research paper on duchenne muscular dystrophy

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The FDA and Gene Therapy for Duchenne Muscular Dystrophy

• 1 Institute for Clinical and Economic Review, Harvard Medical School, Boston, Massachusetts
• Research Letter Spending on Targeted Therapies for Duchenne Muscular Dystrophy Liam Bendicksen, BA; Aaron S. Kesselheim, MD, JD, MPH; Benjamin N. Rome, MD, MPH JAMA
• Original Investigation Patient Characteristics in Novel Muscular Dystrophy Drug Trials vs Routine Care Dongzhe Hong, PhD; Jerry Avorn, MD; Richard Wyss, PhD; Aaron S. Kesselheim, MD, JD, MPH JAMA Network Open

The US Food and Drug Administration (FDA) grants accelerated approval that includes the standard of a surrogate outcome that is “reasonably likely” to predict clinical benefit. 1 Gene therapy for Duchenne muscular dystrophy represents a test case for whether the FDA can appropriately apply accelerated approval to a novel gene therapy.

Duchenne muscular dystrophy is a fatal, X-linked neuromuscular disease that results in progressive loss of muscle function. It is caused by alterations in the dystrophin gene ( DMD ) that reduce dystrophin protein production to less than 3% of the normal level. 2 Signs of Duchenne muscular dystrophy usually occur in early childhood. Symptoms include muscle weakness, clumsiness, and difficulty going up and down stairs; untreated children usually progress to a loss of ambulation by 10 years of age. 2 Fatal respiratory or cardiac complications commonly develop in the second or third decade of life. Duchenne muscular dystrophy has a prevalence of 1 in 3500 to 5000 live male births, or about 400 to 600 live male births per year in the US. 2 With treatments such as corticosteroids, assisted ventilation, spinal surgery, and management of cardiomyopathy-related heart failure, some patients are now living into their 30s or 40s.

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Rind DM. The FDA and Gene Therapy for Duchenne Muscular Dystrophy. JAMA. Published online May 01, 2024. doi:10.1001/jama.2024.5613

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• Review Article
• Published: 31 August 2023

Therapeutic approaches for Duchenne muscular dystrophy

• Thomas C. Roberts   ORCID: orcid.org/0000-0002-3313-7631 1 , 2 , 3 ,
• Matthew J. A. Wood 1 , 2 , 3 &
• Kay E. Davies   ORCID: orcid.org/0000-0001-8807-8520 3 , 4  

Nature Reviews Drug Discovery volume  22 ,  pages 917–934 ( 2023 ) Cite this article

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Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.

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Therapeutic developments for Duchenne muscular dystrophy

Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy

Genome editing for Duchenne muscular dystrophy: a glimpse of the future?

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Roberts, T.C., Wood, M.J.A. & Davies, K.E. Therapeutic approaches for Duchenne muscular dystrophy. Nat Rev Drug Discov 22 , 917–934 (2023). https://doi.org/10.1038/s41573-023-00775-6

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Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disease, characterized by progressive deterioration of skeletal muscle that causes rapid loss of mobility. The failure in respiratory and cardiac muscles is the underlying cause of premature death in most patients with DMD. Mutations in the gene encoding dystrophin result in dystrophin deficiency, which is the underlying pathogenesis of DMD. Dystrophin-deficient myocytes are dysfunctional and vulnerable to injury, triggering a series of subsequent pathological changes. In this review, we detail the molecular mechanism of DMD, dystrophin deficiency-induced muscle cell damage (oxidative stress injury, dysregulated calcium homeostasis, and sarcolemma instability) and other cell damage and dysfunction (neuromuscular junction impairment and abnormal differentiation of muscle satellite). We also describe aberrant function of other cells and impaired muscle regeneration due to deterioration of the muscle microenvironment, and dystrophin deficiency-induced multiple organ dysfunction, while summarizing the recent advances in the treatment of DMD.

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Skeletal muscle: a brief review of structure and function.

Diagnostic Approach to Proximal Myopathy

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Acknowledgements

I am grateful for the contribution to language help and writing assistance from Lai Xu at Nantong University during the research.

This work was supported by the National Natural Science Foundation of China (Nos. 82072160, 32130060, 81901933, 32000725), the Major Natural Science Research Projects in Universities of Jiangsu Province (No. 20KJA310012), the Natural Science Foundation of Jiangsu Province (Nos. BK20202013, BK20201209, BK20200973), the "QingLan Project" in Jiangsu Universities, the Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program (Nos. JC22022037, MS22022010).

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Mengyuan Chang, Yong Cai, and Zihui Gao have contributed equally to this work.

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Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

Mengyuan Chang, Zihui Gao, Boya Liu, Cheng Zhang, Qianqian Cao, Yuntian Shen, Xinlei Yao & Hualin Sun

Department of Neurology, Binhai County People’s Hospital, Yancheng, 224500, Jiangsu, People’s Republic of China

Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

Department of Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

Xiaoyang Chen

Research and Development Center for E-Learning, Ministry of Education, Beijing, 100816, People’s Republic of China

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Conceptualization: HS, XY and XC. Methodology: MC, YC, ZG, XC, BL, CZ, WY, QC, YS. Resources: MC, YC, ZG, XC, BL, CZ, WY, QC, YS. Data curation: MC, YC, ZG, XC, BL, CZ, WY, QC, YS. Writing—original draft preparation: MC, YC, ZG, XY, XC and HS. Review and editing: MC, XY, XC and HS. Visualization: MC, YS, and HS. Supervision: HS. Project administration: HS. Funding acquisition: HS.

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Chang, M., Cai, Y., Gao, Z. et al. Duchenne muscular dystrophy: pathogenesis and promising therapies. J Neurol 270 , 3733–3749 (2023). https://doi.org/10.1007/s00415-023-11796-x

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The clinical course of Duchenne muscular dystrophy in the corticosteroid treatment era: a systematic literature review

• Shelagh M. Szabo   ORCID: orcid.org/0000-0002-9044-3192 1 ,
• Renna M. Salhany 2 ,
• Alison Deighton 1 ,
• Meagan Harwood 1 ,
• Jean Mah 3 &
• Katherine L. Gooch 2  

Orphanet Journal of Rare Diseases volume  16 , Article number:  237 ( 2021 ) Cite this article

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Duchenne muscular dystrophy (DMD) is a severe rare progressive inherited neuromuscular disorder, leading to loss of ambulation (LOA) and premature mortality. The standard of care for patients with DMD has been treatment with corticosteroids for the past decade; however a synthesis of contemporary data describing the clinical course of DMD is lacking. The objective was to summarize age at key clinical milestones (loss of ambulation, scoliosis, ventilation, cardiomyopathy, and mortality) in the corticosteroid-treatment-era.

A systematic review was conducted using MEDLINE and EMBASE. The percentage experiencing key clinical milestones, and the mean or median age at those milestones, was synthesized from studies from North American populations, published between 2007 and 2018.

From 5637 abstracts, 29 studies were included. Estimates of the percentage experiencing key clinical milestones, and age at those milestones, showed heterogeneity. Up to 30% of patients lost ambulation by age 10 years, and up to 90% by 15 years of age. The mean age at scoliosis onset was approximately 14 years. Ventilatory support began from 15 to 18 years, and up to half of patients required ventilation by 20 years of age. Registry-based estimates suggest that 70% had evidence of cardiomyopathy by 15 years and almost all by 20 years of age. Finally, mortality rates up to 16% by age 20 years were reported; among those surviving to adulthood mortality was up to 60% by age 30 years.

Conclusions

Contemporary natural history studies from North America report that LOA on average occurs in the early teens, need for ventilation and cardiomyopathy in the late teens, and death in the third or fourth decade of life. Variability in rates may be due to differences in study design, treatment with corticosteroids or other disease-modifying agents, variations in clinical practices, and dystrophin mutations. Despite challenges in synthesizing estimates, these findings help characterize disease progression among contemporary North American DMD patients.

Duchenne muscular dystrophy (DMD) is a rare, progressive, life-limiting neuromuscular disorder [ 1 ] occurring in 15.9 to 19.5 per 100,000 live male births [ 2 , 3 , 4 ]. It is caused by mutations in the dystrophin gene [ 2 , 5 ]; lack of dystrophin compromises muscle structure and integrity, leading to progressive muscular degeneration [ 6 , 7 ]. Patients with DMD are typically identified in early childhood with symptoms including delays in motor milestones and frequent falls [ 8 ]. Over time, these patients experience progressive functional impairments leading to loss of ambulation (LOA), pulmonary insufficiency, cardiomyopathy, and early mortality [ 2 , 5 , 9 ].

Although there is presently no cure for DMD, advancements to the standard of care, including the introduction of systemic corticosteroids in the 1990s, have helped slow disease progression and improve survival [ 10 , 11 , 12 ]. However, the impact of these changes in standard of care across the full range of clinically-relevant disease progression milestones experienced by those with DMD has not been fully characterized. In 2017, Ryder et al. published a systematic review examining the epidemiology, burden, and treatment of DMD; however this review focused only on studies published between 2011 and 2015 [ 6 ]. Other reviews focused on the prevalence of DMD [ 13 ] or the impact of surgery on pulmonary decline [ 14 ]. While robust outcomes data are available from large cohort studies including the Cooperative International Neuromuscular Research Group (CINRG) [ 15 ], Duchenne Registry [ 16 ], and Centers for Disease Control and Prevention’s Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) [ 17 ], a synthesis of data from recent studies is lacking [ 18 ]. The objective of this systematic review was to characterize the clinical course of DMD in the era of corticosteroid treatment in North America.

A comprehensive search of the Medline/Medline In-Process and EMBASE databases was performed (see Additional file 1 : Table S1 for search strategy), the design of which was guided by the study-specific PECOS (Population, Exposures, Comparators, Outcomes, Study design) criteria (Table 1 ). Studies published in English between database inception (1946) and November 2018 that reported estimates of the age at occurrence of key clinical milestones occur among males with DMD were selected. To focus on more generalizable outcomes from a more homogeneous set of patients, the review targeted observational studies from North America (or international studies including North America patients) that aimed to estimate the frequency of key clinical events from large (n > 50) samples of DMD patients treated with corticosteroids. Animal studies, or studies that included patients with other muscular dystrophies, were excluded.

Outcomes of interest that describe the clinical course of DMD included LOA, scoliosis, need for ventilatory support (stratified by any ventilation/type unspecified, non-invasive ventilation [NIV] or invasive ventilation [IV]), pulmonary dysfunction, cardiomyopathy, and mortality. Relevant measures included the mean or median age at the outcome of interest, or the percentage experiencing the outcome over time or at a particular time ( t ) . Scores on assessments of ambulatory, pulmonary, or cardiac function over a minimum of one year of follow-up were also included (Table 1 ). Two reviewers independently screened abstracts and potentially eligible full-text articles for inclusion, and any discrepancies were resolved through discussion to achieve consensus.

