title: Identification of serum protein biomarkers for utrophin based DMD therapy.
abstract: Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic.
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Guiraud
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Edwards
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Squire
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Arran
authors.initials: A
authors.lastname: Babbs
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Nandini
authors.initials: N
authors.lastname: Shah
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Berg
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Huijia
authors.initials: H
authors.lastname: Chen
authors.affiliation: Medical Research Council Functional Genomics Unit at the University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, United Kingdom.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000818:Animals; D015415:Biomarkers; D001798:Blood Proteins; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009137:Muscular Dystrophy, Animal; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000235:genetics / Q000628:therapy; D020543:Proteome; D040901:Proteomics / Q000379:methods; D057170:Translational Research, Biomedical; D049411:Utrophin / Q000097:blood* / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D020543:Proteome; D049411:Utrophin