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Annals of Neurology Nov 2023Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103;...
Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).
OBJECTIVE
Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec.
METHODS
In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 10 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control.
RESULTS
The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001.
INTERPRETATION
Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.
Topics: Male; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Genetic Therapy; Infusions, Intravenous; Muscle Fibers, Skeletal
PubMed: 37539981
DOI: 10.1002/ana.26755 -
BMJ Case Reports Mar 2024-associated myopathy is a rare genetic form of limb-girdle muscular dystrophy (LGMD) with only 23 previous cases having been reported in the literature. The exact role...
-associated myopathy is a rare genetic form of limb-girdle muscular dystrophy (LGMD) with only 23 previous cases having been reported in the literature. The exact role of in the pathophysiology of LGMD remains unclear. We describe two brothers who presented to the neuromuscular clinic with progressive weakness of their upper and lower limbs over the preceding decades. Our case highlights how recent advancements in genetic sequencing have revolutionised the diagnostic classification process for LGMD and provided opportunities to establish diagnoses for previously unclassified myopathies. We also illustrate how the increased adoption of muscle MRI to identify disease and target muscle biopsy can provide better quality and more informative samples for classification. Finally, our report details the clinical and histopathological findings found in both cases adding valuable data to the currently limited information published on -associated myopathy.
Topics: Male; Humans; Muscular Diseases; Muscular Dystrophies, Limb-Girdle; Muscles; Mutation
PubMed: 38553017
DOI: 10.1136/bcr-2024-259907 -
Journal of Neurology Aug 2023Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in...
Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis.
OBJECTIVE
Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).
METHODS
Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression.
RESULTS
As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone.
CONCLUSION
Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.
Topics: Humans; Codon, Nonsense; Muscular Dystrophy, Duchenne; Registries; Disease Progression
PubMed: 37115359
DOI: 10.1007/s00415-023-11687-1 -
Current Opinion in Neurology Oct 2023Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our... (Review)
Review
PURPOSE OF REVIEW
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present.
RECENT FINDINGS
To date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations. Accordingly, FSHD drug development has been escalating in the last years in an attempt to silence DUX4 or to block its downstream effectors. Breakthroughs in the field include the awareness that new biomarkers and outcome measures are required for tracking disease progression and patient stratification. The need to develop personalized therapeutic strategies is also crucial according to the phenotypic variability observed in FSHD subjects.
SUMMARY
We analysed 121 literature reports published between 2021 and 2023 to assess the most recent advances in FSHD clinical and molecular research.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Biomarkers; Drug Development; Homeodomain Proteins; Muscle, Skeletal
PubMed: 37338810
DOI: 10.1097/WCO.0000000000001176 -
Biomolecules Oct 2023Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as... (Review)
Review
Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair. Here, we examine the pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies.
Topics: Humans; Muscular Dystrophy, Duchenne; Heart; Cardiomyopathies; Inflammation; Fibrosis
PubMed: 37892218
DOI: 10.3390/biom13101536 -
Pediatric Pulmonology Dec 2023
Topics: Humans; Muscular Dystrophy, Duchenne; Respiratory Rate
PubMed: 37737458
DOI: 10.1002/ppul.26692 -
Muscle & Nerve Jan 2024Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular...
INTRODUCTION/AIMS
Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD.
METHODS
An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 10 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests.
RESULTS
Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125).
DISCUSSION
Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.
Topics: Child; Child, Preschool; Humans; Male; Disease Progression; Genetic Therapy; Muscular Dystrophy, Duchenne; Prednisone
PubMed: 37577753
DOI: 10.1002/mus.27955 -
International Journal of Molecular... Jul 2023Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on... (Review)
Review
Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on human disease. As a result, targeted splicing therapeutics have been developed, treating various diseases including spinal muscular atrophy and Duchenne muscular dystrophy. These advancements are very promising and emphasize the critical role of proper splicing in maintaining human health. Herein, we provide an overview of the current information on the composition and assembly of early splicing complexes-commitment complex and pre-spliceosome-and their association with human disease.
Topics: Humans; RNA Splicing; Spliceosomes; Muscular Dystrophy, Duchenne; Muscular Atrophy, Spinal; RNA Precursors
PubMed: 37511171
DOI: 10.3390/ijms241411412 -
Trends in Molecular Medicine Jul 2023Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children... (Review)
Review
Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.
Topics: Humans; AMP-Activated Protein Kinases; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Myotonic Dystrophy
PubMed: 37080889
DOI: 10.1016/j.molmed.2023.03.008 -
Circulation. Heart Failure Aug 2023
Topics: Humans; Muscular Dystrophy, Duchenne; Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated; Biomarkers
PubMed: 37288552
DOI: 10.1161/CIRCHEARTFAILURE.123.010700