Development of digital tissue image analysis solution for muscle biopsies in support of disease-modifying therapies for Duchenne muscular dystrophy

2016 ◽  
Vol 26 ◽  
pp. S155 ◽  
Author(s):  
J. Tinsley ◽  
C. Pulliam ◽  
A. Milici ◽  
F. Aeffner ◽  
K. Davies ◽  
...  
Keyword(s):  
Image Analysis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Muscle Biopsies

scholarly journals Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (21) ◽  
pp. e2270-e2282 ◽  
Author(s):  
Diane E. Frank ◽  
Frederick J. Schnell ◽  
Cody Akana ◽  
Saleh H. El-Husayni ◽  
Cody A. Desjardins ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Exon Skipping ◽  
Study Drug ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Dystrophin Protein ◽  
Muscle Biopsies

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

Mononuclear cell analysis of muscle biopsies in prednisone- and azathioprine-treated Duchenne muscular dystrophy

Neurology ◽  
1993 ◽  
Vol 43 (3, Part 1) ◽  
pp. 532-532 ◽  
Author(s):  
J. T. Kissel ◽  
D. J. Lynn ◽  
K. W. Rammohan ◽  
J. P. Klein ◽  
R. C. Griggs ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mononuclear Cell ◽  
Cell Analysis ◽  
Muscle Biopsies

scholarly journals Clinical and Experimental Results on Cardiac Troponin Expression in Duchenne Muscular Dystrophy

2001 ◽  
Vol 47 (3) ◽  
pp. 451-458 ◽  
Author(s):  
Angelika Hammerer-Lercher ◽  
Petra Erlacher ◽  
Reginald Bittner ◽  
Rudolf Korinthenberg ◽  
Daniela Skladal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Cardiac Troponin ◽  
Western Blot Analysis ◽  
Clinical Evidence ◽  
Mdx Mouse ◽  
Muscle Biopsies

Abstract Background: Because of controversial earlier studies, the purpose of this study was to provide novel experimental and additional clinical data regarding the possible reexpression of cardiac troponin T (cTnT) in regenerating skeletal muscle in Duchenne muscular dystrophy (DMD). Methods: Plasma from 14 patients (mean age, 7.5 years; range, 5.7–19.4 years) with DMD was investigated for creatine kinase (CK), the CK MB isoenzyme (CKMB), cTnT and cardiac troponin I (cTnI), and myoglobin. cTnT concentrations were measured by an ELISA (second-generation assay; Roche) using the ES 300 Analyzer. cTnI, myoglobin, and CKMB were measured by an ELISA using the ACCESS System (Beckman Diagnostics). Troponin isoform expression was studied by Western blot analysis in remnants of skeletal muscle biopsies of three patients with DMD and in an animal model of DMD (mdx mice; n = 6). Results: There was no relation of cTnT and cTnI to clinical evidence for cardiac failure. cTnI concentrations remained below the upper reference limit in all patients. cTnT was increased (median, 0.11 μg/L; range, 0.06–0.16 μg/L) in 50% of patients. The only significant correlation was found for CK (median, 3938 U/L; range, 2763–5030 U/L) with age (median, 7.5 years; range, 6.8–10.9 years; r = −0.762; P = 0.042). Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms. Conclusions: We found no evidence for cTnT reexpression in human early-stage DMD and in mdx mouse skeletal muscle biopsies. Discrepancies of cTnT and cTnI in plasma samples of DMD patients were found, but neither cTnT nor cTnI plasma concentrations were related with other clinical evidence for cardiac involvement.

Dexmedetomidine and ketamine sedation for muscle biopsies in patients with Duchenne muscular dystrophy

2014 ◽  
Vol 24 (8) ◽  
pp. 851-856 ◽  
Author(s):  
Hiromi Kako ◽  
Marco Corridore ◽  
John Kean ◽  
Jerry R. Mendell ◽  
Kevin M. Flanigan ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Biopsies

Sarcoplasmic reticulum Ca2+-ATPase and acylphosphatase activities in muscle biopsies from patients with Duchenne muscular dystrophy

1986 ◽  
Vol 158 (3) ◽  
pp. 245-251 ◽  
Author(s):  
Nerina Landi ◽  
Paolo Nassi ◽  
Gianfranco Liguri ◽  
Susanna Bobbi ◽  
Cinzia Sbrilli ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Sarcoplasmic Reticulum ◽  
Muscular Dystrophy ◽  
Muscle Biopsies

scholarly journals Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ivana Dabaj ◽  
Justine Ferey ◽  
Florent Marguet ◽  
Vianney Gilard ◽  
Carole Basset ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
High Resolution Mass Spectrometry ◽  
Phospholipid Metabolism ◽  
Ion Cyclotron Resonance ◽  
Unbiased Manner ◽  
Phosphatidic Acids ◽  
Muscle Biopsies

AbstractDuchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.

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