Data were extracted by two researchers; study characteristics extracted included authors, year, study duration, objective(s) and design, sample size, and inclusion and exclusion criteria. Patient characteristics included details of corticosteroid treatment and baseline demographics. Cohorts were classified as ‘corticosteroid-treated’ if all patients were so treated, ‘mixed corticosteroid use’ if the sample represented a mix of corticosteroid-treated and -untreated patients, and ‘likely corticosteroid-treated’ if the study was published after 2005 and did not state the sample was untreated . Available data on use of cardioprotective medications, such as angiotensin-converting enzyme (ACE) inhibitors, were also extracted where available.

For continuous variables, the mean, median, standard deviation (SD), confidence interval (CI), interquartile ranges (IQR), and range was extracted whenever available. For dichotomous and categorical variables, the number of patients and proportion was extracted. For studies reporting on the mean or median age at the outcome, the range of estimates was tabulated. The percentage of the sample who experienced the outcome at time of reporting was also described (where available). Data on the percentage experiencing the outcome at specific time points or over time were described using Kaplan–Meier (KM) curves, as well as presented as point estimates at time t by the original authors. Where available, scores on functional and clinical measures of interest over time were plotted using line graphs.

The strength of the available evidence was assessed using the STrengthening the Reporting of Observational studies in Epidemiology (STROBE) Statement for observational studies and non-randomized clinical trials [ 19 ].

The search strategy identified 5,637 potentially-relevant records; four (< 1%) were removed after de-duplication and 5,213 (92.5%) were excluded on abstract review (Fig.  1 ). Of the remaining 410 records, 381 were excluded on full-text review, leaving 29 eligible studies. Study designs included single-center or multicenter chart reviews and DMD registries (including 6 publications from CINRG and 4 publications from MD STARnet; Table 2 ). Available details of corticosteroid treatment (including the age at initiation, follow-up protocols, and frequency of reported side effects) are summarized in Additional file 1 : Table S2; however, the level of detail provided varied by study, and few studies examined how variability in parameters such as age at corticosteroid initiation impacted the clinical course of DMD. Available details of treatment with cardioprotective medications are summarized in Additional file 1 : Table S3. A summary of the quality of included studies in Additional file 1 : Table S4.

PRISMA diagram outlining study inclusion and exclusion. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, CS corticosteroid, RTC randomized controlled trial

• Loss of ambulation

Six studies reported on the mean age at [ 20 , 21 , 22 , 23 , 24 , 25 ], 10 studies on median age at [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], and 13 studies on the percentage experiencing LOA (Table 2 ) [ 20 , 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 33 , 34 , 36 , 37 ]. Two studies provided subgroup-specific estimates [ 21 , 31 ]. Among studies of corticosteroid-treated patients, the mean (SD) age at LOA ranged from 9.5 (0.2) years (among 112 patients from MD STARnet) [ 21 ] to 12.5 (3.0) years (in 68% of 75 patients from a single-center chart review [ 22 ]; Fig.  2 a). Estimates were similar from the three studies reporting on mixed corticosteroid use patients; the mean ages at LOA ranged from 9.8 (2.2) years (in 26.6% of 432 Mexican DMD patients) [ 24 ] to 10.8 (2.1) years (in 63.2% of 462 patients from MD STARnet) [ 20 ]. The earliest mean age at LOA (9.5 years) was observed among patients with ≤ 3 years of corticosteroid treatment, compared with 12.3 years among those with > 3 year corticosteroid use (MD STARnet) [ 21 ].

Age at LOA or mortality: a mean/median age at LOA; b LOA over time, c mean/median age at mortality; and d Mortality over time. LOA = loss of ambulation; CS = corticosteroid; LT = long-term; NR = not reported; ST = short term; yrs = years DFZ = deflazacort; NR = not reported; Pred = prednisone; yrs = years; CINRG-DNHS = The Cooperative International Neuromuscular Research Group Duchene Natural History Study; MD STARnet = Muscular Dystrophy Surveillance, Tracking, and Research Network; CM = cardiomyopathy; CPT = cardiopulmonary therapies; Died RF = died from respiratory failure; Died CF = died cardiac failure; Died Oth = died from other causes; IV = invasive ventilation; LVD = left ventricular dysfunction; NIV = non-invasive ventilation; CV = cardiovascular. Notes **Middle value in range of medians. Long follow up = 10–20 years; median follow up = 5.4–7.1 years; short follow up = 1.9–2 years; unknown = not reported

Thirteen estimates from ten studies described median age at LOA (Fig.  2 b) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Estimates from 7 studies of corticosteroid-treated samples ranged from 12.0 (11.3–14.0) years (in 63 patients from CINRG) [ 29 ] to 16.0 (NR) years (in 765 patients from the Duchenne Registry) [ 26 ]. The latter study reported age at LOA by genotype, from 12 years (patients with exon 51 and 53 skip amenable mutations) to 20 years (patients with exon 44 skip amenable mutations). Six studies reported estimates from mixed corticosteroid use samples, and the range was tighter; from 10.0 (range: 4.0–14.0) years (in 67.4% of 85 patients from a single-center chart review) [ 34 ] to 12.4 years (in 64.9% of 225 patients from CINRG) [ 29 ].

The percentage who experienced LOA increased with time (Fig.  2 c) [ 20 , 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 33 , 34 , 36 , 37 ], from 12.3% at 10 years (from 223 corticosteroid-treated CINRG patients) [ 30 ] to 89.9% at 15 years (from 53 corticosteroid-treated MD STARnet patients) [ 31 ]. Estimates from longitudinal studies report that up to 30% of DMD patients lose ambulation by 10 years (CINRG) [ 28 ], and 90% by 15 years (MD STARnet) [ 31 ]. While these effects were fairly consistent across studies of different sample sizes, mixed corticosteroid use samples tended to have higher rates of LOA at a given age than corticosteroid-treated samples.

One study reported the mean age at scoliosis [ 38 ], 2 studies the median age at scoliosis [ 31 , 35 ], and 5 studies the percentage with scoliosis by age (Table 2 ) [ 22 , 30 , 31 , 35 , 37 ]. How scoliosis was defined varied across studies. In a single-center study of 56 patients, the mean age at spinal surgery was 14.0 years; and 14.5 years in the subset (n = 20) undergoing pulmonary function testing (Fig.  3 a) [ 38 ]. The median (range) age at scoliosis surgery among a mixed corticosteroid use sample from MD STARnet was 14.6 (10.2–20.2) years (with surgery observed in 52.4% of n = 208) [ 35 ]. In the remaining study of 274 corticosteroid-treated patients (also from MD STARnet), the median (range) age (by spinal curvature > 30° or surgery) was 14.2 (12.5–15.6) years among the 107 patients with scoliosis [ 31 ]. The percentage with scoliosis increased with increasing age (Fig.  3 b) [ 22 , 30 , 31 , 35 , 37 ]. Results from a longitudinal study from MD STARnet suggest that up to 59% of patients with DMD will have scoliosis by 15 years of age, and up to 72% by 20 years of age [ 31 ].

Occurrence of other key clinical milestones: a Mean/median age at scoliosis; b Percentage with scoliosis over time; c Mean/median age at respiratory support; d Percentage on respiratory support over time; e Mean/median age at cardiomyopathy; f Percentage with cardiomyopathy over time. 6MWD = 6 min walk distance; PEF = peak expiratory flow; FVC = forced vital capacity; SF = shortening fraction; LVED = left ventricular end-diastolic dimension; EF = ejection fraction. Notes: **Scoliosis includes both severe scoliosis and spinal surgery

Pulmonary function and need for ventilatory support

Four studies reported the mean or median age at ventilation [ 33 , 35 , 39 , 40 ], 3 studies reported the percentage needing ventilation by age [ 30 , 33 , 35 ], 4 studies reported the age at transitioning to key pulmonary functional milestones [ 30 , 41 , 42 , 43 ], and 2 studies reported pulmonary function over time (Table 2 ) [ 42 , 43 ].

In terms of age at need for ventilation, one multicenter chart review of 324 mixed corticosteroid-treated DMD patients reported a median age at ‘any ventilation’ of 15 years (Fig.  3 c) [ 33 ]. Three studies reported the age at NIV to range from a median (IQR) age of 18.0 (9.4–26.8) years (in 47.6% of 208 mixed corticosteroid-treated patients on nasal NIV from MD STARnet) [ 35 ], to a mean of 22.3 (4.7) years (in 39.3% of 275 likely-corticosteroid-treated patients receiving continuous NIV in a single-center chart review) [ 39 ]. Two studies reported age at IV; a single-center chart review reporting a mean (SD) age of 18.6 (2.3) years (in 9.1% of 275 likely-corticosteroid-treated patients with continuous tracheostomy mechanical ventilation) [ 39 ], and an MD STARnet study reporting a median (IQR) age of 19.1 (13.4–27.0) years (in 21.2% in 208 mixed-corticosteroid-treated patients with tracheostomy) [ 35 ].

The percentage of patients requiring ventilation tended to increase over time, with variability in estimates observed due to type of ventilation (Fig.  3 d) [ 30 , 33 , 35 ]. By 20 years of age, 27.2% (n = 88) of mixed corticosteroid use patients in a multicenter chart review required ‘any ventilation’ [ 33 ]. Two studies describing NIV reported estimates of 21.2% (among 44 corticosteroid-treated patients from MD STARnet) [ 35 ], and 39.6% (among 21 mixed corticosteroid-treated patients from CINRG) [ 30 ] by 20 years. The MD STARnet study also reported that 47.6% of patients with mixed corticosteroid use were on IV by 20 years [ 35 ].

Absolute measures of pulmonary function generally show relatively preserved function until adolescence, which declines with increasing age (Fig.  4 a, c). Two studies reported absolute and percent predicted peak expiratory flow (PEF). A substantial decline in PEF was observed among 330 corticosteroid-treated CINRG patients, from 243.7 L/min (age = 17 years) to 76.1 L/min (age = 29 years). Trends were similar among 60 mixed corticosteroid-treated patients from a single-center chart review (from 269.4 L/min [age = 18 years] to 67.9 L/min [age = 24 years]) [ 42 ]. Estimates of percent predicted PEF show loss of function relative to age-matched healthy controls; the magnitude increases with age (Fig.  4 a), reaching a low of 11.8% by age 29 years in the CINRG study. Those same two studies also reported FVC (L) over time (Fig.  4 d) which demonstrated an initial increase in function followed by progressive decline after approximately 15 years; the percent predicted FVC showed loss of function relative to age-matched controls with increasing age, to 10.4% at 29 years of age (Fig.  4 c) [ 42 , 43 ].

