Longitudinal natural history in young boys with Duchenne muscular dystrophy

Coratti, Giorgia; Brogna, Claudia; Norcia, Giulia; Ricotti, Valeria; Abbott, Lianne; D’Amico, Adele; Berardinelli, Angela; Vita, Gianluca; Lucibello, Simona; Messina, Sonia; Sansone, Valeria; Albamonte, Emilio; Colia, Giulia; Salmin, Francesca; Gardani, Alice; Manzur, Adnan; Main, Marion; Baranello, Giovanni; Arnoldi, Maria Teresa; Parsons, Julie; Carry, Terri; Connolly, Anne M.; Bertini, Enrico; Muntoni, Francesco; Pane, Marika; Mercuri, Eugenio

doi:10.1016/j.nmd.2019.09.010

Cited by 26 publications

(20 citation statements)

References 22 publications

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“…At baseline, the patient population had decreased ambulation and endurance comparable to similarly-aged DMD patients [34 , 36] , which were reduced compared to historical data for healthy subjects of similar age. During the off-treatment control period, all functional assessments showed decline, and the decline in NSAA was consistent with that observed in the boys of similar age in a recent study [33] . Edasalonexent treatment was associated with a positive change in the trajectory of decline for NSAA and age-appropriate timed function tests.…”

Section: Discussionsupporting

confidence: 89%

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Finkel

Finanger

Vandenborne

et al. 2021

Neuromuscular Disorders

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Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-< 8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T 2 relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.

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Section: Discussionsupporting

confidence: 89%

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Finkel

Finanger

Vandenborne

et al. 2021

Neuromuscular Disorders

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“…The NSAA is a strength-based functional mobility scale developed for administration in ambulant boys with Duchenne Muscular Dystrophy (DMD), 22 as young as 3 years. 22,56 Typically developing children with independent motor function should attain an NSAA full score of 34, 57 while an NSAA score of 13 predicts DMD loss of ambulation within 24 months from the time of measurement. 58 In our MM cohort, NSAA revealed a mean score of 25.1 ± 1.3, mean ± SEM (n = 58, Table S10), which would be equivalent to the mean score of a 7-to 8-year-old boy with DMD on daily prednisolone.…”

Section: Comparison Of MM Objective Assessments To the North Star Ambulatory Assessment (Nsaa) Of Motor Functionmentioning

confidence: 99%

Development of a Mitochondrial Myopathy‐Composite Assessment Tool

Flickinger

Fan

Wellik

et al. 2021

JCSM Clinical Reports

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Background‘Mitochondrial Myopathy’ (MM) refers to genetically‐confirmed Primary Mitochondrial Disease (PMD) that predominantly impairs skeletal muscle function. Validated outcome measures encompassing core MM domains of muscle weakness, muscle fatigue, imbalance, impaired dexterity, and exercise intolerance do not exist. The goal of this study was to validate clinically‐meaningful, quantitative outcome measures specific to MM.MethodsThis was a single centre study. Objective measures evaluated included hand‐held dynamometry, balance assessments, Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), 30 second Sit to Stand (30s STS), and 6‐minute walk test (6MWT). Results were assessed as z‐scores, with < −2 standard deviations considered abnormal. Performance relative to the North Star Ambulatory Assessment (NSAA) of functional mobility was assessed by Pearson's correlation.ResultsIn genetically‐confirmed MM participants [n = 59, mean age 21.6 ± 13.9 (range 7 – 64.6 years), 44.1% male], with nuclear gene aetiologies, n = 18/59, or mitochondrial (mtDNA) aetiologies, n = 41/59, dynamometry measurements demonstrated both proximal [dominant elbow flexion (−2.6 ± 2.1, mean z‐score ± standard deviation, SD), hip flexion (−2.5 ± 2.3), and knee flexion (−2.8 ± 1.3)] and distal muscle weakness [wrist extension (−3.4 ± 1.7), palmar pinch (−2.5 ± 2.8), and ankle dorsiflexion (−2.4 ± 2.5)]. Balance [Tandem Stance (TS) Eyes Open (−3.2 ± 8.8, n = 53) and TS Eyes Closed (−2.6 ± 2.7, n = 52)] and dexterity [FDT (−5.9 ± 6.0, n = 44) and 9HPT (−8.3 ± 11.2, n = 53)] assessments also revealed impairment. Exercise intolerance was confirmed by strength‐based 30s STS test (−2.0 ± 0.8, n = 38) and mobility‐based 6MWT mean z‐score (−2.9 ± 1.3, n = 46) with significant decline in minute distances (slope −0.9, p = 0.03, n = 46). Muscle fatigue was quantified by dynamometry repetitions with strength decrement noted between first and sixth repetitions at dominant elbow flexors (−14.7 ± 2.2%, mean ± standard error, SEM, n = 21). All assessments were incorporated in the MM‐Composite Assessment Tool (MM‐COAST). MM‐COAST composite score for MM participants was 1.3 ± 0.1 (n = 53) with a higher score indicating greater MM disease severity, and correlated to NSAA (r = −0.64, p < 0.0001, n = 52) to indicate clinical meaning. Test–retest reliability of MM‐COAST assessments in an MM subset (n = 14) revealed an intraclass correlation coefficient (ICC) of 0.81 (95% confidence interval: 0.59–0.92) indicating good reliability.ConclusionsWe have developed and successfully validated a MM‐specific Composite Assessment Tool to quantify the key domains of MM, shown to be abnormal in a Definite MM cohort. MM‐COAST may hold particular utility as a meaningful outcome measure in future MM intervention trials.

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“…Projects dedicated to genetic diagnosis and geno-phenotype correlation led to the characterization of large disease-specific patient cohorts [12][13][14][15][16][17][18][19][20]. In addition to increasing disease knowledge, these studies contributed to identifying patients and families still missing a genetic diagnosis that underwent new genetic examination, with many families receiving appropriate genetic counselling [21][22][23][24].…”

Section: Outcomes Of the Studiesmentioning

confidence: 99%

Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients

Ambrosini

Baldessari

Pozzi

et al. 2021

Orphanet J Rare Dis

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In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

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Longitudinal natural history in young boys with Duchenne muscular dystrophy

Cited by 26 publications

References 22 publications

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Development of a Mitochondrial Myopathy‐Composite Assessment Tool

Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients

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