Neurology Care, Diagnostics, and Fawn Leigh, MD,a,b Alessandra Ferlini, PhD,c Doug Biggar, MD,d Katharine Bushby, MD,e EmergingRichard Finkel, MD,f Lauren P. Morgenroth, Therapies MS,g Kathryn R. Wagner, of MD, thePhDh,i Patient With Duchenne Muscular Dystrophy abstract DMD Duchenne muscular dystrophy is the most common form of childhood muscular dystrophy. A mutation in the gene disrupts dystrophin (protein) production, causing damage to muscle integrity, weakness, loss of ambulation, and cardiopulmonary compromise by the second decade of life. Life expectancy has improved from mid-teenage years to mid- 20s with the use of glucocorticoids and beyond the third decade with ventilator support and multidisciplinary care. However, Duchenne muscular dystrophy is associated with comorbidities and is a fatal disease. Glucocorticoids prolong ambulation, but their side effects are significant. Emerging investigational therapies have surfaced over the past decade and have rapidly been tested in clinical trials. Gene-specific strategies include nonsense readthrough, exon skipping, gene editing, utrophin modulation, and gene replacement. Other mechanisms include muscle regeneration, antioxidants, and antifibrosis and anti-inflammatory pathways. With potential therapies emerging, early diagnosis is needed to initiate treatment early enough to minimize morbidity and mortality. Newborn screening can be used to significantly improve early diagnosis, especially for gene-specific therapeutics.
– DMD Duchenne muscular dystrophyDMD 1 (DMD),3 although rare, is the most common muscular dystrophy, with a prevalence of 1 in 5000. It is an X-linked disorder caused by a mutation in the gene located on Xp21. The gene is large (79 exons; 427 Kilodalton) and encodes a 427-Kilodalton muscle isoform protein dystrophin. The gene is located in the dystrophin-associated glycoprotein complex at the sarcolemma and in the cytoskeleton. The protein is located primarily in4,5 skeletal muscle to stabilize the plasma membrane and maintain the strength of muscle fibers. The absence of dystrophin causes muscle membrane damage, elevated serum creatinine kinase (CK), aMassachusetts General Hospital and Harvard Medical School, Harvard University, Cambridge, Massachusetts; cUniversity of Ferrara, Ferrara, Italy; dHolland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada; eJohn Walton Centre for Muscular Dystrophy Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; fNemours Children’s Health System, Orlando, Florida; gChildren’s National Health System, Washington, District of Columbia; hKennedy Krieger Institute, Baltimore, Maryland; and iSchool of Medicine, Johns Hopkins University, Baltimore, Maryland bSeattle Children's Hospital, University of Washington, Seattle, Washington
The guidelines or recommendations in this article are not American Academy of Pediatrics policy, and publication that was partially supported herein does not imply endorsement.
Dr Wagner served as the chairperson of the Duchenne Muscular Dystrophy Care Considerations Neuromuscular Management Working Group as convened by the Centers for Disease Control and Prevention and reviewed and revised the manuscript; Dr Leigh served in the Duchenne Muscular Dystrophy Care Considerations Neuromuscular Management Working Group as convened by the Centers for Disease Control and Prevention, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Biggar, Bushby, and Finkel served in the Duchenne Muscular Dystrophy Care Considerations Neuromuscular Management Working Group as convened by the Centers for Disease Control and Prevention, contributed to the development of corresponding recommendations, and reviewed and revised the manuscript; Drs Ferlini and Morgenroth served in the Duchenne Muscular Dystrophy Care Considerations Diagnostics Management Working Group as convened by the Centers for Disease Control and Prevention, contributed to the development of corresponding recommendations, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. DOI: https://doi.org/10.1542/peds.2018-0333C Accepted for publication Jul 26, 2018
Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number s2, October 2018:e20180333C SUPPLEMENT ARTICLE FIGURE 1 Summary of neuromuscular management depending on the clinical stage of patients with DMD. (Adapted with permission from Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):252.)