Measures of functional status over time: a – d pulmonary function measures; e – g cardiac function measures. PEF = peak expiratory flow; FVC = forced vital capacity; SF = shortening fraction; LVED = left ventricular end-diastolic dimension; EF = ejection fraction. Notes a = HR in the upper quartile (> 96 BPM), b = HR in the lower quartile (≤ 96 BPM), c = Left ventricular dysfunction, d = No Left ventricular dysfunction

Four studies reported the age at transitioning to key pulmonary milestones; specifically, reaching FVC < 1L, FVC < 30% or PEF < 30% [ 30 , 41 , 42 , 43 ]. FVC < 1L was first reported at 20 years of age in the 60 mixed corticosteroid-treated patients from a single-center chart review [ 42 ] and 23 years of age in a CINRG study of 330 corticosteroid-treated patients [ 30 ]. Mean (SD) ages at FVC < 30% and PEF < 30% were similar from a CINRG study of 223 mixed corticosteroid-treated patients (FVC < 30%: 24.0 (1.5) years, and PEF < 30%: 24.9 (0.8) years); the same CINRG study also reported that 50% progressed to FVC < 30% or PEF < 30% by 25 years of age [ 41 ]. Estimates of the percentage with severe pulmonary dysfunction (FVC < 50%) at 20 years of age ranged from 13.6% [ 43 ] to 29.7% [ 30 ]. Finally, among 330 corticosteroid-treated patients from CINRG, among those with LOA at < 10 years, the median age at FVC < 1L was 18.1 years, vs 20.1 years among those with LOA between 10–13 years of age, and 24.4 years among patients with LOA at ≥ 13 years [ 30 ].

Cardiac function and cardiomyopathy

Seven studies reported the mean or median age at diagnosis [ 20 , 25 , 26 , 31 , 34 , 35 , 44 ] and 9 studies reported the percentage of patients with cardiomyopathy [ 20 , 25 , 31 , 34 , 35 , 37 , 44 , 45 , 46 ]; 3 studies reported changes in cardiac function over time (Table 2 ) [ 45 , 46 , 47 ].

Of the 7 studies reporting the age at cardiomyopathy, 5 described samples not selected using cardiovascular-risk-related criteria (Fig.  3 e) [ 20 , 31 , 34 , 35 , 44 ]. The mean (SD) age at cardiomyopathy ranged from 12.7 (3.0) years (in 37.0% of 67 corticosteroid-treated patients from a multicenter chart review) [ 44 ] to 15.8 (range: 9–29) years (in 48.2% of 85 patients of mixed corticosteroid-treatment status from a single-center chart review) [ 34 ]. Estimates of median (IQR) age at cardiomyopathy ranged from 14.9 (4.9) years (in 69.7% of 208 mixed corticosteroid-treated patients from MD STARnet) [ 35 ] to 18.0 (CI: 6.9–18.5) years (in 39.0% of 218 corticosteroid-treated patients from MD STARnet) [ 31 ]. The reported age at cardiomyopathy was lower among two studies reporting on mixed corticosteroid-treated samples either treated with cardiopulmonary therapy (median 18.0 (7.0–27.3) years, in 70.2% of 57 patients) [ 46 ], or with LV dysfunction (mean, 15.4 (8–27) years, in 32.5% of 77 patients) [ 25 ].

The percentage with cardiomyopathy was higher with increasing age (Fig.  3 f) [ 20 , 25 , 31 , 34 , 35 , 37 , 44 , 45 , 46 ]; this effect was consistent across studies of different sample sizes. At 15 years of age, the percentage with cardiomyopathy ranged from 23.3% (among 218 patients who initiated corticosteroids after 5 years of age) [ 31 ] to 69.7% (among 208 mixed corticosteroid-treated patients) [ 35 ]; both estimates were from MD STARnet. By 20 years of age, the percentage with cardiomyopathy ranged from 68.2% (of 85 mixed corticosteroid-treated patients from a single-center chart review) [ 34 ] to 92.8% (of 47 patients who initiated corticosteroids before 5 years of age from MD STARnet) [ 31 ]. By age 25, the percentage with cardiomyopathy ranged from 87.6% (of 85 mixed corticosteroid-treated patients from a single-center chart review) [ 34 ] to 100% (291 corticosteroid-treated patients from MD STARnet) [ 20 ].

Measures of cardiac function show preserved function until adolescence and then decline with age (Fig.  4 e–g) [ 45 , 46 , 47 ]. In a long-term observational study of 63 DMD patients treated with cardiopulmonary therapies and corticosteroids, the ejection fraction decreased to 53% by 20 years of age [ 45 ]. That study and two other single-center studies also reported worsening of cardiac function by left ventricular end diastolic diameter (LVED) and shortening fraction (SF) among corticosteroid-treated patients with DMD [ 45 , 46 , 47 ].

Eight studies reported the mean age [ 24 , 32 , 35 , 39 , 40 , 44 , 45 , 46 ] and 1 study the median age at mortality [ 35 ]; 9 studies reported case fatality by age (Table 2 ) [ 24 , 30 , 32 , 34 , 35 , 40 , 44 , 46 , 48 ].

Of the 8 studies reporting mean (SD) age at mortality [ 24 , 32 , 35 , 39 , 40 , 44 , 45 , 46 ], 4 were reflective of the overall DMD population [ 24 , 32 , 44 , 45 ] one was from a sample of DMD patients with cardiomyopathy [ 46 ], and 3 were from samples of patients who were non-ambulatory or on ventilation [ 35 , 39 , 40 ]. From studies of the overall population, the mean (SD) age at mortality ranged from 18.1 (3.8) years (in 11% of 101 mixed corticosteroid-treated patients from a multicenter chart review) [ 44 ] to 20.0 (15–31) years (in 13% of 437 mixed corticosteroid-treated patients from an administrative database study; Fig.  2 d) [ 32 ]. In the single study that described outcomes among DMD patients with cardiomyopathy, the mean (SD) age at mortality was 26.0 (6.8) years (in 47.4% of 57 mixed corticosteroid-treated patients from a single-center chart review; Fig.  2 d). The mean (SD) age at mortality among DMD patients who were non-ambulatory or on ventilation ranged from 25.8 (7.8) years (in 17 likely-corticosteroid-treated patients from a single-center chart review, who died from causes other than respiratory or cardiac dysfunction) [ 40 ] to 31.4 (5.7) years (in 14 likely-corticosteroid-treated patients from that single-center chart review, with death due to respiratory complications; Fig.  2 d) [ 40 ]. The median (IQR) age at mortality among DMD patients who were non-ambulatory or on ventilation was 21.5 (3.8) years (in 28.3% of 208 mixed corticosteroid-treated patients from MD STARnet; Fig.  2 d) [ 35 ].

In terms of the proportion surviving over time, up to 16.2% mortality was reported by age 20 years (Fig.  2 e) [ 24 ]. Estimates of survival after 20 years are available only from studies enrolling adult patients with DMD; and these reported rates of 44.2% to 56.8% mortality by age 30 years (Fig.  2 e) [ 40 ].

A comprehensive systematic review was conducted to identify estimates of the age at key clinical milestones, and trajectories on relevant functional measures over time, among studies including North American patients with DMD. Age at LOA was the most widely reported with estimates available from many large studies; these tended to range from 10 to 14 years of age [ 27 , 34 ]. However, robust data on the timing of the onset of scoliosis-, cardiac-, pulmonary- and ventilation-related outcomes were less frequently presented, particularly from large longitudinal studies. While reported estimates of the mean age at diagnosis of scoliosis were fairly consistent across studies (at 14–15 years of age), how scoliosis was classified differed widely [ 31 , 35 , 38 ]. Pulmonary function in DMD patients declines with age from the mid-teens [ 30 , 41 ], and while most have severe pulmonary dysfunction by 25 years [ 30 ], the mean age at initiation of ventilatory support ranged from 15 to 22 years depending on the type of ventilation considered and treatment center [ 33 , 39 ]. Data on age at mortality in DMD were also variable, and estimates were impacted by the inclusion criteria of the individual studies; for example estimates of mortality among those with cardiomyopathy or on ventilation were drawn from populations surviving to adulthood [ 40 , 46 ]. In addition to selection criteria, factors impacting the timing of key clinical milestones include corticosteroid regimen [ 31 ] and disease genotype [ 26 ]. The findings of this review help summarize the likely timing of disease progression milestones for North American patients with DMD, and also highlight potential heterogeneity in timing observed both within and across study populations.

Estimates of time to key clinical milestones in this review included data from studies from the large North American registries (e.g. CINRG and MD STARnet), and findings are consistent with those from large observational studies and registries from outside of North America. The Translational Research in Europe—Assessment and Treatment of Neuromuscular Diseases (TREAT-NMD) network of DMD registries have published studies documenting the clinical course of patients with DMD [ 49 , 50 , 51 , 52 ]. In a large survey of over 1500 DMD patients that characterized the impact of corticosteroid use, mean estimates of age at LOA ranged from 10.1 (non-corticosteroid-treated patients) to 11.4 (corticosteroid-treated) years [ 49 ]. An analysis of over 5000 patients also from TREAT-NMD reported age at LOA of 13 years among corticosteroid-treated patients, and that up to 50% of patients required ventilation by 20 years of age [ 50 ]

That longitudinal data describing survival specifically among North American DMD patients are few, was one of the major gaps identified in this review. However, mortality rates from included studies were consistent with findings of two important studies on mortality in dystrophin gene-related muscular dystrophy, which did not meet the inclusion criteria for the current review as they also included patients with Becker muscular dystrophy (BMD). The first study, which was based on vital statistics, estimated that 71% of mortality among those with BMD/DMD occurred between the ages of 15 and 29 years; the authors assumed it was most likely related to DMD [ 53 ]. The second study, from MD STARnet, estimated mortality in almost 60% of that cohort by age 25 years, with most deaths occurring among those aged 20 to 25 years [ 54 ]. Further follow-up from existing large DMD cohorts will help improve contemporary estimates of the timing of key clinical milestones.

