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Identification of G...
Identification of Gene-Therapy Responsive Blood Biomarkers for Duchenne Muscular Dystrophy
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- Johansson, Camilla (författare)
- KTH,Systembiologi
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- Boehler, Jessica F. (författare)
- Solid Biosciences, 500 Rutherford Ave., Charlestown, MA 02129, United States
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- Brown, Kristy J. (författare)
- Solid Biosciences, 500 Rutherford Ave., Charlestown, MA 02129, United States
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- Koeks, Zaïda (författare)
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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- van de Velde, Nienke (författare)
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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- Verschuuren, Jan J.G.M. (författare)
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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- Niks, Erik H. (författare)
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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- Spitali, Pietro (författare)
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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- Al-Khalili Szigyarto, Cristina (författare)
- KTH,Proteinvetenskap
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- IntroductionAssessing muscle dystrophin expression systemically is important for understanding the effect of dystrophin-restoring therapies in Duchenne muscular dystrophy (DMD). Many potential blood biomarkers have been identified in DMD patients which are either more or less abundant in blood samples compared to healthy individuals and that have been shown to 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 microdystrophin therapies. MethodsPlasma samples from mdx mice treated with the microdystrophin therapy SGT-001 were analysed with an antibody suspension bead array consisting of 87 antibodies targeting 83 proteins previously identified as biomarker candidates for DMD. Each sample was assayed at two different plasma dilutions to cover a broader concentration range. Median fluorescent intensities (MFI) for each antibody were correlated to dystrophin expression in muscle tissue, as measured by immunohistochemistry and Western blot. 13 targets were selected and validated in a DMD and Becker muscular dystrophy (BMD) longitudinal natural history cohort using a suspension bead array. Results10 proteins were found significantly elevated in untreated mdx mice compared to C57 wild-type mice and 10 were found to correlate with dystrophin expression (Spearman’s correlation, FDR < 0.05) upon gene transfer. Abundance of TTN, ADSSL1, LONP1, OTUD5, MYL3 as well as DMD protein were associated with dystrophin expression in BMD patients. Of these, MYL3 and ADSSL1 had different abundance in DMD compared to healthy individuals, and MYL3 also displayed different age trajectories between DMD and BMD patients. DiscussionThe ten proteins identified in mouse plasma are related to muscle contraction (ADSSL1, ASAH1, CA3, MYL3, TTN), microtubule formation (TPI1), and protein degradation (PSMA2, OTUD4, LONP1). Of these, MYL3 and ADSSL1 showed the most promise as a dystrophin monitoring biomarker in patient samples.
Ämnesord
- NATURVETENSKAP -- Biologi -- Bioinformatik och systembiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Bioinformatics and Systems Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- Duchenne muscular dystrophy
- Becker muscular dystrophy
- biomarkers
- antibodies
- suspension bead array
- plasma proteomics
- rare disorders
- Biotechnology
- Bioteknologi
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