NEUROLOGY fiber necrosis, muscle degeneration, ventilatory support. The mean age 6 ∼ and regeneration. Constant at which patients lose ambulation 11 DMD is a proximal myopathy muscle breakdown and necrosis is is 9 to 10 years. Glucocorticoids affecting muscles, such as the followed by inflammatory processes are used to improve muscle strength 12 quadriceps and gluteals. Fast- that lead to the– replacement of and function in patients with DMD 13 twitch (type IIb) myofibers are muscle with fibrotic7 9 tissue and fat and prolong ambulation by an 14 preferentially affected, leaving accumulation. additional 2 to 3 years ; patients the slow-twitch18,19 (type I) type to Common presenting symptoms with DMD who are treated with predominate. The disease include delayed motor milestones, glucocorticoids become wheelchair is characterized by muscle inability to run or hop, toe walking, dependent by 12 to 13 years of age. wasting, weakness, myofiber size difficulty climbing stairs, and Loss of ambulation is associated variation with muscle necrosis, fat hypertrophy of calf muscles. with greater morbidity and mortality accumulation, connective tissue Nonmotor presentations include as the disease progresses; not replacement, and paradoxical failure to thrive, speech delay, surprisingly, the primary objective hypertrophy of calf muscles. Gait fatigue, abnormal transaminases, of researchers in most clinical abnormality and difficulty getting myoglobinuria, and complications trials is prolonging ambulation. up from a chair or from a supine because of anesthesia (ie, malignant Cardiomyopathy and respiratory position are common clinical hyperthermia or rhabdomyolysis). insufficiency can shorten the life features. However, the onset of symptoms can vary in age, severity, Global developmental delay is a span, but with ventilator support, common presentation. Early signs and presentation. Individuals survival in DMD has been extended and symptoms present at ages 2 to affected by DMD typically present to >30 years, and cardiac function 3 years, whereas the average age with delayed motor development is the remaining determinant of diagnosis is 3 to 5 years. It has 15 or a gait abnormality, especially been reported that it takes >1 year of survival. Investigational toe walking or delayed age of drugs that are used to improve to confirm DMD10 from the time of ambulation, and are often referred presentation, which is far too long cardiopulmonary function also to physical therapy. Although the in a disease for which time means have emerged in clinical trials (for average age of presentation ranges loss of muscle function and the additional details, see the specialty from 2 to 5 years, the recognition familial risk of recurrence is up to article on cardiac management16 that of loss of milestone and the use of 50% in male siblings. is part of this supplement ). Our Bayley Scales of Infant Development, purpose in this article is to guide Third Edition can improve the – With recent advancements in clinicians in the diagnosis and identification of affected infants 20 22 clinical trials, there is an unmet treatment of DMD itself, expanding before motor impairment occurs. need to diagnose affected infants 1 on principles outlined in the 2018 and children early. Mendell et al GLUCOCORTICOIDS Duchenne Muscular Dystrophy Care presented data on newborn screening in Ohio initiated with a CK level from Considerations sponsored by the dried blood spot followed by genetic Centers for 17Disease Control and Prednisone prolongs ambulation Prevention. In Fig 1, we provide an confirmation of11 those with elevated and has been shown to have long- overall guide for the neuromuscular CK. Eagle et al reported that life ’ term benefits for– respiratory and management of patients with DMD expectancy in the 1960s was 14 cardiac function12,13, 23 25 in nonambulatory years; in the 1990s, life expectancy according to each patient s clinical patients. Some researchers was 25 years for those receiving stage. suggest there may be fewer side Downloaded from www.aappublications.org/news by guest on September 25, 2021 S6 LEIGH et al effects with 26,deflazacort27 than prednisone. However, the relative efficacy and side effects of different glucocorticoid regimens remains untested in well-designed, head-to-head trials. The standard dose for prednisone is 0.75 mg/kg per day and for deflazacort is 0.9 mg/kg per day (Fig 2). For a more detailed discussion on glucocorticoid management, see the Supplemental Information. DIAGNOSIS