Accurately estimating the time of onset of gradually progressive manifestations of DMD can be difficult, and this along with changes in practice patterns and symptom detection, contribute to observed variability in estimates. For example, many studies reporting on scoliosis classify outcomes based on surgery, however with changing treatment patterns [ 55 ] the utility of surgery as a proxy for clinically-significant scoliosis will decrease. Similarly, recommended strategies for ventilation vary among clinical centers [ 39 , 56 , 57 ], and practice is changing (in particular for how IV is used) [ 58 ], which will impact the comparability of estimates of the timing of respiratory decline across studies from different periods. Finally for cardiomyopathy, with advancements in screening tools [ 59 , 60 ] as well as evidence of benefits to early treatment [ 61 ], it is likely that initial signs will now be detected earlier, which would result in an apparent decrease in the mean age at cardiomyopathy over the coming years.

There are several additional factors impacting the timing of key clinical milestones that require consideration. To capture the impact of corticosteroids in the management of DMD, only studies including patients from the corticosteroid treatment era were included. While details of corticosteroid treatment regimens were extracted and reviewed, there were important limitations that precluded analyzing outcomes according to regimen. First, details on the timing of initiation, duration, type, and dose varied within and between studies. Only a small number of studies reporting on LOA presented results according to agent; but the remainder of the studies for that outcome, and all of the studies for other outcomes of interest, did not stratify by corticosteroid regimen. However, variations in corticosteroid treatment patterns (in terms of duration and dosing) may have affected the timing when patients reached LOA [ 28 , 31 , 62 , 63 ], and other important clinical milestones [ 20 , 31 , 46 , 62 , 63 , 64 , 65 ]. Evidence on the impact of early initiation of corticosteroids (e.g. before age 6 years) remains mixed [ 31 , 66 ]; more work is needed to disentangle the potential confounding effect of disease severity and the potential risk for adverse effects of corticosteroid treatment on outcomes in real-world studies. Treatment with ACE inhibitors has also been shown to impact the clinical course of DMD by delaying the onset of cardiomyopathy; however, the use of ACE inhibitors remains variable [ 20 , 67 ]. While it might be anticipated that studies describing later cohorts would show delayed onset of milestones that define the clinical course of DMD, the interplay between treatment advances and the impact of earlier diagnostics would make these relationships less apparent. Finally, other genetic modifiers may also play a role in the timing of DMD progression [ 26 , 29 , 50 ]; however, outcomes according to genotype are infrequently reported outside of treatment trials [ 68 , 69 ]. The move from biomarkers to precise genetic diagnosis may also impact the apparent clinical course [ 70 ].

Variability in methodology and data sources may also have affected estimates. Data from the CINRG and MD STARnet registries, both large well-documented US cohorts that comprehensively collect longitudinal data on the clinical course of DMD, were used in ten studies within this review. Outside of those, most observational studies and treatment trials do not follow patients for a sufficient time to describe changes across the range of key clinical milestones [ 21 , 30 ]. Other challenges for studying disease progression in rare diseases include small sample sizes which can amplify the impact of heterogeneity in diseases with varied clinical courses; data presented from convenience samples and case series may not be generalizable, and the impact of selection biases on outcomes (particularly for diseases with high early fatality among more severe cases) can be substantial [ 71 , 72 ]. The numerous outcome measures used to assess progression in DMD also make comparisons difficult, a limitation recently acknowledged in a workshop held by the DMD research community [ 73 ]. Finally, there are useful measures for characterizing DMD progression that were infrequently reported in the studies of this review, such as the North Star Ambulatory Assessment or upper arm function, which are important in understanding patient functional status and ability to participate in activities of daily living.

Some limitations to the published data warrant mention. First, while time to event data using KM curves were presented in some studies, many reported the mean age at an occurrence where the entire sample had not experienced the event at the time of study reporting. As such, these values can be interpreted as the lower limit for when key clinical milestones will occur in DMD. Second, some measures may only be administered to individuals who still have some functional capacity (e.g. tests of ambulation), and patients unable to complete the test would have been excluded. This type of survival bias would result in an inflation of apparent functional status for cohorts as a whole. Third, mean scores on functional tests may reflect the inclusion criteria of each study, rather than the underlying distribution of scores on that functional test among the DMD population. Fourth, because of heterogeneity in designs employed, measures selected, and populations included across studies, meta-analysis was judged to be infeasible [ 74 , 75 ]; as a result, overall summary estimates of the time to key clinical milestones were not calculable.

This is the first systematic review of published estimates of the frequency and timing of important milestones that characterize the clinical course of DMD in the corticosteroid era. This review has also leant insight into a number of challenges in the interpretation and comparison of estimates of outcomes to characterize the clinical course of DMD. Additional studies on the ages at occurrence of other important DMD clinical milestones, and the relationships between short-term and long-term outcomes, will be valuable in the continuation of knowledge regarding disease progression in DMD.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Angiotensin-converting enzyme

Becker muscular dystrophy

Confidence interval

Cooperative International Neuromuscular Research Group

• Duchenne muscular dystrophy

Forced vital capacity

Interquartile ranges

Invasive ventilation

Kaplan–Meier

Left ventricle

Left ventricular end diastolic diameter

Muscular Dystrophy Surveillance, Tracking, and Research Network

Non-invasive ventilation

Peak expiratory flow

Standard deviation

Shortening fraction

STrengthening the Reporting of Observational studies in Epidemiology

Translational Research in Europe—Assessment and Treatment of Neuromuscular Diseases

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. Search strategy. Supplementary Table 2 . Details of corticosteroid treatment, by study. Supplementary Table 3 . Details of ACE inhibitor treatment, by study. Supplementary Table 4 . STROBE assessments of included studies.

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Szabo, S.M., Salhany, R.M., Deighton, A. et al. The clinical course of Duchenne muscular dystrophy in the corticosteroid treatment era: a systematic literature review. Orphanet J Rare Dis 16 , 237 (2021). https://doi.org/10.1186/s13023-021-01862-w

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Mini review article, treating duchenne muscular dystrophy: the promise of stem cells, artificial intelligence, and multi-omics.

• 1 Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States
• 2 Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States

Muscular dystrophies are chronic and debilitating disorders caused by progressive muscle wasting. Duchenne muscular dystrophy (DMD) is the most common type. DMD is a well-characterized genetic disorder caused by the absence of dystrophin. Although some therapies exist to treat the symptoms and there are ongoing efforts to correct the underlying molecular defect, patients with muscular dystrophies would greatly benefit from new therapies that target the specific pathways contributing directly to the muscle disorders. Three new advances are poised to change the landscape of therapies for muscular dystrophies such as DMD. First, the advent of human induced pluripotent stem cells (iPSCs) allows researchers to design effective treatment strategies that make up for the gaps missed by conventional “one size fits all” strategies. By characterizing tissue alterations with single-cell resolution and having molecular profiles for therapeutic treatments for a variety of cell types, clinical researchers can design multi-pronged interventions to not just delay degenerative processes, but regenerate healthy tissues. Second, artificial intelligence (AI) will play a significant role in developing future therapies by allowing the aggregation and synthesis of large and disparate datasets to help reveal underlying molecular mechanisms. Third, disease models using a high volume of multi-omics data gathered from diverse sources carry valuable information about converging and diverging pathways. Using these new tools, the results of previous and emerging studies will catalyze precision medicine-based drug development that can tackle devastating disorders such as DMD.

Introduction

Duchenne muscular dystrophy (DMD) is a lethal genetic disorder, primarily characterized by muscle deterioration and wasting. Ultimately, the majority of DMD patients succumb to cardiac and respiratory complications ( 1 ). DMD is caused by mutations in the X-chromosome-linked DMD gene that codes for the dystrophin protein, which is an important component of muscle cells' cytoskeleton. Mutations in DMD generally result in large deletions of the dystrophin protein that reduce structural integrity in muscle cells ( 2 ). Loss of dystrophin heavily disrupts the connection between the inner cytoskeleton and the extracellular matrix, known as the dystrophin associated protein complex, leading to structural and functional abnormalities in these mechanically active muscle cells ( 3 ). As DMD progresses, additional cell functions are impacted (e.g., disrupted calcium regulation, accumulation of reactive oxygen species, poor mitochondrial energetics, etc.). Muscle cells try to adapt to the disrupted processes ( 4 ), but can quickly overcompensate, causing the cell to transition from a stressed to a destabilized state; at this point it begins to secrete inflammatory cytokines, activates fibrosis, and ultimately dies ( 5 ). As more cellular processes are disrupted, more evidence of cellular dysfunction is exhibited that can be detected in the form of higher levels of serum biomarkers like creatine kinase and myoglobin as signs of muscle wasting, and TNF-α, IFN-γ, IL-5 and IL-6 as signs of chronic inflammation ( 6 – 9 ). Therapeutic efforts for DMD are therefore divided between targeting (i) the underlying cause of DMD, loss of dystrophin, or (ii) targeting a secondary pathology ( 10 ).

DMD is a rapidly progressing disease: it presents between the ages 2–5, loss of ambulation can happen by age 12, and premature death can happen by age 25–30 ( 1 ). The guidelines for managing DMD include recommendations on nutrition, physical therapy, and cardiovascular health that can help slow down disease progression ( 11 ), but there is currently no cure for the disease. Emerging therapies are targeting the underlying loss of dystrophin via several ideas like transcriptionally inducing the production of more dystrophin, utilizing oligonucleotides to promote exon-skipping of the mutant region, and genome editing the mutant exon, all with the goal of producing a healthy dystrophin molecule ( 12 – 14 ). All these promising strategies are currently being evaluated, but they are not ready to provide current DMD patients with useful options to delay pathologic onset. Furthermore, fixing the dystrophin issue would not spontaneously fix all the incurred muscle damage, and thus some additional therapy will likely be needed to achieve healthy skeletal muscle and cardiac function. Many of the current interventions target the compensatory processes that contribute to muscle inflammation and oxidative stress, but are able to only mildly decelerate loss of ambulation and cardiomyopathy ( 5 , 13 ). The information gathered through decades of pre-clinical, clinical, and pharmaceutical studies has provided a strong foundation for understanding and treating DMD, and can be used to identify other targets; additionally, the information gathered in clinical trials for any compound can inform on efficacy for these chemicals. Clinical studies have also helped us establish checkpoints for disease progression from early-stage to end-stage, allowing us to predict disease progression and informing treatment.

The advent of combining several new approaches holds promise for better and more specific treatments of DMD in the future ( Figure 1 ). First, stem cell-based studies can investigate cellular processes and the effects of different treatments on DMD-afflicted muscle cells without risk to patients. Second, the evolving AI tools could be used to perform high dimensional drug screening with more efficiently streamlined analysis. Third, multi-omics approaches allow the synthesis of information from diverse sources and enable a more holistic understanding of the mechanisms underlying the disease. In this review, we will discuss all three of these approaches, their recent applications, and their potential.

