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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.

SUBMITTER: Guiraud S

PROVIDER: S-EPMC5333102 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Identification of serum protein biomarkers for utrophin based DMD therapy.

Guiraud Simon S Edwards Benjamin B Squire Sarah E SE Babbs Arran A Shah Nandini N Berg Adam A Chen Huijia H Davies Kay E KE

Scientific reports 20170302

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 i ...[more]

PMID: 28252048

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Project description:Rheumatoid arthritis is an autoimmune disorder of complex disease etiology. Currently available serological diagnostic markers lack in terms of sensitivity and specificity and thus additional biomarkers are warranted for early disease diagnosis and management. We aimed to screen and compare serum proteome profiles of rheumatoid arthritis serotypes with healthy controls in the Pakistani population for identification of potential disease biomarkers. Serum samples from rheumatoid arthritis patients and healthy controls were enriched for low abundance proteins using ProteoMinerTM columns. Rheumatoid arthritis patients were assigned to one of the four serotypes based on anti-citrullinated peptide antibodies and rheumatoid factor. Serum protein profiles were analyzed via liquid chromatography-tandem mass spectrometry. The changes in the protein abundances were determined using label-free quantification software ProgenesisQITM followed by pathway analysis. Findings were validated in an independent cohort of patients and healthy controls using an enzyme-linked immunosorbent assay. A total of 213 proteins were identified. Comparative analysis of all groups (false discovery rate < 0.05, >2-fold change, and identified with ≥2 unique peptides) identified ten proteins that were differentially expressed between rheumatoid arthritis serotypes and healthy controls including pregnancy zone protein, selenoprotein P, C4b-binding protein beta chain, apolipoprotein M, N-acetylmuramoyl-L-alanine amidase, catalytic chain, oncoprotein-induced transcript 3 protein, Carboxypeptidase N subunit 2, Apolipoprotein C-I and Apolipoprotein C-III. Pathway analysis predicted inhibition of liver X receptor/retinoid X receptor activation pathway and production of nitric oxide and reactive oxygen species pathway in macrophages in all serotypes. A catalogue of potential serum biomarkers for rheumatoid arthritis were identified. These biomarkers can be further evaluated in larger cohorts from different populations for their diagnostic and prognostic potential.

Dataset Information

Identification of serum protein biomarkers for utrophin based DMD therapy.

Publications

Identification of serum protein biomarkers for utrophin based DMD therapy.

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