ClinicalDMD variability, genetic heterogeneity, and the large size of the gene contribute to the complexity of diagnosis (Fig 3). Mutational analysis has made the confirmation of a molecular diagnosis possible in the majority of cases. However, diagnosis and prognosis are also dependent on clinical presentation and genetic profile. Genotype-phenotype correlation can help prognosticate, but age of presentation and family history are FIGURE 2 also important. For example, most Care considerations for glucocorticoid (steroid) initiation and use for patients with DMD. ACTH, exon deletions are correlated with adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary- “ ” adrenal. (Reproduced with permission from Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and disease severity on the basis of the ∼ management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, reading-frame28 rule and apply to endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):255.) 92% of cases. The vast majority of whole-exon deletions or duplications are correlated with a pathogenic mutation. The reading-frame stop biopsies were routinely performed to transcription testing to identify codon caused by an out-of-frame diagnose DMD. With advancements intronic changes. – mutation disrupts the open reading in genetic testing strategies, including In a child with a family history frame and ablates the translation multiplex ligation dependent probe DMD of DMD, a serum CK level is of dystrophin, causing a more amplification, comparative genomic recommended. In a child without severe phenotype. An in-frame hybridization, Sanger sequencing, a family history, the presence mutation can still translate the open and next-generation sequencing, of global development delay, reading frame to a partial-length a molecular diagnosis can be psychomotor delay, and/or dystrophin, resulting in Becker – obtained from genomicDMD DNA so that motor delay prompts a serum CK muscular dystrophy and a milder 29 muscle biopsies are rarely needed level (CK is elevated 50 100 times phenotype. In some cases, in-frame to diagnose DMD. If a gene normal in DMD). The liver enzymes, mutations with worsening myopathy mutation cannot be identified by aspartate aminotransferase, are more clinically consistent with using genetic testing, clinicians may and alanine aminotransferase DMD. choose to perform a muscle biopsy are also elevated but from the γ The methods used to diagnose DMD to determine the percentage of muscle instead of the liver. include clinical history, physical dystrophin by using histopathological -glutamyl transferase is the examination, serum CK, liver staining and immunoblot analysis. preferred laboratory test to enzymes, genetic testing, and perhaps If dystrophin staining is equivocal, check for liver disease in DMD. muscle biopsy. In the past, muscle the muscle can be sent for RNA If CK is elevated, then DNA should Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number s2, October 2018 S7 TABLE 1 Types of DMD Mutation Mutation % Deletions 65 Duplications 6–10 Point mutations 25 Complex mutations <2
evolution of next-generation sequencing has enabled the sequencing of millions of copies of
DNA fragments simultaneously32 and has reduced time and cost. If the deletion and/or duplication test result is negative, then sequencing is conducted to identify smaller mutations. Sequencing the entire coding region can reveal small mutations, splicing mutations, or single base changes. If no mutation is identified after sequencing, a muscle biopsy can be obtained to determine the presence or absence of dystrophin by using histologic staining. The absence of dystrophin confirms a diagnosis of DMD. Reduced dystrophin could be associated with Becker muscular dystrophy or DMD depending on the presence and severity of muscle weakness on examination. ≥ Dystrophin <3% is consistent with DMD, whereas 20% on muscle biopsy suggests that DMD is unlikely. Some variation in muscle biopsy results occurs depending on the age of the child and what part of the affected muscle was biopsied. Alternatively, tissue from the muscle can be tested through RNA FIGURE 3 transcription analysis to assess for Diagnosis of Duchene muscular dystrophy. Described early signs and symptoms of DMD are based intronic mutations that may have on Ciafaloni et al.10 (Reproduced with permission from Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, been identified in the other genetic rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. strategiesDMD . Immunoblotting of the 2018;17(3):253.) muscle biopsy also can be used. If no mutation is identified, the clinician can consider an alternative diagnosis, such as limb-girdle or be sent to test for exonic deletions used technique and can be used congenital muscular dystrophy. ∼ and duplications, 30,which31 are seen to test all 79 exons. Comparative Imaging with quantitative magnetic in 65% of cases. Table genomic hybridization is an resonance and magnetic resonance 1 includes the types of gene oligoclonal-based method that spectroscopy reveal an increase in fat – 33,34 mutations in DMD. Multiplex can be used to detect complex fraction with disease progression. ligation dependent probe rearrangements, intronic 30alteration, Given the heterogeneity of affected amplification is the most widely or mutation break points. The skeletal muscle in DMD, an Downloaded from www.aappublications.org/news by guest on September 25, 2021 S8 LEIGH et al FIGURE 4 Drug discovery chart for DMD clinical trials. Illustrated is the active pace of drug discovery in DMD.
