NEUROMUSCULAR DISORDERS Duchenne Muscular Dystrophy Well‑established corticosteroid therapy prolongs life, and potentially curative new treatments are in development. By Craig Zaidman, MD

Duchenne muscular dystrophy (DMD) is an proteins, the central helical coiled rod region confers flex‑ inherited X‑linked recessive severe progres‑ ibility and elasticity, the WW domain binds intracellular sive muscle disease affecting 1 in 5,000 boys. signal transduction proteins, and the N‑terminus binds to Mutations in the dystrophin gene on the X F‑actin, one of the major components of the internal scaf‑ chromosome cause a lack of functional dystro‑ folding cytoskeleton.2 Loss of dystrophin function impairs phin, which results in progressive replacement several key structural elements that are required for muscle of muscle fibers with fat and fibrotic tissue. Boys who have fiber function. Muscle cell membrane stability is lost, result‑ DMD often have delayed ambulation and develop progressive ing in damage to the muscle membrane from mechanical weakness and loss of muscle that is typically noticed in the stress, abnormal signaling pathways cause chronic inflam‑ first 2 to 3 years of life. Most boys lose the ability to walk by matory changes, and loss of the nitric oxide‑signaling (NOS) age 12 years, which is followed by progressive restrictive lung pathways results in functional muscle ischemia. The final disease and cardiomyopathy. Eventually, assisted ventilation is common pathway is muscle fibrosis, replacement of muscle needed and death often occurs in the second to third decade fibers by fat, and muscle weakness. Primary therapeutic tar‑ of life. Multidisciplinary care is required as needs change gets aim to correct or improve the production of functional throughout the lifespan (Table 1).1 dystrophin. Secondary therapeutic targets aim to improve downstream effects of inflammatory and antioxidant path‑ Pathophysiology ways, muscle blood flow, calcium homeostasis, muscle fiber The dystrophin gene is the largest known human gene, size and function, and connective tissue and fibrosis. encompassing 2.4Mb at loci Xp21.2. Isoforms of the dystro‑ phin protein are expressed in skeletal and cardiac muscle, Treatments the brain, and the retina. The skeletal muscle‑specific iso‑ Corticosteroids form is a 427 kDa protein that spans the cell membrane and Corticosteroid Efficacy. Corticosteroids are the most com‑ has 4 distinct domains. The C‑terminus binds extracellular monly used therapy for therapy for DMD (Table 2) since it

TABLE 1. SUMMARY OF MONITORING AND TREATMENT FOR DUCHENNE MUSCULAR DYSTROPHY Early Ambulatory Late Ambulatory Early Non‑Ambulatory Late Non‑Ambulatory Ensure immunizations up to date including annual influenza and pneumococcal vaccine Initiate and continue corticosteroids, stress dose, prescription, and instructions Monitor height and weight every 6 months Monitor pubertal development beginning at age 9 years Annual assessments of calcium and 25‑OH vitamin D and supplement as needed Annual pulmonary assessments, sleep study if clinically indicated Pulmonary assessment every 6 months and consult pulmonlogy for cough assist and assisted ventilation Annual cardiac assessment (Echocardiogram or cardiac MRI) Assess for rhythm abnormalities Ace inhibitor therapy (initiate before age 10 years) Lateral spine X‑rays very 1‑2 years if on steroids, every 2‑3 years if not Annual scoliosis monitoring Scoliosis monitoring every 6 months Start daily stretching, physical therapy and orthotics Orthopedic referral for contracture / scoliosis management as indicated

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by 2 years more than prednisone treatment.13 A recent TABLE 2. STEROID MANAGEMENT FOR DUCHENNE meta‑analysis also identified a functional advantage of MUSCULAR DYSTROPHY deflazacort with slower disease progression over 48 weeks Steroid Dose compared with prednisone/prednisolone treatment. A Prednisone 0.75mg / kg / day or 10mg / kg divided single center retrospective study also found a 2‑year benefit prednisolone Saturday / Sunday on maintained ambulation with deflazacort.14 Importantly, Deflazacort 0.9mg / kg / day about one‑third of participants in these comparison stud‑ ies who were treated with prednisone were treated with an intermittent dosing regimen, whereas more than 90% of the Side Effects Management boys treated with deflazacort had daily dosing. Weight gain Monitor weight, nutritional goals, calorie Corticosteroid Side