Alexander Peter Murphy1, Elizabeth Greally1, Dara O'Hogain2, Andrew Blamire2, Peter Caravan3, Volker Straub1. 1. The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, The International Centre for Life, Newcastle University, Central Parkway, Newcastle Upon Tyne, United Kingdom. 2. Institute of Cellular Medicine, Newcastle Magnetic Resonance Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. 3. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
Abstract
PURPOSE: Duchenne muscular dystrophy (DMD) is a genetic condition caused by mutations in the DMD gene leading to muscle degeneration, fatty replacement of muscle cells and fibrosis. A major obstacle to advancing therapeutic research into muscular dystrophies is development of sensitive, noninvasive outcome measures. To date, no validated method to noninvasively quantify fibrosis within skeletal muscle exists. EP3533 is a gadolinium-based MRI contrast agent with an affinity to collagen-1. The purpose of this study was to determine whether EP3533-enhanced MRI could quantify fibrosis in a murine model of DMD (mdx) in muscle. METHODS: Mdx (n = 8) and control mice (BL10; n = 5) underwent contrast-enhanced MRI acquisitions with EP3533. T1 mapping pre- and postcontrast was performed in skeletal and cardiac muscle. Post-MRI the tibialis anterior (TA) and gastrocnemius (GCN) muscles and the heart were removed for fibrosis quantification by means of Masson's trichrome staining and the hydroxyproline assay. RESULTS: Significant differences in postcontrast R1 were demonstrated between mdx and BL10 mice using EP3533 (cardiac P = 0.02, GCN P = 0.04, TA P = 0.04). Change in R1 from baseline following EP3533 administration correlated strongly to hydroxyproline levels (GCN: r = 0.83, P = 0.001; TA: r = 0.73, P = 0.01). CONCLUSIONS: This study provides evidence for the suitability of EP3533 in the quantification of muscular fibrosis in mdx mice and demonstrated that EP3533-derived measurements correlated strongly to ex vivo fibrosis measurement.
PURPOSE:Duchenne muscular dystrophy (DMD) is a genetic condition caused by mutations in the DMD gene leading to muscle degeneration, fatty replacement of muscle cells and fibrosis. A major obstacle to advancing therapeutic research into muscular dystrophies is development of sensitive, noninvasive outcome measures. To date, no validated method to noninvasively quantify fibrosis within skeletal muscle exists. EP3533 is a gadolinium-based MRI contrast agent with an affinity to collagen-1. The purpose of this study was to determine whether EP3533-enhanced MRI could quantify fibrosis in a murine model of DMD (mdx) in muscle. METHODS: Mdx (n = 8) and control mice (BL10; n = 5) underwent contrast-enhanced MRI acquisitions with EP3533. T1 mapping pre- and postcontrast was performed in skeletal and cardiac muscle. Post-MRI the tibialis anterior (TA) and gastrocnemius (GCN) muscles and the heart were removed for fibrosis quantification by means of Masson's trichrome staining and the hydroxyproline assay. RESULTS: Significant differences in postcontrast R1 were demonstrated between mdx and BL10 mice using EP3533 (cardiac P = 0.02, GCN P = 0.04, TA P = 0.04). Change in R1 from baseline following EP3533 administration correlated strongly to hydroxyproline levels (GCN: r = 0.83, P = 0.001; TA: r = 0.73, P = 0.01). CONCLUSIONS: This study provides evidence for the suitability of EP3533 in the quantification of muscular fibrosis in mdx mice and demonstrated that EP3533-derived measurements correlated strongly to ex vivo fibrosis measurement.
Authors: Philip A Waghorn; Diego S Ferreira; Derek J Erstad; Nicholas J Rotile; Ricard Masia; Chloe M Jones; Chuantao Tu; Mozhdeh Sojoodi; Yin-Ching I Chen; Franklin Schlerman; Jeremy Wellen; Robert V P Martinez; Kenneth K Tanabe; Bryan C Fuchs; Peter Caravan Journal: Sci Rep Date: 2021-03-17 Impact factor: 4.379
Authors: Alexander Peter Murphy; Elizabeth Greally; Dara O'Hogain; Andrew Blamire; Peter Caravan; Volker Straub Journal: Front Neurol Date: 2021-06-17 Impact factor: 4.003
Authors: Saskia Lassche; Benno Küsters; Arend Heerschap; Maxime V P Schyns; Coen A C Ottenheijm; Nicol C Voermans; Baziel G M van Engelen Journal: J Neuromuscul Dis Date: 2020