Figure 1 . Schematic of the approaches to broaden the therapeutics available to DMD patients. Patient-derived or genome-edited iPSCs provide a human model for disease specific modeling of various cell types and benefits from previous knowledge using the mdx mouse. Newer experimental technologies are detailing the intricacies of complex phenotypes. Next-generation computational tools are enabling high-dimensional analysis of multi-omics data. This figure was created with BioRender.com .

Human Stem Cells Provide Cell Type- and Disease-Specific Insights

Both DMD-like mouse models and DMD patient samples have yielded mechanistic insights by comparing differential expression of wild-type (WT) and healthy human tissues, pointing to potential pharmaceutical targets ( 16 – 18 ). The mdx mouse has been a standard pre-clinical model for DMD for deciphering how these markers interact and contribute to muscle wasting ( 19 ). It has also been extensively used to test the efficacy of the current interventions for DMD ( 20 ). However, the reliability of animal models in biomedical research has been questioned due to issues concerning physiological context, species specificity, and clinical relevance ( 21 ). An mdx mouse study noted a delayed onset of cardiomyopathy, as opposed to humans which is the main cause of death ( 22 ). Even with their contributions to our understanding of the disease, better models that recapitulate the phenotype are necessary ( 23 ). By utilizing induced pluripotent stem cells (iPSCs), human disease models hold substantial promise for the clinic, because one can study patient-specific pathologies in multiple different tissues and cell types ( 24 , 25 ). The use of human iPSCs, in which somatic cells can be reprogrammed to a pluripotent state by introducing four key transcription factors (Oct4, Sox2, Klf4, and c-Myc) and then be chemically programmed to become a cell type of interest ( 25 , 26 ), has been a ground-breaking technology that promises to treat an entire spectrum of intractable diseases including DMD.

A current effort to directly correct the dystrophin deficiency in DMD is being piloted in the mdx mouse using CRISPR/Cas9 to edit the genetic defect as a therapeutic strategy ( 15 , 27 ). These efforts have generated a single-cell atlas of skeletal muscle from a dystrophic mouse model that covers both its diseased-state and a CRISPR-corrected state ( 28 ). Many known differential expression changes in metabolism, inflammation, and regulatory networks were recapitulated. Moreover, the crosstalk between skeletal myocytes, endothelial cells, macrophages, and various other cell types was explored. In addition, Chemello et al. were able to analyze diverse transcriptional programs stemming from various nuclei, which is important considering that skeletal muscle can house several myonuclei per cell. These spatially defined tissue studies using single-cell RNA-seq can show how different cell types could be targeted for their modified state. Even with the innovation and excitement for spatial transcriptomics studies, there still are trade-offs in utilizing these experiments for mechanistic inference ( 29 ). Depending on the question, if a tissue is too large, certain information could be missed if multiple spaces are not covered or considered for analysis, leading to biases. In addition, processing different samples using different tissue separation or cell isolation protocols can create significant variations in the experimental results, which is why there is much interest in automation. Future advances in spatial transcriptomics may overcome some of the present limitations of these experiments ( 30 ). Studies utilizing iPSCs can be designed for characterizing the disease-state phenotype of various cell types and testing for drugs.

Recently, human stem cell models have been utilized to study DMD. For example, by identifying issues with cell fate during differentiation, studies have highlighted new potential therapeutic targets ( 31 , 32 ). There are other examples of how stem cells were successfully deployed to better understand DMD ( 14 , 33 ). DMD patient-derived iPSCs were used to show accelerated telomere shortening that is seen in DMD patients' heart muscle cells ( 34 ). In yet another example, a recent study combined data from both the mdx mouse and DMD patient-derived iPSC-cardiomyocytes to show the overlap in phenotypes between both species and also how both species' cells react to adrenergic receptor stimulation with an agonist (isoproterenol) and antagonist (beta-blocker) ( 35 ). This is important because it supports the use of iPSC-derived models as a proper tool for characterizing common DMD treatment effects, just as the mdx mouse has been used for decades. Another recent study characterized the functional effects of known Chinese herbal medicine components on DMD iPSC-cardiomyocytes, highlighting the potential of stem cells for drug discovery ( 36 ). This work showed that the anti-oxidant effects of these herbal compounds can be effective at reducing oxidative stress. In a recent review of DMD therapeutics, a meta-analysis of gene expression comparisons of other DMD samples showed that extracellular matrix (ECM) and cell-to-cell interaction molecules are prime targets for reversing late-stage DMD, which makes logical sense because to restore ambulation, the musculature would need to be strengthened ( 10 ). Stem cells give us the ability to generate and characterize the different cell types affected by DMD, as well as the ability to perform high-throughput drug screens, paving the way toward patient-specific treatment programs.

AI Facilitates High-Dimensional Analysis of Large DMD Datasets

Recent advances in omics technologies have led to substantial data generation for disease modeling. However, the wealth of information has resulted in a predictable challenge: how to aggregate and interpret disparate data types, such as transcriptomic, epigenomic, functional, and textual data, which may be distributed across siloed databases ( 37 ). Advances in AI have led to models that perform automated text processing and comprehension. Additional AI models can process high-dimensional, non-linear omics data and learn new features about the data that would not be obvious using traditional analysis ( 38 ). Simultaneously, progress in computational hardware has increased the ability of researchers to develop and train models to aggregate, analyze, and make predictions using very large datasets. An emerging benefit of using “big-data” algorithms on biomedical information is the ability to tailor treatment programs for individual patients. Information obtained from a person's genome is becoming more reliable and pharmaceutically applicable every day ( 39 ). However, designing a specific therapy still requires precisely matching the correct treatment with the unique underlying defect and health state of the patient. The competitive pace of the computational market is driving the current efforts in biotech and pharma to be in position to produce innovative therapies.

Natural language processing (NLP), a machine learning tool with the capability to process text to achieve automated comprehension, translation, and generation, is perhaps one of the most critical AI tools for biomedical research. Initially, NLP primarily relied on recurrent neural networks as the main model of choice. However, recurrent neural networks were limited in the size of the datasets they could train on, and therefore delivered limited performance on clinical and biomedical text comprehension ( 40 ). Transformers and attention-based language models have reshaped the landscape of NLP by bypassing existing limitations of recurrent neural networks ( 41 ). Importantly, transformers are capable of handling larger datasets than seen before and delivering greater text comprehension, both of which are required to discover novel biological mechanisms and therapeutics from existing biomedical literature and databases ( 42 ). When applied to DMD, these recent advances in NLP can query large amounts of DMD-related text and databases to identify key words of interest, annotate DMD with additional clinical phenotypes, molecular pathways, and protein-protein interactions. In drug development, NLP is capable of extracting biological and chemical molecules from existing literature that may interact with DMD pathways and have therapeutics effects.

As an example, Insilico Medicine has been developing an AI-driven platform that combines multiple datasets from various sources to classify therapeutic targets by their disease relevance, “druggability,” and clinical trajectory. One of the tools is called PandaOmics, which uses deep-learning and cloud-stored data to enable researchers to search information on diseases and their drug targets. The OMICs-sourced analysis of disease relevance is derived from Genome Wide Association Studies, Transcriptome Wide Association Studies, Online Mendelian Inheritance in Man, and the Library of Integrated Network-Based Cellular Signatures, to name a few data bases. For example, PandaOmics combs through clinical trial reports, grant applications, and publications data stemming from the labs mostly associated with the study of a specific disease or compound. This can help inform the larger community, including regulatory agencies, investors, and start-ups, on the basic importance of a target. Their proprietary pathway analysis approach uses iPANDA (in silico Pathway Activation Network Decomposition Analysis) to infer pathway alterations and find significant targets ( 43 ). Microarray expression data of skeletal muscles from DMD patients compared to healthy controls are used to quantify common transcriptional changes ( 44 – 47 ). Figures 2A,B illustrate a sample output of a PandaOmics meta-analysis showing some known disease targets and compounds used to treat DMD from the pre-clinical and clinical research stages to full approval for use. Thus, the advent of AI, in particular NLP, allows researchers to aggregate and unearth DMD mechanisms and potential therapeutics that was previously impossible due to the monumental size and siloed nature of existing DMD literature and databases.

Figure 2 . Sample meta-analysis from an A.I. driven therapeutics platform. (A) Summary of some of the top gene targets associated to DMD. (B) Summary of some of the top compounds associated to DMD for therapy. The evidence for classifying these molecules as the top targets is gleaned from various public databases plus the funding and publications landscape using PandaOmics ( http://pandaomics.com/ ).

Emerging DMD Multi-Omics Analysis Show Concord and Complexity

Multi-omics experiments for mechanistic insights of DMD have been performed on both animal models (e.g., mdx mouse) and human tissues (e.g., muscle biopsies), thus significantly increasing the diversity of datasets available for analysis. One of the earliest studies into the differences between normal and DMD skeletal muscle transcriptomes was performed on the hind limb and diaphragm muscles of mdx mice compared to control mice ( 48 ). This study reported several mechanisms of DMD, including differential expression of IGF-II, NF-kB, SERCA1, RYR1, α-tubulin, and collagens, among many others. A follow-up study comparing mRNA from the gastrocnemius muscle of mdx vs. control mouse used an array analysis of >12,000 genes ( 49 ). This study was in agreement with previous reports confirming differential expression of myogenin, α 2 -tubulin, lysozyme M, and myostatin, among others. It also reported upregulation of both IGF-I and IGF-II in dystrophic muscles, but discovered inhibitory IGF-binding proteins and regulators were also increased, thus counteracting the potential beneficial effects of their upregulation. This demonstrates an example of which analyses of multiple datasets are necessary to provide deeper understanding of mechanistic insights. More importantly, Bakay et al. compared their study with human DMD mRNA analyses ( 49 ). This revealed notable differences between the transcriptomes of the mdx mouse and human samples, including discordant directional changes in mRNA for myogenin, guanidinoacetate methyltransferase, calponin, and mast cell chymase.

