence the full RNA cDNA , decode the encoded protein, and start characterizing the protein product using antibody reagents.
This paper also showed the diversity, frequency, and preferential localization of deletion mutations, including the hotspot for initiation of deletions near the center of the gene. Michel and Tony continued to work on completing the sequence of the complete human cDNA, a feat completed the following year [ 8 ].
In parallel, I began working on making antibodies to identify the protein product of the DMD gene. As we had published cDNA and predicted protein sequence, many laboratories began synthesizing peptides against our published sequences with the goal of making antibodies to identify the encoded protein. I felt that I was poorly positioned to compete with other expert biochemical laboratories doing peptide and antibody work, so I thought I would instead leverage the extensive set of cDNA clones we had assembled for both mouse and human to construct and express large fusion proteins as antigens for polyclonal antibodies.
In asking around the Enders Building at Boston Children's Hospital, some noted the very high levels of fusion proteins that could be generated by bacterial tryptophan E gene TrpE fusions [ 9 ]. I initially cloned two large segments of the mouse dystrophin cDNA encoding 60 and 30 kd fragments of the putative DMD locus protein product Fig. As the immunized animals were building up antibodies, I looked to make affinity columns with the fusion proteins.
However, the insolubility of the fusion proteins complicated coupling to Sepharose columns. This first paper confirmed the large size of the protein predicted by cDNA cloning and sequencing kDa and confirmed the absence of dystrophin in muscle biopsies from DMD patients expected by the recessive inheritance loss of function. In , dystrophin immunostaining showing localization at the myofiber membrane in normal skeletal muscle, and absence in DMD muscle, was published in collaboration with Eduardo Bonilla at Columbia University [ 11 ] Fig.
The mdx mouse model was a potential model of muscular dystrophy that had arisen sporadically at Jackson Laboratory, but genetic mapping had placed the potential mdx gene locus in an area seemingly inconsistent with the human DMD genetic map [ 12 ]. In the initial dystrophin paper, skeletal muscle from mdx mice showed the absence of dystrophin protein, further bolstering the likelihood that mdx mice and DMD patients shared the same genetic and primary biochemical defect [ 10 ].
The specific mutation causing the original sporadic mdx allele was later identified stop codon in exon 23 [ 14 ]. The Kunkel laboratory, as well as the broader DMD research community, had a strong culture of sharing of reagents and information, often before publication, and we quickly broadly distributed TrpE fusion constructs and proteins, as well as sheep antibodies. Wales Institute [ 16 ] used the TrpE fusion proteins to make a series of monoclonal antibodies and then distribute these to the scientific community via Novocastra Laboratories and later the Iowa Hybridoma Bank.
Nigel Fleming, the instructor at McLean with the sheep, asked if he could start a new biotech based on use of the dystrophin antibodies for clinical testing of patient muscle biopsies. Beauty is in the eyes of the beholder.
With this caveat that these are my personal assessments, I feel that the intersections of basic, translational, and clinical research around dystrophin have been particularly illuminating and impactful.
Indeed, nearly publications have appeared defining and citing the complex glycoprotein network associated with dystrophin, connecting the basal lamina of myofibers through the plasma membrane. Skeletal muscle is one of the largest organ systems in the body, and the constituent myofibers show dramatic adaptation based on the demands placed on muscle by the body.
The myofibers need strong connections to the basal lamina to carry out their function of moving the body but also need to tear down and rebuild these connections to respond to physiological demands; dystrophin seems to be a cornerstone of myofiber remodeling. The identification of the DMD gene and dystrophin protein led to hopes for new therapeutic approaches that addressed the primary defect. Intrinsic features of both the gene and protein slowed progress in translation of molecular understanding to effective therapeutics.
The DMD gene is the largest in the human genome 2 base pairs, where a typical gene is perhaps 30 base pairs. It is technically challenging to harness and work with a gene that large. The dystrophin mRNA is 11 bases and is much too large to fit in gene therapy vectors. The dystrophin protein is also large kDa and requires a specialized intracellular structural niche within myofibers throughout the body recalling that myofibers account for more cell volume in the body than any other cell type.
The required tools to translate DMD molecular knowledge to therapeutics were in hand, but terribly cumbersome to use. Can the process of the failure of muscle regeneration be understood, and the process slowed or stopped? I think the discoveries regarding the clinically milder Becker muscular dystrophy BMD have been illuminating at multiple levels.
From some of the earliest DMD gene mutational studies, it was seen that Duchenne and Becker patients showed overlapping deletion mutations and that DMD patients could in fact have much smaller deletions than Becker patients [ 4 ].
The exons remaining in a DMD patient are spliced together into a mRNA transcript, but the exons neighboring the deletion do not share the same reading frame, leading to a frameshift, and premature truncation of translation of dystrophin.
It became clear that the dystrophin protein could sustain enormous damage to its primary structure, yet still retain some or much biochemical function, evidenced by a milder clinical course of the Becker dystrophy patient. Importantly, the dystrophin protein was imparted a status by the FDA enjoyed by few proteins—surrogate biomarker outcome measure sufficient for drug approval.
Evidence of some rescue of dystrophin in patient muscle by exon skipping has been defined by FDA as sufficient for accelerated regulatory approval, without the typical requirement of clear evidence of clinical benefit.
Dystrophin rescue by exon skipping in a viltolarsen clinical trial in DMD. Standard curves for dystrophin are shown from mixed normal and DMD skeletal muscle samples. Taken from Clemens et al. It seems that FDA may not accept microdystrophins as a surrogate biomarker outcome measure sufficient for drug approval; clinical benefit must be shown.
However, they do not retain all function. Thus, it is expected that the clinical response to both exon skipping and gene therapy will be variable from patient to patient. One of more than 30 forms of muscular dystrophy.
Occurs in 1 in 3, to 5, males born world wide. Average age of diagnosis. Time from initial symptoms to diagnosis is 2. One of the most serious genetic diseases in children worldwide.
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.
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