Restore Protein (Dystrophin)
MRI-guided muscle biopsy can be uses antisense oligonucleotides. ’ applied in the diagnosis and/or Two chemical constructs, Exon skipping and nonsense confirmation of DMD when genetic 2 -O-methyl phosphorothioate and readthrough can restore the testing is unrevealing. phosphorodiamidate morpholino expression of the gene product oligomers, have been used in dystrophin. These agents generate EMERGING THERAPIES clinical studies to bind to exon- a functional or partially functional ’ splice junctions and generate exon protein in DMD. 35,36 Exon Skipping skipping. The 2 -O-methyl phosphorothioate drug, drisapersen, Numerous treatment strategies have for exon 51 skipping, which initially been investigated for DMD. After The concept behind exon skipping showed improvement on the decades of searching for targets, is targeted at the messenger RNA 6-minute walk test in early clinical identifying molecular pathways, and level and is based on the reading- trials, progressed to a larger phase preclinical investigations in animal frame rule. The intent is to skip (or III study in which it did37, not38 reach models, potential therapeutic targets delete) an out-of-frame mutation its primary end point. The have been translated to clinical and restore the reading frame by phosphorodiamidate morpholino trials in DMD. In this section, we making an in-frame mutation that oligomers drug, eteplirsen, is also review some of the main strategies encodes a more functional protein designed for exon 51 skipping. – and active clinical trials. Figure 4 is that is consistent with the milder, Researchers in an initial study a chart of the potential drugs in the Becker muscular dystrophy like enrolled 12 patients for >3 years, and DMD drug discovery pipeline. phenotype. This technology these treated patients demonstrated Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number s2, October 2018 S9 TABLE 2 Exon Skipping–Amenable Mutations Exon Amenable to Skip % a slower rate of decline in ambulation an oral anti-inflammatory steroid – compared with untreated historical 51 13.0 with fewer side effects in preclinical 39,40 45 8.1 controls. Exon skipping and phase I trials compared with ∼ ∼ 53 7.7 amenable mutations constitute 44 6.2 traditional glucocorticoids, has 80% of all DMD, of which 13% 46 4.3 advanced to phase II in an ongoing, 52 4.1 of cases are41 amenable to exon 51 larger clinical trial to assess safety 50 4.0 Antioxidantsand efficacy. skipping (Table 2). Drisapersen 43 3.8 is administered subcutaneously, 6 and 7 3.0 and eteplirsen is delivered by 8 2.3 intravenous infusion. A drisapersen 55 2.0 Oxidative stress can damage cellular application to the US Food and function, specifically mitochondria. Drug Administration (FDA) was not Replace Lost Dystrophin The overproduction and/or approved, but eteplirsen was granted accumulation of reactive oxygen accelerated approval by the FDA species can lead to mitochondrial ∼ dysfunction in neuromuscular while an ongoing42 confirmatory study Utrophin is an analog of dystrophin– is underway. disease. Studies have revealed that that shares 80% sequence Nonsense Suppression 50 52 increased reactive oxygen species homology with dystrophin. in DMD contribute to membrane SMT C1100 is a molecule that permeability and protein degradation works as a utrophin modulator and and activates inflammatory is an investigational drug with the Nonsense mutations generate a pathways, thereby exacerbating potential to replace lost dystrophin stop codon, resulting in a truncated, 53 necrosis and fibrosis. Idebenone, with utrophin. Safety and nonfunctional protein. Nonsense an antioxidant that inhibits lipid ∼ tolerability has been shown in (stop-codon) mutations comprise43,44 54 peroxidation, has shown efficacy in a study of 12 patients with DMD. 10% to 15% of DMD cases. The a phase III trial, with improvement A phase II study is ongoing to readthrough strategy, which involves seen in respiratory function (ie, evaluate the activity and safety 57 the suppression of the stop-codon forced vital capacity). Idebenone of this orally administered drug mutation, encourages the ribosome is orally administered and currently Targetin a larger Signaling cohort Pathways of patients. to read through the stop codon, undergoingAntifibrosis regulatory review. which promotes45 the production of Anti-inflammatory Approaches dystrophin. Proof of concept for nonsense suppression was initially In DMD, endomysial fibrosis is a