Since these early investigations on the transcriptomic differences, subsequent studies further built upon these mechanistic insights using other omics approaches. For example, studies into microRNAs and chromatin changes revealed the importance of nitric oxide and its associated pathway in DMD pathogenesis ( 50 , 51 ). Proteomic analysis revealed that Bromodomain and extra-terminal domain (BET) protein BRD4 is significantly increased in the mdx mouse due to direct association to chromatin regulatory regions of the NADPH oxidase subunits ( 52 ). Epigenomic analysis, including that on histone acetylation of H3K14 and H3K9 and DNA methylations of Notch1, has revealed its role in regulating satellite cell fate during skeletal muscle regeneration and its dysregulation in DMD ( 53 ). Additional chromatin studies also revealed that nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in mdx hearts ( 54 ). Recent studies began looking more comprehensively into multi-omics analysis of mdx mouse and human iPSCs. These studies found discrepancies between different omics, such as only a 53% agreement in fold-change data between the proteome and transcriptome in mdx mice ( 55 ). Nonetheless, multi-omics studies continue to be a valuable approach in elucidating disease mechanisms as demonstrated by their ability to provide insight into early developmental manifestations of DMD in iPSC models of skeletal muscle differentiation ( 32 ). A main challenge remains in integrating these numerous multi-omics datasets into something more precisely meaningful and individually translatable for the patients.

Discovering, developing, and delivering targeted therapeutics requires substantial support and collaboration from both academia and industry. It also requires interdisciplinary studies and combinations of skillsets to enable progress. Much is said about how interdisciplinary research is the proper approach to tackling complex diseases even if it also brings challenges in communication and prioritization ( 56 , 57 ). These challenges can spill over to therapeutics studies where we evaluate how the data we generate correlate with seemingly disconnected sets and how certain factors influence the phenomena we are studying. Machine-learning may not be a new concept, but the influence it has had on biological studies in the past decade is founded on the many novel insights it has generated into how we visualize biological processes and problems ( 58 ). The field of DMD has been enriched by advancements in AI and deep learning that now make it possible to aggregate, interpret, and visualize high volumes of high-dimensional and non-linear datasets.

Theoretically, by combining better models of disease risk and severity with detailed analysis of different compounds, we will significantly improve our ability to treat and reduce cardiomyopathy-related deaths. Furthermore, as we approach the goal of fixing the underlying pathological mechanism of diseases like DMD, we must remember to rehabilitate and regenerate healthy tissues to counter persistent dysfunctions and avoid long-term hauling of these issues. To realize these precise therapies will require a convergence of data acquired from state-of-the-art tools and the prioritization of different research agencies and institutes. This will undoubtedly change business models for pharmaceutical and biotech companies, because this will involve a much greater role for drug repurposing, intellectual property disputes and bargains in the coming years. Moreover, on the scientific front, as the quality of analytical tools increases, we will also need the data to be reproducible and of higher quality. The tools we utilize to study cells from different tissues and lineages like iPSCs are becoming ever more reliable and sustainable with single-cell analysis being the standard. Some advances in AI are providing visually interesting graphics that link disease targets to compounds with clinical context. Multi-omics analysis is highlighting the different pathways a disease can take. These developments hold a great potential for improving healthcare by providing clinical researchers with accurate, high-resolution disease-models that will help illuminate the paths to improving patient outcomes.

Author Contributions

CV wrote the manuscript. AZ, PP, and JW revised the manuscript and provided critical input. All authors contributed to the article and approved the submitted version.

This work is supported by National Institutes of Health grants R01 HL126527, R01 HL130020, R01 HL123968, and R01 HL141371 (JW). Due to space limitation, we apologize in advance for not being able to include all references on this topic.

Conflict of Interest

JW is a co-founder of Greenstone Biosciences.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors would like to thank Blake Wu and Dr. Adrienne Mueller for critical feedback on the manuscript. The authors would like to acknowledge the platforms BioRender.com and PandaOmics.com for providing the means for creating the figures in this manuscript.

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Keywords: Duchenne muscular dystrophy, cardiomyopathy, iPSC disease modeling, drug testing, single-cell technology, artificial intelligence

Citation: Vera CD, Zhang A, Pang PD and Wu JC (2022) Treating Duchenne Muscular Dystrophy: The Promise of Stem Cells, Artificial Intelligence, and Multi-Omics. Front. Cardiovasc. Med. 9:851491. doi: 10.3389/fcvm.2022.851491

Received: 10 January 2022; Accepted: 31 January 2022; Published: 10 March 2022.

Reviewed by:

Copyright © 2022 Vera, Zhang, Pang and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Joseph C. Wu, joewu@stanford.edu

This article is part of the Research Topic

Intercellular Communication and Crosstalk in Cardiac Development and Disease

Duchenne Muscular Dystrophy Gene Therapy in 2023: Status, Perspective, and Beyond

Affiliations.

• 1 Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri, USA.
• 2 Department of Neurology, School of Medicine, University of Missouri, Columbia, Missouri, USA.
• 3 Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, USA.
• 4 Department of Chemical and Biomedical Engineering, College of Engineering, University of Missouri, Columbia, Missouri, USA.
• PMID: 37219994
• PMCID: PMC10325806
• DOI: 10.1089/hum.2023.29242.ddu

Duchenne muscular dystrophy (DMD) was named more than 150 years ago. About four decades ago, the DMD gene was discovered, and the reading frame shift was determined as the genetic underpinning. These pivotal findings significantly changed the landscape of DMD therapy development. Restoration of dystrophin expression with gene therapy became a primary focus. Investment in gene therapy has led to the approval of exon skipping by regulatory agencies, multiple clinical trials of systemic microdystrophin therapy using adeno-associated virus vectors, and revolutionary genome editing therapy using the CRISPR technology. However, many important issues surfaced during the clinical translation of DMD gene therapy (such as low efficiency of exon skipping, immune toxicity-induced serious adverse events, and patient death). In this issue of Human Gene Therapy , several research articles highlighted some of the latest developments in DMD gene therapy. Importantly, a collection of articles from experts in the field reviewed the progress, major challenges, and future directions of DMD gene therapy. These insightful discussions have significant implications for gene therapy of other neuromuscular diseases.

Keywords: CRISPR editing; Duchenne muscular dystrophy (DMD); adeno-associated virus (AAV); exon skipping; gene therapy; microdystrophin.

Publication types

• Research Support, Non-U.S. Gov't
• Research Support, U.S. Gov't, Non-P.H.S.
• Research Support, N.I.H., Extramural
• Clustered Regularly Interspaced Short Palindromic Repeats
• Gene Editing
• Genetic Therapy
• Muscular Dystrophy, Duchenne*

Grants and funding

• R01 AR070517/AR/NIAMS NIH HHS/United States
• R01 NS090634/NS/NINDS NIH HHS/United States
• R21 AR081018/AR/NIAMS NIH HHS/United States
• R56 AR081544/AR/NIAMS NIH HHS/United States

Duchenne Muscular Dystrophy Overview Research Paper

Introduction, background and symptoms, genetic issues, diagnostic process, medical management, and prognosis, concluding remarks.

Even mild muscle weakness can cause children discomfort and reduce their quality of life. Such a severe genetic disorder as Duchenne muscular dystrophy (DMD) leads to tremendous consequences for the muscular system and affects children very early in their development. Understanding the causes and implications of DMD for young children is imperative not only for raising awareness of the problem and recommending solutions for the management of the condition. The purpose of this paper is to provide an in-depth exploration of DMD, including its background and symptomology, genetic significance, diagnostic process and management, as well as prognosis.

Duchenne muscular dystrophy (DMD) is a genetic condition that is characterized by the continuous deterioration and weakness of muscle associated with changes in the composition of a protein called dystrophin, which maintains the functioning of muscle cells. The disorder is rare and affects males predominantly, with women being diagnosed with it only in exceptional cases. DMD causes the muscles in the body to become less resistant to physical impact and get damaged over time. Thus, the purpose of the paper is to explore Duchenne muscular dystrophy in great detail, including its causes, demographic data, signs and symptoms, the overall effect on the body, discuss the diagnostic process and prognosis for the disease.

Duchenne’s dystrophy develops as a result of a genetic mutation that does not allow the body to produce dystrophin, a protein needed to build muscles. Without the availability of enough dystrophin in the body, muscle cells weaken and become damaged. Children diagnosed with the disease at the early stages of life experience significant issues with walking and breathing, which decreases the quality of their lives (Birnkrant et al., 2018). Eventually, the muscles responsible for breathing stop working, which causes death. DMD is an irreversible, progressive disease that currently has no cure that could have alleviated the burden of the disease.

The estimated global prevalence of DMD is 4.78 per 100,000 males (Walter & Reilich, 2017). The implications of the condition also include a yearly disease burden of more than $130 million, without including costs for respiratory management, extra direct costs per one patient, as well as additional medical aids (Walter & Reilich, 2017). According to the official website dedicated to DMD, the average age of diagnosis is 5 years, while it takes 2.5 tears between the initial symptoms and diagnosis (“Duchenne muscular dystrophy: The basics,” 2019).

Being one of the most severe genetic diseases that affect children globally, DMD causes more than 90% of individuals being confined to a wheelchair by age 15 (“Duchenne muscular dystrophy: The basics,” 2019). The burden of the disease is severe, with DMD being diagnosed in 1 among 3,500 to 5,000 males around the world (“Duchenne muscular dystrophy: The basics,” 2019). The statistics on the disease show that it has an adverse effect on the young male population.

The principal symptom of DMD is muscle weakness, which can begin in patients as early as at ages 2-3 (Birnkrant et al., 2018). The proximal muscles get affected first due to the fact that they are the closest to body’s core. The distal limb muscles get affected later because they are close to the body’s extremities (Birnkrant et al., 2018). Furthermore, it is notable that lower external muscles usually show DMD symptoms prior to the upper ones. In affected children, there are noticeable difficulties walking, running, and jumping, which decreases the quality of movement. Other symptoms of the disease include calves’ enlargement, waddle in the gait, as well as lumbar lordosis (Birnkrant et al., 2018).

The latter is a DMD sign implying an inward spine curve. Due to the difficulties associated with muscle strength, the affected children develop issues with the heart and respiratory muscles. The progressive weakness in the body, coupled with scoliosis, can lead to the development of impaired pulmonary function that causes acute respiratory failure.

When exploring the possible symptoms of DMD in their children, parents should understand that muscle deterioration may not be as painful as it is. This is because muscular dystrophy does not have a direct effect on the nerves, with touch and other senses being normal. This is also true for the functions of the bladder and the bowel. Furthermore, it is essential to note the development of learning disabilities among children with DMD.

While serious cognitive disabilities are rare, dystrophin abnormalities in the brain can have minor effects on both cognition and behavior (“Duchenne muscular dystrophy: The basics,” 2019). Learning problems can occur with focusing attention, memory and verbal learning, as well as emotional interactions. Children with learning disabilities who have DMD are usually evaluated by developmental or pediatric neuropsychologists who provide referrals to special education departments. Therefore, the manifestations of DMD can vary from developmental to physical impairments, which points to the need for managing the complications from the point of a multi-dimensional approach.

