Identification of Gene‐Therapy Responsive Blood Biomarkers in mdx Mouse Model

ABSTRACT Introduction Identifying serum biomarkers that reflect the restoration of dystrophin in skeletal muscle is important for evaluating the effect of dystrophin‐restoring therapies in preclinical and clinical trials. Many potential blood biomarkers have been identified in Duchenne muscular dyst...

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Published in:JCSM communications 2024-07, Vol.7 (2), p.187-198
Main Authors: Johansson, Camilla, Boehler, Jessica F., Brown, Kristy J., Koeks, Zaïda, Schrama, Esther J., Velde, Nienke, Verschuuren, Jan J. G. M., Niks, Erik H., Spitali, Pietro, Al‐Khalili Szigyarto, Cristina
Format: Article
Language:English
Subjects:
antibodies
Becker muscular dystrophy
biomarkers
Duchenne muscular dystrophy
plasma proteomics
rare disorders
suspension bead array
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Summary:ABSTRACT Introduction Identifying serum biomarkers that reflect the restoration of dystrophin in skeletal muscle is important for evaluating the effect of dystrophin‐restoring therapies in preclinical and clinical trials. Many potential blood biomarkers have been identified in Duchenne muscular dystrophy (DMD) patients, which change with disease progression or respond to pharmacological treatment. In this study, it was suggested that a panel of such blood biomarker candidates could be used to monitor dystrophin rescue in mdx mice treated with microdystrophin based therapies. Methods Plasma samples from mdx mice treated with the microdystrophin therapy SGT‐001 were analysed with an antibody suspension bead array consisting of 87 antibodies. The array targets 83 unique proteins previously identified as biomarker candidates for DMD. Each sample was assayed at two different plasma dilutions to cover a broader concentration range. Protein concentrations estimated as Median fluorescent intensities (MFI) were correlated to dystrophin expression in muscle tissue, as measured by immunohistochemistry and Western blot. Thirteen of the targets were selected and analysed in a DMD and Becker muscular dystrophy (BMD) longitudinal natural history cohort using a suspension bead array. Results Ten proteins were found to be significantly elevated in untreated mdx mice compared with C57 wild‐type mice and to correlate with dystrophin expression (Spearman's correlation, FDR 
ISSN:2996-1394
2996-1394
DOI:10.1002/rco2.112