Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics
There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presen...
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| Veröffentlicht in: | Scientific reports 2015-11, Vol.5 (1), p.17014-17014, Article 17014 |
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| creator | Coenen-Stass, Anna M. L. McClorey, Graham Manzano, Raquel Betts, Corinne A. Blain, Alison Saleh, Amer F. Gait, Michael J. Lochmüller, Hanns Wood, Matthew J. A. Roberts, Thomas C. |
| description | There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and
mdx
(dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (
P
|
| doi_str_mv | 10.1038/srep17014 |
| format | Article |
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mdx
(dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (
P
< 0.001,
q
< 0.01) in
mdx
mice. Additionally, systemic treatment with a peptide-antisense oligonucleotide conjugate designed to induce
Dmd
exon skipping and recover dystrophin protein expression caused many of the differentially abundant serum proteins to be restored towards wild-type levels. Results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b, Cycs and Adamts5) were validated by ELISA in the mouse samples. Furthermore, ADAMTS5 was found to be significantly elevated in human DMD patient serum. This study has identified multiple novel, therapy-responsive protein biomarkers in the serum of the
mdx
mouse with potential utility in DMD patients.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep17014</identifier><identifier>PMID: 26594036</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/79 ; 631/45 ; 692/53/2423 ; 82/80 ; ADAM Proteins - blood ; ADAM Proteins - genetics ; ADAMTS5 Protein ; Animals ; Aptamers, Nucleotide - pharmacology ; Biomarkers, Pharmacological - blood ; Blood Proteins - genetics ; Blood Proteins - metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - blood ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics ; Disease Models, Animal ; Dystrophin - agonists ; Dystrophin - deficiency ; Dystrophin - genetics ; Gene Expression Profiling ; Gene Expression Regulation ; Humanities and Social Sciences ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; multidisciplinary ; Muscular Dystrophy, Duchenne - genetics ; Muscular Dystrophy, Duchenne - metabolism ; Muscular Dystrophy, Duchenne - pathology ; Muscular Dystrophy, Duchenne - therapy ; Oligonucleotides, Antisense - pharmacology ; Phosphoric Monoester Hydrolases - blood ; Phosphoric Monoester Hydrolases - genetics ; Protein Kinases - blood ; Protein Kinases - genetics ; Protein Serine-Threonine Kinases ; Proteomics - methods ; Science</subject><ispartof>Scientific reports, 2015-11, Vol.5 (1), p.17014-17014, Article 17014</ispartof><rights>The Author(s) 2015</rights><rights>Copyright © 2015, Macmillan Publishers Limited 2015 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-1542c09c6ab989ce7c2d7bdfc10f668686c07ea58e13d75672790ce749d4bb713</citedby><cites>FETCH-LOGICAL-c476t-1542c09c6ab989ce7c2d7bdfc10f668686c07ea58e13d75672790ce749d4bb713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655324/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655324/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,41119,42188,51575,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26594036$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coenen-Stass, Anna M. L.</creatorcontrib><creatorcontrib>McClorey, Graham</creatorcontrib><creatorcontrib>Manzano, Raquel</creatorcontrib><creatorcontrib>Betts, Corinne A.</creatorcontrib><creatorcontrib>Blain, Alison</creatorcontrib><creatorcontrib>Saleh, Amer F.</creatorcontrib><creatorcontrib>Gait, Michael J.</creatorcontrib><creatorcontrib>Lochmüller, Hanns</creatorcontrib><creatorcontrib>Wood, Matthew J. A.</creatorcontrib><creatorcontrib>Roberts, Thomas C.</creatorcontrib><title>Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and
mdx
(dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (
P
< 0.001,
q
< 0.01) in
mdx
mice. Additionally, systemic treatment with a peptide-antisense oligonucleotide conjugate designed to induce
Dmd
exon skipping and recover dystrophin protein expression caused many of the differentially abundant serum proteins to be restored towards wild-type levels. Results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b, Cycs and Adamts5) were validated by ELISA in the mouse samples. Furthermore, ADAMTS5 was found to be significantly elevated in human DMD patient serum. This study has identified multiple novel, therapy-responsive protein biomarkers in the serum of the
mdx
mouse with potential utility in DMD patients.</description><subject>38/79</subject><subject>631/45</subject><subject>692/53/2423</subject><subject>82/80</subject><subject>ADAM Proteins - blood</subject><subject>ADAM Proteins - genetics</subject><subject>ADAMTS5 Protein</subject><subject>Animals</subject><subject>Aptamers, Nucleotide - pharmacology</subject><subject>Biomarkers, Pharmacological - blood</subject><subject>Blood Proteins - genetics</subject><subject>Blood Proteins - metabolism</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - blood</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics</subject><subject>Disease Models, Animal</subject><subject>Dystrophin - agonists</subject><subject>Dystrophin - deficiency</subject><subject>Dystrophin - genetics</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred mdx</subject><subject>multidisciplinary</subject><subject>Muscular Dystrophy, Duchenne - genetics</subject><subject>Muscular Dystrophy, Duchenne - metabolism</subject><subject>Muscular Dystrophy, Duchenne - pathology</subject><subject>Muscular Dystrophy, Duchenne - therapy</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Phosphoric Monoester Hydrolases - blood</subject><subject>Phosphoric Monoester Hydrolases - genetics</subject><subject>Protein Kinases - blood</subject><subject>Protein Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases</subject><subject>Proteomics - methods</subject><subject>Science</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNptkd9OHCEYxUnTphr1oi9guLRNR4FhYLlp0tjWmpj0xl4TBr5x0RkYYWaTeYs-smxWNzYREv59vxzgHIQ-UXJOSb26yAlGKgnl79AhI7ypWM3Y-1frA3SS8z0prWGKU_URHTDRKE5qcYj-XTsIk--8NZOPAccOh7iB_iue1pDMuFQJ8hhD9hvAY4oT-IBbHweTHiBlXHYGD3HOUEYH_Vbgx2zXEEI5mbOde5OwW_KU4rhecLtgM05mgFS1JoPDGdI87JTj4G0-Rh8602c4eZ6P0N9fP28vf1c3f66uL7_fVJZLMVW04cwSZYVp1UpZkJY52brOUtIJsSrdEgmmWQGtnWyEZFKRgnHleNtKWh-hbzvdcW4HcLa4kEyvx-TL1xYdjdf_V4Jf67u40Vw0Tc14ETh7FkjxcYY86cFnC31vAhQ_NJW14JRytUU_71CbYi55dftrKNHbEPU-xMKevn7XnnyJrABfdkAupXAHSd_HOYXi1RtqT5vYquQ</recordid><startdate>20151123</startdate><enddate>20151123</enddate><creator>Coenen-Stass, Anna M. L.</creator><creator>McClorey, Graham</creator><creator>Manzano, Raquel</creator><creator>Betts, Corinne A.</creator><creator>Blain, Alison</creator><creator>Saleh, Amer F.</creator><creator>Gait, Michael J.</creator><creator>Lochmüller, Hanns</creator><creator>Wood, Matthew J. A.</creator><creator>Roberts, Thomas C.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151123</creationdate><title>Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics</title><author>Coenen-Stass, Anna M. L. ; McClorey, Graham ; Manzano, Raquel ; Betts, Corinne A. ; Blain, Alison ; Saleh, Amer F. ; Gait, Michael J. ; Lochmüller, Hanns ; Wood, Matthew J. A. ; Roberts, Thomas C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-1542c09c6ab989ce7c2d7bdfc10f668686c07ea58e13d75672790ce749d4bb713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>38/79</topic><topic>631/45</topic><topic>692/53/2423</topic><topic>82/80</topic><topic>ADAM Proteins - blood</topic><topic>ADAM Proteins - genetics</topic><topic>ADAMTS5 Protein</topic><topic>Animals</topic><topic>Aptamers, Nucleotide - pharmacology</topic><topic>Biomarkers, Pharmacological - blood</topic><topic>Blood Proteins - genetics</topic><topic>Blood Proteins - metabolism</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - blood</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics</topic><topic>Disease Models, Animal</topic><topic>Dystrophin - agonists</topic><topic>Dystrophin - deficiency</topic><topic>Dystrophin - genetics</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred mdx</topic><topic>multidisciplinary</topic><topic>Muscular Dystrophy, Duchenne - genetics</topic><topic>Muscular Dystrophy, Duchenne - metabolism</topic><topic>Muscular Dystrophy, Duchenne - pathology</topic><topic>Muscular Dystrophy, Duchenne - therapy</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><topic>Phosphoric Monoester Hydrolases - blood</topic><topic>Phosphoric Monoester Hydrolases - genetics</topic><topic>Protein Kinases - blood</topic><topic>Protein Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases</topic><topic>Proteomics - methods</topic><topic>Science</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coenen-Stass, Anna M. L.</creatorcontrib><creatorcontrib>McClorey, Graham</creatorcontrib><creatorcontrib>Manzano, Raquel</creatorcontrib><creatorcontrib>Betts, Corinne A.</creatorcontrib><creatorcontrib>Blain, Alison</creatorcontrib><creatorcontrib>Saleh, Amer F.</creatorcontrib><creatorcontrib>Gait, Michael J.</creatorcontrib><creatorcontrib>Lochmüller, Hanns</creatorcontrib><creatorcontrib>Wood, Matthew J. A.</creatorcontrib><creatorcontrib>Roberts, Thomas C.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coenen-Stass, Anna M. L.</au><au>McClorey, Graham</au><au>Manzano, Raquel</au><au>Betts, Corinne A.</au><au>Blain, Alison</au><au>Saleh, Amer F.</au><au>Gait, Michael J.</au><au>Lochmüller, Hanns</au><au>Wood, Matthew J. A.</au><au>Roberts, Thomas C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2015-11-23</date><risdate>2015</risdate><volume>5</volume><issue>1</issue><spage>17014</spage><epage>17014</epage><pages>17014-17014</pages><artnum>17014</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and
mdx
(dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (
P
< 0.001,
q
< 0.01) in
mdx
mice. Additionally, systemic treatment with a peptide-antisense oligonucleotide conjugate designed to induce
Dmd
exon skipping and recover dystrophin protein expression caused many of the differentially abundant serum proteins to be restored towards wild-type levels. Results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b, Cycs and Adamts5) were validated by ELISA in the mouse samples. Furthermore, ADAMTS5 was found to be significantly elevated in human DMD patient serum. This study has identified multiple novel, therapy-responsive protein biomarkers in the serum of the
mdx
mouse with potential utility in DMD patients.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26594036</pmid><doi>10.1038/srep17014</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 38/79 631/45 692/53/2423 82/80 ADAM Proteins - blood ADAM Proteins - genetics ADAMTS5 Protein Animals Aptamers, Nucleotide - pharmacology Biomarkers, Pharmacological - blood Blood Proteins - genetics Blood Proteins - metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 2 - blood Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics Disease Models, Animal Dystrophin - agonists Dystrophin - deficiency Dystrophin - genetics Gene Expression Profiling Gene Expression Regulation Humanities and Social Sciences Humans Male Mice Mice, Inbred C57BL Mice, Inbred mdx multidisciplinary Muscular Dystrophy, Duchenne - genetics Muscular Dystrophy, Duchenne - metabolism Muscular Dystrophy, Duchenne - pathology Muscular Dystrophy, Duchenne - therapy Oligonucleotides, Antisense - pharmacology Phosphoric Monoester Hydrolases - blood Phosphoric Monoester Hydrolases - genetics Protein Kinases - blood Protein Kinases - genetics Protein Serine-Threonine Kinases Proteomics - methods Science |
| title | Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics |
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