established 46with an aminoglycoside: Muscle fibers in DMD undergo hallmark clinical feature associated gentamicin. Translarna (ataluren), inflammatory and fibrotic changes with muscle weakness and poor β β an oral medication with a better that have been responsive to long-term outcome; transforming safety profile compared with glucocorticoids. As a result, anti- growth factor (TGF- ) is a target gentamicin (formerly referred to as inflammatory approaches to in antifibrosis therapy. Therapeutic β PTC124), promotes the readthrough treat DMD remain a focus in drug agents aimed at blocking cytokine of premature translation termination discovery. Myofiber necrosis is signaling by inhibiting the TGF- κ codons. Safety and tolerability was reported to result from chronic pathway in preclinical models α established, and a phase IIa proof- NF- B activation9,55, 56 and tumor necrosis have been shown– to decrease of-concept trial revealed increased factor . Prednisone and fibrosis in some58 61studies, although dystrophin47 posttreatment on muscle deflazacort, used to treat DMD, not in others. Losartan, an biopsy. Due to the unmet need for have anti-inflammatory effects antihypertensive drug with a known κ treatments in DMD and promising and are presumed to inhibit the safety profile, was an attractive early phase findings, this drug has NF- B pathways. However, these therapeutic target, but the preclinical been approved by 48the European drugs are generally nonspecific studies that initially revealed reduced Medicines Agency. A phase III anti-inflammatory agents with fibrosis later revealed minimal κ 62,63 trial revealed enrichment of effect multisystem side effects. New drugs functional benefit. Another agent, α in a subgroup of patients with a aimed at specifically targeting NF- B oral halofuginone hydrobromide baseline 6-minute walk test between49 or tumor necrosis factor are being (also known as HT-100), is currently 300 and 400 m at enrollment. moved forward in drug discovery and in a phase II trial to assess safety, However, the FDA voted that the are currently in the preclinical stages, tolerability, and dose selection for data used to support Translarna poised to move to clinical trials. future trials. Givinostat, an oral were inconclusive. Vamorolone (also known as VBP15), inhibitor of histone deacetylases Downloaded from www.aappublications.org/news by guest on September 25, 2021 S10 LEIGH et al aimed at reducing fibrosis of muscle I or II trials in ambulatory DMD transfer has addressed76,77 some of the fibers and promoting muscle patients. This agent is delivered technicalDMD barriers. However, AAV regeneration in DMD,64 is in a phase III Improvesubcutaneously Cardiac. Function has a limited capacity to package the globalPhosphodiesterase clinical trial. 5A Inhibition Geneentire Replacement gene. DMD CAP-1002 is a novel therapeutic Diminished blood flow can cause65,66 approach in which cell therapy is In DMD, the large size of the muscle damage. Mendell et al used to treat cardiomyopathy in gene poses the challenge of packagingDMD showed in the mouse model that DMD. This investigational treatment into an AAV. Mini-dystrophins (ie, functional ischemia produces is already being investigated as miniaturized versions of the78, 79 similar changes seen in muscle fiber a treatment of postmyocardial gene) have been developed. degeneration and regeneration in infarction. The agent is an allogenic Investigators also have packaged the DMD. Researchers in more studies cell therapy derived from human gene into 2 vectors in a dual-AAV have since implicated the nitric oxide heart tissue that is administered approach and showed that it restored synthase pathway in ischemia and directly to the heart through sarcolemmal neuronal nitric oxide thus inhibition of phosphodiesterase the coronary arteries by cardiac synthase expression80 in dystrophin- (PDE) 67as a potential therapeutic catheterization. This drug is currently deficient mice. Transgene delivery target. Sildenafil, an oral in the phase I or II study stage to by an AAV through intramuscular PDE 5 inhibitor, was studied in investigate safety and tolerability. injection in a phase I clinical trial adult patients with DMD and in humans revealed an immune cardiomyopathy. The trial was Eplerenone, a drug that is already response to the transgene product, terminated early due to worsening used in heart failure and has a known bringing attention to the role of safety profile, has been investigated