Effects. Chronic corticosteroid use is counts, and consult dietitian associated with numerous side effects in children includ‑ Growth or Monitor growth, consult endocrinology for ing delayed puberty, reduced height velocity, weight gain, puberty delay testosterone, human growth hormone osteoporosis and fractures, adrenal suppression, cataracts, Bone Monitor and supplement calcium and vita‑ and behavior changes (Table 2). Alternatives to daily dos‑ demineralization min D, weight bearing activity, bisphospho‑ ing of prednisone have been studied in an effort to mitigate nate therapy, consult endocrinology these side effects while maintaining functional gains. Twice weekly dosing of prednisone (10 mg / kg divided Saturday Behavior changes Adjust dosing regimen, consult psychology and Sunday) results in greater linear growth with equivalent Cataracts Consult ophthalmology improvements in strength compared with 0.75 mg / kg given Adrenal Discuss signs / symptoms and management daily over 12 months.15 Other intermittent treatment regi‑ insufficiency action plan including supplemental steroids, mens are less well established or effective. A trial of intermit‑ endocrinology consult tent treatment of prednisone 0.75 mg / kg / day for the first 10 days of every month is superior to placebo over 6 months was shown in 1974 that 13 of 14 boys treated with prednisone in 17 boys.16 Alternate‑day prednisone dosing, however, does daily had improvements.3 Widespread use of prednisone fol‑ not maintain the same benefits for strength seen with daily lowed after the first placebo‑controlled trial in 103 boys with dosing over 6 months.4 The American Academy of Neurology DMD. This trial confirmed efficacy for improving strength (AAN) practice parameter recommends 0.75 mg / kg / day and function at doses of 0.75 or 1.5 mg / kg / day without clear prednisone as the preferred dosing regimen but recognizes additive benefit at the higher dose.4 A later trial confirmed that 10 mg / kg / weekend is equally effective over 1 year with maximal efficacy of 0.75 mg / kg / day compared with the insufficient data for comparison of long term outcomes.17 higher dose.5 The largest study of corticosteroids for DMD Deflazacort causes less sodium retention and interference (5,345 participants) showed continuous corticosteroid use with carbohydrate metabolism compared with prednisone. prolonged ambulation by 3 years, reduced scoliosis surgery, There is less weight gain with deflazacort than with predni‑ and delayed use of assisted ventilation.6 Corticosteroids main‑ sone (5% vs 18%) and more frequent behavior abnormali‑ tain pulmonary function and upper extremity function even ties with prednisone.11 Increased side effects of deflazacort after loss of ambulation,7‑9 and in infants and young children, include growth retardation, cushingoid appearance, and may also reduce gross motor delay.10 cataracts.12,14 Although deflazacort may be associated with Deflazacort is a corticosteroid approved for DMD by the functional gains compared with prednisone, benefits are Food and Drug Administration (FDA). Several comparison tempered by increased growth retardation, cataracts, and studies demonstrated slightly greater efficacy of deflazacort significantly higher cost. compared with prednisone, although side effects are still Vamorolone is a synthetic “dissociative” steroid that binds present, and some are increased. In a 52‑week trial of to the corticosteroid receptor but does not have the unwant‑ deflazacort at 0.9 or 1.2 mg / kg / day compared with pred‑ ed downstream side effects. Preliminary results from studies nisone at 0.75 mg / kg / day, boys treated with deflazacort of vamorolone show that daily treatment over 6 months had slightly higher muscle strength than boys treated with improved muscle function without most of the glucocorticoid prednisone with no difference between the high vs low related side effects,18 and a phase 2b study comparing treat‑ dose of deflazacort.11 A large natural history study (n=340) ment with vamorolone with daily prednisone is underway.a reaffirmed that treatment over more than 1 year with cor‑ ticosteroids, including deflazacort, delays ambulation loss Antioxidants by 3 years,12 and in a prospective cohort study of 440 par‑ Coenzyme Q10 has been studied in small cohort of boys ticipants, deflazacort treatment delayed loss of ambulation with DMD who are also being treated with corticosteroids a A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)(NCT03439670).

