Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy

Hibma, Jennifer; Jayachandran, Priya; Neelakantan, Srividya; Harnisch, Lutz

doi:10.1002/psp4.12921

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…One of the hurdles in developing novel therapeutics in the DMD space is that there is large interindividual variability in clinical outcome measures, such as the NSAA and the Six Minute Walk Test (6MWT). In literature, population nonlinear mixed‐effect models characterizing longitudinal changes in clinical endpoints, such as 6MWT and NSAA, have been developed to enhance the quantitative understanding of DMD disease progression 63–65 . However, given the large variability in these endpoints, it is difficult to demonstrate treatment effect and thus may require large sample size to achieve adequate statistical power.…”

Section: Discussionmentioning

confidence: 99%

“…In literature, population nonlinear mixed‐effect models characterizing longitudinal changes in clinical endpoints, such as 6MWT and NSAA, have been developed to enhance the quantitative understanding of DMD disease progression. 63 , 64 , 65 However, given the large variability in these endpoints, it is difficult to demonstrate treatment effect and thus may require large sample size to achieve adequate statistical power. For this reason, sensitive and objective surrogate endpoints that can reliably correlate with longer‐term functional measures have utility and hold potential to enable better clinical trial design for the development of novel therapies in DMD.…”

Section: Discussionmentioning

confidence: 99%

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Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy

Deng,

Liu,

Feng

et al. 2024

CPT Pharmacom & Syst Pharma

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Duchenne muscular dystrophy (DMD) is a rare X‐linked recessive disorder characterized by loss‐of‐function mutations in the gene encoding dystrophin. These mutations lead to progressive functional deterioration including muscle weakness, respiratory insufficiency, and musculoskeletal deformities. Three‐dimensional gait analysis (3DGA) has been used as a tool to analyze gait pathology through the quantification of altered joint kinematics, kinetics, and muscle activity patterns. Among 3DGA indices, the Gait Profile Score (GPS), has been used as a sensitive overall measure to detect clinically relevant changes in gait patterns in children with DMD. To enhance our understanding of the clinical translation of 3DGA, we report here the development of a population nonlinear mixed‐effect model that jointly describes the disease progression of the 3DGA index, GPS, and the functional endpoint, North Star Ambulatory Assessment (NSAA). The final model consists of a quadratic structure for GPS progression and a linear structure for GPS‐NSAA correlation. Our model was able to capture the improvement in function in GPS and NSAA in younger subjects, as well as the decline of function in older subjects. Furthermore, the model predicted NSAA (CFB) at 1 year reasonably well for DMD subjects ≤7 years old at baseline. The model tended to slightly underpredict the decline in NSAA after 1 year for those >7 years old at baseline, but the prediction summary statistics were well maintained within the standard deviation of observed data. Quantitative models such as this may help answer clinically relevant questions to facilitate the development of novel therapies in DMD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy

Deng,

Liu,

Feng

et al. 2024

CPT Pharmacom & Syst Pharma

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“…В 3-5 лет наступает фаза плато, когда ребёнок перестаёт осваивать новые моторные навыки, после этого начинается двигательный регресс, который влечёт за собой осложнения со стороны костной, сердечно-сосудистой и дыхательной систем. При естественном течении заболевания уже к 12 годам дети утрачивают способность к самостоятельному передвижению, смерть наступает от дыхательной и сердечно-сосудистой недостаточности в возрасте 20-25 лет [8].…”

Section: Introductionunclassified

Clinical case of management of a patient with Duchenne muscular dystrophy caused by deletion of exons 50–52 of the DMD gene against the background of pathogenetic therapy with viltolarsen

Kuzenkova,

Podkletnova,

Uvakina

et al. 2024

Nevrol. ž. im. L.O. Badalâna

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Duchenne muscular dystrophy (DMD) is the most common lumbar-limb muscular dystrophy with an X-linked recessive type of inheritance. It is characterized by a debut at an early age, rapidly progressive atrophy of the striated musculature of the limbs, trunk, heart muscle, which leads to loss of motor skills, severe cardiovascular and respiratory complications. Currently, a number of new drugs have appeared for the pathogenic therapy of MDD, the effectiveness of which is the most during its early initiation in the ambulatory stage of the disease. One of the new methods of MDD treatment is antisense oligonucleotide therapy. The application of this type of therapy is possible for certain mutations in the DMD gene and is recommended immediately after diagnosis. At the moment, the duration of this method of treatment in the Russian Federation is only a few years. In our article we discuss a clinical case of the study of a patient suffering from Duchenne muscular dystrophy caused by the deletion of 50–52 exons in the DMD gene, who is on therapy with steroids and Viltolarsen. A special feature of the case is the late application of Viltolarsen from the age of 9 years. The results of the observation demonstrate a significant effect in stabilization of motor skills, of the functioning of the cardiovascular and respiratory systems, which gives a chance to slow down the course of the disease, improve the quality of life and increase its duration, even taking into account the late initiation of pathogenic therapy.

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“…Serum profiling and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in DMD patients provide important biomarker correlates of disease trajectories and treatment effects [12][13][14][15][16] . The goal of this study was to identify clinically relevant biomarkers associated with the WSiMD cohort as an aggregate group, and to evaluate whether we could discern a biomarker signature of intermittent prednisone treatment at this comparatively low dose of glucocorticoid exposure.…”

Section: Introductionmentioning

confidence: 99%

Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy

Willis,

Zelikovich,

Sufit

et al. 2024

Preprint

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BackgroundWeekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis.MethodsWSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint.Results/ConclusionsAt baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.

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Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy

Cited by 5 publications

References 33 publications

Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy

Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy

Clinical case of management of a patient with Duchenne muscular dystrophy caused by deletion of exons 50–52 of the DMD gene against the background of pathogenetic therapy with viltolarsen

Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy

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