left-ventricular end-systolic68 volume T-cell immunity to self- and nonself- in a randomized, placebo-controlled in subjects on sildenafil. Tadalafil, dystrophin in the study design81 of another oral PDE inhibitor, was clinical trial in patients with DMD future gene therapy trials. Limb and early cardiomyopathy who shown to restore blood supply to vascular delivery is another method82 muscle in the mdx mouse. However, are already taking an angiotensin- to regionally deliver the gene. tadalafil had no effect on the primary converting enzyme inhibitor. After Systemic delivery can be achieved outcome and did not lessen the 12 months, it was reported that a intravenously, but targeting the gene statistically significant reduction in decline in ambulatory69 ability in to muscle and limiting its off-target patientsMyostatin with Inhibition DMD. left-ventricular strain occurred in delivery are important aspects of the the treatment73 arm compared with gene delivery. Although gene therapy a placebo. Although long-term is still in early stages, the knowledge The inhibition of the myostatin benefits cannot be concluded from gained from the pioneering work pathway is a muscle-building these findings, longitudinal data of many dedicated investigators therapeutic approach for muscular from this cohort will provide greater over several decades has taken the dystrophy. Myostatin regulates insight on the potential benefit of this field closer to becoming a potential muscle growth by breaking down cardiac intervention in DMD. Results therapy. Phase I and II studies to muscle protein, and blocking after a 2-year study revealed that deliver microdystrophin C with AAV myostatin has been shown to eplerenone can be cardioprotective74 vectors are anticipated to begin this inRestore patients Gene with Function DMD. Gene Editing increase70, muscle71 mass and72 reduce year. fibrosis. Wagner et al conducted an early phase clinical trial in adult patients with muscular dystrophy In a monogenetic disorder, such as A novel genetic engineering “ ” using a recombinant human antibody DMD, the idea of replacing a defective technology, clustered regularly and showed safety, although not gene with a corrected gene seems interspaced short palindromic efficacy. New strategies and the simple, but many challenges have repeats (CRISPR) coupled with an formulation of an antimyostatin been encountered to date. Strategies endonuclease (CRISPR-associatedDMD antibody, PF-06252616, have since on how to target the desired muscle, protein 9), has been applied to occurred, and the agent is being circumvent the immune response, edit mutations in the gene. used in an ongoing phase II clinical and achieve efficient systemic Researchers in several laboratories trial in patients with DMD. This delivery75 are some of the major have reported that gene editing can agent is delivered intravenously. hurdles. The discovery of an adeno- be used to improve muscle function Similarly, an antimyostatin adnectin, associated virus (AAV) to be a safe in the mouse model and muscle BMS-0986089, is currently in phase and effective therapeutic tool in gene stem cells. Investigators have shown Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 142, number s2, October 2018 S11 that the editing tool was used– to as possible. Care centers will need intervention are necessary. As the resect the faulty exons and83 87 partially to incorporate health service translational community shepherds restore protein in mice. The considerations into their care plans. novel therapeutics into the clinic, “ ” mice treated with CRISPR did better The molecular diagnoses stored other initiatives are equally important, on functional tests compared with in unified databases, which including newborn screening, the untreated group but not as well include molecular profiles and well- management strategies for infants and as the normal mice. Although gene characterized phenotypes, can be toddlers, neurobehavioral management editing with CRISPR is closer to used to augment the identification for school-aged children, transition clinical translation now than ever and selection of more homogeneous management, and adult considerations before, it may be years before these candidates for specific therapies for affected men. Newborn screening technologies achieve efficiency as gene-derived strategies are and effective treatments may towardTarget Genetic clinical Modifierstrials. translated to the clinics. As genetic ultimately extend