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treated patients. Escalating doses beginning at 400 mg / day ing it nonfunctional. Gentamicin is thought to promote a and ranging from between 8.7 to 48.4 mg / kg / day thereafter “read‑through” of the during transcrip‑ are being used to achieve the targeted serum concentra‑ tion to produce more full‑length dystrophin mRNA, and tions. There are 12 children who completed this 6‑month thus more functional protein. In a 2‑week trial, 10 boys trial and had marginal gains in quantitative motor strength with DMD treated with gentamicin had a 50% reduction in (~1 pound) but no improvements in timed‑walk, stair‑climb, creatine kinase (CK) levels. Subsequently, 16 boys treated or cardiac measures.19 In a randomized placebo‑controlled with gentamicin for 6 months had a 0% to 15% increase phase 3 trial in 64 boys with DMD aged 10 to 18 years, treat‑ in dystrophin from baseline.25 Ataluren also promotes ment for 1 year with idebenone, a synthetic coenzyme Q10 read‑through of nonsense mutations but has had disap‑ analog, improved respiratory function. Idebenone attenuated pointing results in clinical trials. In a randomized , the decline in the percent predicted peak expiratory flow by those treated with ataluren for 48 weeks at 40 mg / kg / day 6% and in the percent predicted forced vital capacity (FVC) were able to walk 31.3 feet further than those treated with by 3% compared with placebo.20 An open‑label extension placebo on a 6‑minute timed walk test (6MWT), but there study showed continued use of idebenone was associated was no difference in walking distance with 80 mg / kg / day with a 50% reduction in the expected annual decline in per‑ vs placebo.26 Ataluren was conditionally approved in the cent predicted FVC that was sustained for up to 6 years.21 A European Union. In a subsequent study of 6 months of phase 3 study of idebenone is underway.b treatment with 40 mg / kg / day of ataluren vs placebo (n=230), preplanned subgroup analysis showed treatment Vitamin D and Calcium with ataluren vs placebo resulted in improvement on the Reduced bone mineral density and increased risk of verte‑ 6MWT only for those who had a baseline 6MWT distances bral and long bone fractures ae associated with DMD. These of 300 to 400 m,27 although other functional outcomes risks are exacerbated by exposure to chronic corticosteroids. trended toward improvement. Open‑label long‑term exten‑ Supplementation with 25‑hydroxy‑vitamin D3 (calcifediol) sion studies are continuing. A recent comparison of boys increased bone mineral density in boys with DMD.22 Practice taking ataluren showed prolonged ambulation compared parameters support routine monitoring of bone health with with matched natural history controls.28 lateral spine X‑rays and dual‑energy X‑ray absorptiometry Exon Skipping. Most mutations in the dystrophin gene (DEXA) scans, and monitoring levels of calcium, and levels are frameshift deletions, leading to prematurely truncated of 25‑hydroxy‑vitamin D (ideal level of 30 ng / mL). Vitamin mRNA and nonfunctional dystrophin. Exon skipping is a D3 supplementation is suggested at 1,000‑4,000 IU daily therapeutic intervention that targets pre‑mRNA splicing depending on the degree of insufficiency. Calcium supple‑ to restore the reading frame. Exon skipping can produce mentation is recommended if daily dietary intake is lower a modified but stable and functional dystrophin protein, than the 1,000‑1,300 mg recommended daily allowance. missing some internal domains but containing the critical binding domains, similar to what is seen in Becker muscu‑ Angiotensin‑Converting Inhibitors and Cardiac lar dystrophy. Antisense oligonucleotides (ASO) are small Protection (8‑50 base) nucleic acid chains designed to join with cor‑ Progressive cardiomyopathy is a leading cause of mortal‑ responding bases in the pre‑mRNA to induce removal of ity in DMD. Early treatment with angiotensin‑converting 1 or more targeted exons by DNA ligase and thus restore enzyme (ACE) inhibitors before onset of cardiac dysfunc‑ the reading frame. Of known DMD genotypes, 60% to 80% tion improves long‑term mortality in DMD. In a study of are amenable to exon skipping; the most common are boys age 9 to 13 years who did not have cardiac dysfunction exons 51 (13%), 45 (8%), and 53 (8%). Candidate therapies (ejection fraction [EF] >55%), those treated with perindopril have thus far targeted these more common genotypes. (n=28) for 3 years longer than boys initially treated with is an intravenously administered ASO placebo (n=29) had higher 10‑year survival rates (93% vs (30 mg / kg weekly) that induces exon 51 skipping and could 65.5% survival).24 Based on this finding, initiation of an ACE potentially treat 13% of people with DMD. Eteplirsen is a inhibitor or angiotensin receptor blocker before age 10 years first‑in‑class drug, approved by the FDA based primarily is recommended in DMD. on a modest 0.9% increase in dystrophin in 11 boys after 180 weeks of therapy.28 Extensions studies showed improved Genetic Modulators 6MWT distances over 3 years compared with historic con‑ Nonsense Mutation Read Through. In 10% to 15% of trols matched for age and genotype,29 and stabilization of boys with DMD, the mutation in dystrophin results in a pulmonary function.30 The FDA has requested additional nonsense codon that shorten the resulting protein, render‑ clinical studies to demonstrate clinical benefits as part of its