The underlying genetic defect that causes the condition’s development occurs in the dystrophin gene with an X-linked trait. This means that there is a mutation, an error, in one of the body’s genes that causes the DMD diagnosis. The dystrophin gene contains 79 exons, which are connected to create instructions intended for forming dystrophin protein, which is needed for muscle development (“Genetic testing: A Duchenne fingerprint,” 2019).

Within DMD, there may be three forms of genetic mutations. The first type of mutation is concerned with large deletions, with one and more exons missing from the dystrophin gene. The second type is concerned with large duplications, which means that one or more exons create copies of one another within the dystrophin gene. The third type refers to other changes in the gene, with small alterations taking place and ranging from deletions to changes in a single letter in a gene makeup.

As seen in the diagram below, large deletions of one or more exons in the gene (Figure 1). Similar to a puzzle, the missing pieces in the gene prevent the remaining exons from properly fitting together. This causes errors in the instructions for making dystrophin, with the body not being able to produce the necessary amount of dystrophin protein.

Understanding the importance of genetic mutations as related to DMD is essential because scholars have recorded more than 1,800 different changes in people’s diagnoses with either Duchenne or Becker types of muscular dystrophy. Knowing the kind of mutation that has occurred in a child is a fundamental step for considering the types of management (Bendixen & Houtrow, 2017). In order to determine the kind of genetic change, doctors prescribe a genetic test that provides further information on disease management. Moreover, children can be subjected to clinical trials that are currently being conducted to develop innovative treatments.

Different methods of genetic testing can be used for getting a full picture of a child’s mutation. For instance, complete gene sequencing can help to reveal small modifications in a gene. It is also important to note that since Duchenne is a genetic disorder, it can be inherited from one family member to another. The characteristic of DMD as an X-linked disease means that mutations are only found in the X chromosome (“Genetic testing: A Duchenne fingerprint,” 2019).

Therefore, in cases when women have Duchenne-causing mutations in their chromosomes, they are considered carriers of the disease. Carriers will most likely have no symptoms of DMD but will be capable of passing the gene along to a child; although, there is no certainty that the mutation will be transferred. The chance of having a boy from Duchenne from a carrier mother is 25%, with the same likelihood of 25% applied to having a carrier girl (“Genetic testing: A Duchenne fingerprint,” 2019).

This means that there is a 50% chance that a mother-carrier will have a baby with no mutation at all. In case when Duchenne is under suspicion, genetic testing is recommended, including carrier testing, in order to provide valuable information for making further decisions on treatment. Besides, the expertise of a genetic counselor can be highly helpful for explaining what genetic results on Duchenne can mean for families.

As mentioned in the previous sections, Duchenne muscular dystrophy is a rare inherited disease of the neuromuscular system that has no known cure at this time. DMD is usually suspected in mostly boys who display abnormal gait patterns and complications with physical activity, such as running or climbing stairs. Despite the fact that the current diagnostic process is straightforward, supported with more than 3 decades of research, there is still no solution to overcoming the healthcare challenge (Bendixen & Houtrow, 2017).

Furthermore, the American Academy of Pediatrics (2015) underlines the importance of addressing the concerns of parents about children’s development as soon as possible, especially in cases of more progressive and pronounced motor delays. Getting a formal DMD diagnosis is imperative for understanding a specific genetic mutation and determining an appropriate care path.

When a family pediatrician is concerned with the possibility of a DMD diagnosis in a child, a recommendation and referral for testing are made. An expert in neuromuscular management or a pediatric neurologist will further work to identify the causes of the symptoms and prescribe appropriate genetic and non-genetic testing.

Thus, the typical steps in identifying the disease include observing the signs and symptoms, conducting blood tests for determining enzyme levels (including CK test), genetic testing, and muscle biopsy when needed (Bendixen & Houtrow, 2017). A CK test will measure the blood’s concentration of creatine kinase, which would signify damage in muscle cells (Bendixen & Houtrow, 2017). The high levels of the enzyme in the blood will point to a muscle problem, but not confirm Duchenne as a final diagnosis as the testing is usually the first step.

Genetic testing is prescribed when an elevated level of CK is found, which means that Duchenne is suspected. This test will analyze the genetic makeup of an individual to determine a change in the dystrophin gene (Bendixen & Houtrow, 2017). When such a modification is identified, further decisions on management are made. A muscle biopsy may be prescribed when there is not enough certainty provided by a genetic test. While most patients do not require the biopsy, it is used for gathering more information.

Since there is no treatment for overcoming muscular dystrophy completely, some preventative and management efforts are taken to reduce the burden of disease. Treatment options predominantly range from medications to surgical procedures that help patients live with DMD and manage the condition’s symptoms. Doctors can prescribe heart medications and corticosteroids, as well as the Food and Drug Administration approved a drug called Eteplirsen (Exondys 51) (Bendixen & Houtrow, 2017). Despite being approved and safe for use, the drug has not shown significant evidence of effectiveness. While it may not cure DMD, it has the potential of improving muscle strength through acting on specific gene variants.

Corticosteroids are sometimes necessary for strengthening the muscle mass and delaying the development of certain types of dystrophy in children. The adverse effects of using corticosteroids over prolonged time periods include weight gain and weakened bone integrity, which increases the risk of fracture. Medications for the heart, such as angiotensin-converting enzyme (ACE) inhibitors and beta blockers, are usually prescribed when muscular dystrophy causes damage to the heart (Bourke et al., 2018). Overall, despite being prescribed to patients with DMD, medications cannot guarantee long-term maintenance of relative well-being.

Therapy and assistive devices are used as additional methods for managing life with DMD. Children diagnosed with the condition may do range-of-motion and stretching exercises to maintain high levels of mobility and flexibility of muscles as the disease causes limbs to be drawn forward and maintain in such a position (Magee, Zachazewski, Quillen, & Manske, 2015). Low-impact aerobic exercises that range from swimming to walking can help patients maintain the general health and mobility of children. Although, any activities should be verified with a doctor first since they can also be damaging. Braces and mobility aids are supplementary tools that maintain mobility independence and muscle stretchiness (Magee et at., 2015).

Breathing assistance is implemented when children’s respiratory muscles weaken. Severe cases of muscular dystrophy may call for the use of a ventilator that would force the air to travel to and from the lungs. It is also important to note that Duchenne may call for a surgery that would improve spiral curvature that limits breathing.

At this time, the prognosis for patients diagnosed with DMD does not include recovery. The adverse impact on children’s health causes a significant deterioration in life quality, leading to the need to monitor vitals continuously. For example, parents should always be aware of respiratory infection risks in more severe stages of muscular dystrophy in their children. Proper nutrition is also necessary to help prevent obesity, dehydration, and bowel movement issues. Seeking support from communities to help families cope with DMD contributes to the increased chances of living with the condition (Magee et at., 2015).

Therefore, psychological assistance is as valuable as physical management of the disease when it comes to complex genetic limitations such as Duchenne muscular dystrophy. Since DMD causes individuals with the condition to die the latest in their early twenties, extensive research is necessary to develop treatments that would be effective in overcoming the disease.

Duchenne muscular dystrophy presents a significant challenge for the health care industry because of its severe impact on the well-being and development of children. Since DMD has no cure at the present time, it requires significant control on the part of children’s families and healthcare providers. While the combination of mild exercising and prescription medication can help patients deal with the disorder, the absence of effective interventions and treatment calls for further research and clinical trials.

American Academy of Pediatrics. (2015). Pediatric clinical practice guidelines & policies: A compendium of evidence-based research for pediatric practice . Elk Grove Village, IL: AAP.

Bendixen, R. M., & Houtrow, A. (2017). Parental reflections on the diagnostic process for Duchenne muscular dystrophy: A qualitative study. Journal of Pediatric Health care: Official Publication of National Association of Pediatric Nurse Associates & Practitioners, 31 (3), 285-292.

Birnkrant, D. J., Bushby, K., Bann, C. M., Apkon, S. D., Blackwell, A., Brumbaugh, D., … DMD Care Considerations Working Group (2018). Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. The Lancet. Neurology, 17 (3), 251-267.

Bourke, J. P., Watson, G., Muntoni, F., Spinty, S., Roper, H., Guglieri, M., … DMD Heart Protection study group (2018). Randomized placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): A protocol study. BMJ Open, 8 (12), e022572.

Duchenne muscular dystrophy: The basics . (2019). Web.

Genetic testing: A Duchenne fingerprint . (2019). Web.

Magee, D., Zachazewski, J., Quillen, W., & Manske, R. (2016 ). Pathology and intervention in musculoskeletal rehabilitation . Maryland Heights, MO: Elsevier.

Walter, M. C., & Reilich, P. (2017). Recent developments in Duchenne muscular dystrophy: facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, 8 (5), 681-685.

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Duchenne Muscular Dystrophy: the global clinical trials landscape 2024

Affecting muscle and skeletal strength, this rare genetic disorder impacts thousands of men worldwide. Innovative new genetic therapies in development across the globe are improving the quality of life for many.

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Impacting approximately 1 in 5,000 males globally, Duchenne Muscular Dystrophy is a rare genetic disorder characterised by progressive muscle weakness and skeletal degeneration. The prevalence of Duchenne Muscular Dystrophy is higher in certain regions, with Europe, particularly Sweden and Norway, along with the US, Canada, and China reporting elevated rates. This emphasises the considerable health burden associated with this condition, necessitating concerted efforts in research and treatment.  

A new report from leading contract research organisation (CRO) Novotech dives deeper into the current clinical trials landscape and the status of experimental treatments for Duchenne Muscular Dystrophy. Treatment typically involves the administration of glucocorticoids, such as deflazacort, to manage symptoms and slow disease progression. These medications have demonstrated effectiveness in improving motor function, strength, and pulmonary function, while also reducing the risk of complications like scoliosis and cardiomyopathy.  

Recent advancements in Duchenne Muscular Dystrophy treatment include genetic therapies, such as exon-skipping treatments like eteplirsen, golodirsen, and viltolarsen, as well as premature termination codon read-through therapy with ataluren. These innovative therapies target the underlying cause of Duchenne Muscular Dystrophy by addressing the deficiency of the dystrophin protein, which is central to the disease’s pathology, and could be the key to relief for thousands of patients around the world. 

Global trials test new treatments 

Novotech’s report finds that the global biotech and biopharmaceutical industry has initiated around 300 clinical trials for Duchenne Muscular Dystrophy since 2019. North America and Europe collectively conducted over 60% of Duchenne Muscular Dystrophy trials, with the UK and US leading in their respective regions. In contrast, the Asia-Pacific region, led by countries like Australia and Japan, contributed around 30% of trials. Europe demonstrated shorter recruitment durations and faster recruitment rates compared to Asia-Pacific and the US, highlighting regional variations in trial efficiency.  