survival in DMD modifiers are validated, biomarkers beyond the third decade. and novel therapeutic targets can ACKNOWLEDGMENT The vast clinical variability in DMD be developed. Putative disease- is well known, and environmental modifying strategies related to factors can contribute to the genetic cardiac function and neuronal We thank Joan Scott (acting modifier effect and heterogeneity involvement in DMD warrant further director, Division of Services for β of phenotypic features. Latent exploration for novel targets. Children with Special Health Needs, CONCLUSIONS TGF- binding proteinSPP1 4 can be Maternal and Child Health Bureau, used to predict88, the89 age of loss DMD ∼ Health Resources and Services of ambulation. , a gene Administration), who served on the encoding osteopontin, acts as a The gene was identified 3 Duchenne Muscular Dystrophy Care decades ago, and the presteroid pharmacodynamic89 biomarker of Considerations steering committee era changed after prednisone was steroidANXA6 response. These 2 pathways 12 and diagnostic subcommittee. β shown to prolong ambulation. converge in the regulation of ABBREVIATIONS TGF- . encodes annexin A6, Glucocorticoids remain the standard a calcium-binding protein, and is of care, but significant side effects correlated with sarcolemmal repair limit their therapeutic window. 90,91 AAV: adeno-associated virus in the mouse model. These As survival has improved with the CK: creatinine kinase modifier genes are correlated with launch of specialized care centers CRISPR: clustered regularly phenotypic variation and serve as and better respiratory support, interspaced short novel therapeutic targets for future cardiac disease has become a more palindromic repeats drug discovery. important cause of death. The DMD: Duchenne muscular FUTURE DIRECTIONS majority of the investigational drugs dystrophy improve skeletal and pulmonary FDA: Food and Drug function, and cardiomyopathy Administration As disease-modifying treatments remains a critical area in need of β PDE: phosphodiesterase emerge, patients with DMD will effective treatment. Furthermore, β TGF- : transforming growth live longer, and they will need to be addressing neurodevelopmental factor prepared to live as independently needs and providing early
Address correspondence to Fawn Leigh, MD, Seattle Children's Hospital, University of Washington, 4800 Sandpoint Way NE, M/S MB.7.420, Seattle, WA 98105. Email: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Other than those listed under potential conflict of interest, the authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported in part by Cooperative Agreement NU38OT000167, funded by the Centers for Disease Control and Prevention. POTENTIAL CONFLICT OF INTEREST: Dr Leigh has served as a consultant to Sarepta Therapeutics and Summit Therapeutics and as principal investigator on clinical research grants sponsored by Sarepta Therapeutics, Pfizer, Atlas 5D, and Solid Biosciences; Dr Bushby has given expert advice to Solid Ventures, Gerson Lehrman Group research, Catabasis Pharmaceuticals, Bristol-Myers Squibb, PTC Therapeutics, BioMarin Pharmaceutical, and Laboratory of the Government Chemist Ltd and has received a grant and speaker fees from PTC Therapeutics; Dr Finkel has received grant support for Duchenne muscular dystrophy–related
Downloaded from www.aappublications.org/news by guest on September 25, 2021 S12 LEIGH et al topics from Bristol-Myers-Squib, Catabasis Pharmaceuticals, the National Institutes of Health, Eli Lilly and Company, the Muscular Dystrophy Association, PTC Therapeutics, ReveraGen BioPharma, Santhera Pharmaceuticals, Sarepta Therapeutics, and Summit Therapeutics and has served as a paid consultant to Catabasis Pharmaceuticals, Eli Lilly and Company, PTC Therapeutics, Sarepta Therapeutics, and Summit Therapeutics, and none of these relationships are directly related to Dr Finkel’s participation in this activity or article; the other authors have indicated they have no potential conflicts of interest to disclose.
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Downloaded from www.aappublications.org/news by guest on September 25, 2021 Neurology Care, Diagnostics, and Emerging Therapies of the Patient With Duchenne Muscular Dystrophy Fawn Leigh, Alessandra Ferlini, Doug Biggar, Katharine Bushby, Richard Finkel, Lauren P. Morgenroth and Kathryn R. Wagner Pediatrics 2018;142;S5 DOI: 10.1542/peds.2018-0333C
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