b A Phase III Double‑blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids (SIDEROS)(NCT02814019) c A Study to Compare Safety and Efficacy of a High Dose of Eteplirsen in Duchenne Muscular Dystrophy (DMD) Patients (MIS51ON)(NCT03992430) d Study for Dose Determination of SRP‑5051, Then Dose Expansion in Patients With Duchenne Muscular Dystrophy Amenable to Exon 51‑Skipping Treatment (MOMENTUM)(NCT04004065)

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7. Pane M, Fanelli L, Mazzone ES, et al. Benefits of glucocorticoids in non‑ambulant boys men with Duchenne muscular dystrophy: a conditional approval. The European Medicines Agency has multicentric longitudinal study using the Performance of Upper Limb test. Neuromuscul Disord. 2015;25(10):749‑753. not approved eteplirsen. A clinical trialc is comparing high 8. McDonald CM, Gordish‑Dressman H, Henricson EK, et al. Longitudinal pulmonary function testing outcome measures in Duchenne d muscular dystrophy: long‑term natural history with and without glucocorticoids. Neuromuscul Disord. 2018;28(11):897‑909. and low doses of eteplirsen, and a phase 2 trial is testing 9. Connolly AM, Florence JM, Zaidman CM, et al. Clinical trial readiness in non‑ambulatory boys and men with duchenne muscular a similar ASO with an added small peptide modifier in the dystrophy: MDA‑DMD network follow‑up. Muscle Nerve. 2016;54(4):681‑689. 10. Connolly AM, Zaidman CM, Golumbek PT, et al. Twice‑weekly glucocorticosteroids in infants and young boys with Duchenne oligomer backbone. muscular dystrophy. Muscle Nerve. 2019;59(6):650‑657. and are ASOs similar in structure to 15. Escolar DM, Hache LP, Clemens PR, et al. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 2011;77(5):444‑452. eteplirsen that induce skipping exons 45 and 53, respectively, 11. Griggs RC, Miller JP, Greenberg CR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular potentially treating 8% of DMD each. Golodirsen (30 mg / kg dystrophy. Neurology. 2016;87(20):2123‑2131. 12. Bello L, Gordish‑Dressman H, Morgenroth LP, et al. Prednisone prednisolone and deflazacort regimens in the CINRG weekly intravenous infusion) was approved by the US FDA Duchenne Natural History Study. Neurology. 2015;85(12):1048‑1055. in 2019 based on a modest 1.0% improvement in dystrophin 13. McDonald CM, Henricson EK, Abresch RT, et al. Long‑term effects of glucocorticoids on function, quality of life, and survival in 31 patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet. 2018;391(10119):451‑461. levels after 48 weeks of treatment. Viltolarsen is an exon 45- 14. Marden JR, Freimark J, Yao Z, Signorovitch J, Tian C, Wong BL. Real‑world outcomes of long‑term prednisone and deflazacort targeting ASO that has a different structure from golodirsen.32 use in patients with Duchenne muscular dystrophy: experience at a single, large care center. J Comp Eff Res. 2020;9(3):177‑189. 16. Beenakker EA, Fock JM, Van Tol MJ, et al. Intermittent prednisone therapy in Duchenne muscular dystrophy: a randomized After 20 to 24 weeks of viltolarsen treatment, average dystro‑ controlled trial. Arch Neurol. 2005;62(1):128‑132. phin level increased to 5.7% of normal and all 16 participants 17. Moxley RT, 3rd, Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the e,f Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology had improved timed functional testing. Viltolarsen and Society. Neurology. 2005;64(1):13‑20. casimersen are inclinical trials.g,h 18. Hoffman EP, Schwartz BD, Mengle‑Gaw LJ, et al. Vamorolone trial in Duchenne muscular dystrophy shows dose‑related improvement of muscle function. Neurology. 2019;93(13):e1312‑e1323. 19. Spurney CF, Rocha CT, Henricson E, et al. CINRG pilot trial of coenzyme Q10 in steroid‑treated Duchenne muscular dystrophy. Muscle Nerve. 2011;44(2):174‑178. 20. Buyse GM, Voit T, Schara U, et al. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not The large size of the dystrophin gene prevents packaging using glucocorticoids (DELOS): a double‑blind randomised placebo‑controlled phase 3 trial. Lancet. 2015;385(9979):1748‑1757. into a viral vector as is typically done for gene replacement. 