Ongoing research initiatives are exploring diverse strategies to comprehend and address the pathogenesis of Duchenne Muscular Dystrophy. Current investigations are actively examining approved gene and RNA therapies, encompassing approaches such as gene replacement, exon skipping, and the suppression of nonsense mutations.  

Promising areas of focus include cell therapies utilising muscle precursor cells or stem cells, techniques geared towards membrane stabilisation, and interventions addressing secondary cascades. These secondary cascades include the development of anti-inflammatory and antifibrotic drugs. The dynamic landscape of gene therapies for Duchenne Muscular Dystrophy has witnessed several approved treatments in the past decade, and numerous investigational therapies contribute to ongoing research and development efforts.  

Among the marketed drugs for Duchenne Muscular Dystrophy treatments, both Small Molecules and Antisense Oligonucleotides play prominent roles. Drugs like Casimersen, Viltolarsen, Deflazacort, and Delandistrogene Moxeparvovec are available globally, providing tangible options for individuals and families navigating the complexities of managing Duchenne Muscular Dystrophy. 

This multifaceted approach to Duchenne Muscular Dystrophy, encompassing genetic therapies, clinical trials, and pharmacologic treatments, offers hope for improved outcomes and enhanced quality of life for those affected by this challenging disorder. Continued research and collaborative efforts worldwide underscore the commitment to addressing the complexities of Duchenne Muscular Dystrophy. 

To learn more about the Duchenne Muscular Dystrophy clinical trials landscape in 2024, download the free report below.  

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Duchenne muscular dystrophy - global clinical trial landscape (2024).

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Parent project muscular dystrophy awards $250,000 to support clinical research network for duchenne babies identified by newborn screening.

WASHINGTON , April 29, 2024 /PRNewswire/ -- Parent Project Muscular Dystrophy (PPMD) , a nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne) , is excited to announce a $250,000 award to Bo Hoon Lee , MD, from the University of Rochester to support the development of a clinical research network for Duchenne babies identified through newborn screening efforts in New York State (NYS). The initiative aims to support newborn screening implementation efforts, inform clinical care guidelines for young patients, and lay the foundation for expansion of the network across states.

Duchenne is the most common genetic condition diagnosed in childhood, affecting approximately one in 5,000 live male births. Early diagnosis is critical for implementing timely interventions, establishing strong relationships with care teams, and exploring all available treatment options. Yet, a significant diagnostic delay results in patients not receiving a Duchenne diagnosis until reaching a mean age of 4-5 years.

For over a decade, PPMD has championed newborn screening for Duchenne, including spearheading a pilot study in NYS that took place between 2019 and 2021. The pilot study was a collaborative effort between PPMD, the New York State Newborn Screening (NYS NBS) program, Northwell Health Hospitals, New York-Presbyterian Hospitals, the National Institutes of Health (NIH)-supported Newborn Screening Translational Research Network (NBSTRN) housed at the American College of Medical Genetics and Genomics (ACMG), along with generous funders. In October 2023 , New York Governor Hochul signed bill S6814/A5042, making Duchenne newborn screening mandatory for all babies born in the state.

With the anticipated start of newborn screening in NYS later this year, there is an imminent need and unique opportunity to prospectively collect natural history and clinical outcomes data in these young patients. While outcome measures and rates of progression for children over age 4 are well understood, major gaps persist in trial readiness and evidence-based clinical care guidelines for the 0- to 3-year-old group. Dr. Lee's project, referred to as Baby Duchenne , aims to establish a collaborative clinical network and database to enroll and prospectively follow all babies identified by newborn screening in NYS with genetically confirmed Duchenne. This network will provide the much-needed early natural history of Duchenne, advance understanding of the benefits of early diagnosis to support national newborn screening efforts, and inform clinical trial design for the very young Duchenne patient population.

Dr. Lee's team will leverage the currently established clinical network of pediatric neuromuscular centers initially designated for spinal muscular atrophy newborn screening to build a network infrastructure to capture all Duchenne diagnoses identified via newborn screening in NYS. The network will include two  Certified Duchenne Care Centers in NYS, the University of Rochester Medical Center and Stony Brook Children's Hospital, which will serve as the downstate and upstate hubs of the network. Through the development of a REDCap database of minimum core evaluations and assessments to be collected, the team aims to inform guidelines to standardize outcome measures across states implementing newborn screening over time. The ultimate goal is to establish a strong statewide network to allow expansion and inclusion of other early-screening states, such as Ohio and Minnesota , over time into the Baby Duchenne network.

Pat Furlong , PPMD's President and CEO, emphasizes the critical significance of newborn screening and the importance of this project, stating, "Newborn screening is vital for ensuring early diagnosis and intervention for babies with Duchenne. Dr. Lee's Baby Duchenne project holds immense promise in supporting these newborn screening implementation efforts. By establishing a robust clinical research network and database, we aim to not only advance our understanding of Duchenne but also pave the way for more effective treatments and improved outcomes. This initiative further extends PPMD's commitment to break down barriers related to the diagnosis, care, and treatment of every single person living with Duchenne, at all stages of life."

Dr. Lee expresses gratitude for the funding from PPMD, stating:

"This generous support from PPMD is pivotal in our work to advance care for Duchenne babies identified through newborn screening. With this funding, we can establish a collaborative clinical research network and database, enabling us to collect vital data that will inform early care guidelines and improve outcomes for these young patients. PPMD's investment underscores their commitment to advancing research and improving the lives of individuals with Duchenne, and we are deeply grateful for their partnership in this important endeavor."

ABOUT PARENT PROJECT MUSCULAR DYSTROPHY

Duchenne  is a genetic disorder that slowly robs people of their muscle strength. Parent Project Muscular Dystrophy (PPMD) fights every single battle necessary to end Duchenne.

We demand optimal care standards and ensure every family has access to expert healthcare providers, cutting edge treatments, and a community of support. We invest deeply in treatments for this generation of Duchenne patients and in research that will benefit future generations. Our advocacy efforts have secured hundreds of millions of dollars in funding and won eight FDA approvals.

Everything we do—and everything we have done since our founding in 1994—helps those with Duchenne live longer, stronger lives. We will not rest until we end Duchenne for every single person affected by the disease. Join our fight against Duchenne at EndDuchenne.org . Follow PPMD on Facebook , Twitter , Instagram , and YouTube .

View original content to download multimedia: https://www.prnewswire.com/news-releases/parent-project-muscular-dystrophy-awards-250-000-to-support-clinical-research-network-for-duchenne-babies-identified-by-newborn-screening-302130082.html

SOURCE Parent Project Muscular Dystrophy (PPMD)

My son's smile gives me hope for Duchenne muscular dystrophy. A new law could help others

Opinion: newborn testing can give families a head start on giving a child with the degenerative muscular disease a shot at the best outcome in life..

Like most mothers, I only saw perfection when my first son was born. That quickly changed when we began to question pediatricians about his physical and cognitive delays.

Don’t worry, they said. Boys develop slower; they all catch up by 3.

However, by that time, Anthony still couldn’t climb stairs, fell often and barely spoke.

Finally, when we were approved for evaluation, we received a devastating diagnosis: Duchenne muscular dystrophy .

Duchenne muscular dystrophy is rare

Duchenne is a rare, progressive disorder in which muscle cells are in a constant state of destruction.

The doctor estimated Anthony would need a wheelchair between ages 8 and 10 , and his heart and lungs would give out between 12 and 20 . There was nothing we could do, they said. We should just go home and love Anthony for the time we had.

I refused to follow those directions, even though zero Duchenne therapies existed.

And today, I’m still challenging passive norms.

With eight  FDA-approved tre atments commercially available and 39 more in the pipeline , families shouldn’t have to wait years for symptoms to show when a simple test could deliver a diagnosis and ensure optimal care from birth.

Arizona lawmakers, led by Sen. T.J. Shope, are actively reviewing  Senate Bill 1020  to adopt statewide newborn screening for Duchenne. Once the bill passes the budget committee, it will head to the floor for a final vote.

I urge every member to quickly pass this legislation. There is no time to spare when a child’s freedom of mobility is wasting away. In DMD, time is muscle.

Early diagnosis, treatment makes a difference

Our family lived the harrowing diagnostic odyssey firsthand: two years of appointments, three gene-sequencing tests and six doctors to finally get Anthony’s results. Doctors were often unsupportive when I uncovered and attempted to share information they didn’t know.

Several dismissed me as just a “crazy” mom.

My desperation paid off in 2008 when Anthony became Patient No. 1 in the first trial for a Duchenne treatment. We considered ourselves the luckiest of the unlucky.

Most families didn’t (and still don’t) get a diagnosis until after age 5. Although we spent those years putting Anthony through surgeries, traveling back and forth to the clinical site, and missing school and work ... at least we had hope.

Every family that unwillingly joins our Duchenne community deserves the same.

Arizona tests newborns for 35 conditions on the  Recommended Uniform Screening Panel from the U.S. Department of Health and Human Services.

Our state lawmakers have life-changing power to add Duchenne to the routine testing every infant already receives.

Universal screening could help other families

By pushing to discover DMD earlier than most, I had time to figure out how to still earn a living despite all the doctor visits and clinical trial travel. I had time to save for a handicap van, home modifications and all the durable medical equipment insurance doesn’t cover.

I had time to get emotional support so I could be healthy and strong enough to care for Anthony and his brother, Oliver.

Arizona must screen: For more disorders

With the benefit of newborn screening, the next generation of families will have even more time to evaluate, pursue and access FDA-approved Duchenne therapies while avoiding extensive surgeries, limitations and suffering.

Even though most new treatments won’t benefit Anthony, his early interventions did.

Today at 24, partly due to staying up on his feet until 14, there has been far less impact on his heart and lungs compared to what was originally projected. He has enjoyed many adventures and been encouraged to pursue his dreams.

And although he now has only limited use of his hands, the muscles DMD don’t impact are the ones he uses to smile.

Even though almost every daily living task — including showering, toileting, eating and even scratching an itch — requires help from family and caregivers, Anthony manages to seek joy every day.

Because of that, when I think about his sacrifices and our legacy efforts to improve Duchenne outcomes for other newborns and families in Arizona, I smile, too.

Jill Castle is an education and behavioral specialist, an adjunct professor at Arizona State University, and a national advocacy leader with  Little Hercules Foundation . She's a consultant with  Parent Project Muscular Dystrophy . Reach her at  [email protected] .