21. Servais L, Straathof CSM, Schara U, et al. Long‑term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy. Neuromuscul Disord. 2020;30(1):5‑16. Instead, a microdystrophin transgene has been designed to 22. Bianchi ML, Morandi L, Andreucci E, Vai S, Frasunkiewicz J, Cottafava R. Low bone density and bone metabolism alterations in produce a modified dystrophin with the essential compo‑ Duchenne muscular dystrophy: response to calcium and vitamin D treatment. Osteoporos Int. 2011;22(2):529‑539. 23. Ward LM, Hadjiyannakis S, McMillan HJ, Noritz G, Weber DR. Bone health and osteoporosis management of the patient with nents for function. In a nonrandomized cohort trial, 4 boys Duchenne muscular dystrophy. Pediatrics. 2018;142(Suppl 2):S34‑S42. received a single intravenous infusion of the microdystro- 24. Duboc D, Meune C, Pierre B, et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ 33 follow‑up. Am Heart J. 2007;154(3):596‑602. phin. After 12 weeks, the mean microdystrophin expres‑ 25. Malik V, Rodino‑Klapac LR, Viollet L, et al. Gentamicin‑induced readthrough of stop codons in Duchenne muscular sion was 95.8% of normal dystrophin levels after adjusting dystrophy. Ann Neurol. 2010;67(6):771‑780. 26. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. for fat or fibrosis; at 1 year functional improvements were 2014;50(4):477‑487. seen and CK levels were reduced compared with baseline. A 27. McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT i DMD): a multicentre, randomised, double‑blind, placebo‑controlled, phase 3 trial. Lancet. 2017;390(10101):1489‑1498. phase 3 clinical trial is underway. 28. Mercuri E, Muntoni F, Osorio AN, et al. Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study. J Comp Eff Res. Apr 2020;9(5):341-360. 29. Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and Conclusion dystrophin production. Neurology. 12 2018;90(24):e2146‑e2154. Corticosteroid therapy, with either daily or weekend 30. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79(2):257‑271. prednisone or daily deflazacort, is the most well‑estab‑ 31. Khan N, Eliopoulos H, Han L, et al. Eteplirsen treatment attenuates respiratory decline in ambulatory and non‑ambulatory lished therapy for DMD. Steroid‑related side effects are patients with Duchenne muscular dystrophy. J Neuromuscul Dis. 2019;6(2):213‑225. 32. Frank DE, Schnell FJ, Akana C, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular common and require routine monitoring. Recent advances dystrophy. Neurology. 2020;94(21):e2270‑e2282. in exon‑skipping treatments show promise, although FDA 33. Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with Duchenne muscular dystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol. 2020. approved exon‑skipping therapies only marginally improve 34. Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro‑dystrophin in children dystrophin production. Other therapeutic avenues to with Duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. 2020. restore dystrophin, including adenovirus vector delivery of microdystrophin, are in clinical trials and hold promise for Craig Zaidman, MD improving the lives of boys and young men with DMD. n Associate Professor

1. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and Department of Neurology neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251‑267. Divisions of Child Neurology and Neuromuscle 2. Koenig M, Monaco AP, Kunkel LM. The complete sequence of dystrophin predicts a rod‑shaped cytoskeletal protein. Cell. 1988;53(2):219‑228. Washington University in St. Louis School of Medicine 3. Drachman DB, Toyka KV, Myer E. Prednisone in Duchenne muscular dystrophy. Lancet. 1974;2(7894):1409‑1412. St. Louis, MO 4. Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double‑blind six‑month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med. 1989;320(24):1592‑1597. 5. Griggs RC, Moxley RT, 3rd, Mendell JR, et al. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time Disclosures course and dose response. Arch Neurol. 1991;48(4):383‑388. 6. Koeks Z, Bladen CL, Salgado D, et al. Clinical outcomes in Duchenne muscular dystrophy: a study of 5345 patients from the CZ has disclosures at www.practicalneurology.com TREAT‑NMD DMD Global Database. J Neuromuscul Dis. 2017;4(4):293‑306.

e The Expanded Access Use of Viltolarsen in Duchenne Muscular Dystrophy With Confirmed Exon 53 Amenable Mutation (NCT04337112) f Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys With DMD (RACER53)(NCT04060199) g A 48‑Week, Open Label, Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects With Duchenne Muscular Dystrophy Carrying Eligible DMD Duplications (NCT04179409) h An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy (NCT03532542) i A Randomized, Double‑blind, Placebo‑controlled Study of SRP‑9001 for Duchenne Muscular Dystrophy (DMD)(NCT03769116) JULY/AUGUST 2020 PRACTICAL NEUROLOGY 23