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Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy

  1. Larry Goldb,1
  1. aResearch Center for Genetic Medicine, Children’s National Medical Center, Washington, DC 20012;
  2. bSomaLogic, Inc., Boulder, CO 80301;
  3. cNeurology Service, Department of Veteran Affairs Medical Center, Pittsburgh, PA 15240;
  4. dUniversity of Pittsburgh, Pittsburgh, PA 15213;
  5. eThe Heart Center, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH 15213;
  6. fParent Project Muscular Dystrophy, Hackensack, NJ 07601;
  7. gDepartment of Physical Medicine and Rehabilitation, University of California Davis School of Medicine, Davis, CA 95618;
  8. hDepartment of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202;
  9. iThe Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229;
  10. jDepartment of Pediatrics, University of Calgary, Alberta Children’s Hospital, Calgary, AB, Canada T3B 6A8;
  11. kDivision of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045;
  12. lDepartment of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610

  1. Contributed by Larry Gold, April 29, 2015 (sent for review March 6, 2015; reviewed by Allan Jacobson)

Significance

Duchenne muscular dystrophy (DMD) is a rare and devastating muscle disease caused by mutations in the X-linked DMD gene (which encodes the dystrophin protein). Serum biomarkers hold significant potential as objective phenotypic measures of DMD disease state, as well as potential measures of pharmacological effects of and response to therapeutic interventions. Here we describe a proteomics approach to determine serum levels of 1,125 proteins in 93 DMD patients and 45 controls. The study identified 44 biomarkers that differed significantly between patients and controls. These data are being made available to DMD researchers and clinicians to accelerate the search for new diagnostic, prognostic, and therapeutic approaches.

Abstract

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy–Cincinnati Children’s Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: lgold{at}somalogic.com.

  • Author contributions: Y.H., P.R.C., L.C., P.F., L.H., E.H., E.P.H., C.M., S.N., H.L.S., and L.G. designed research; L.C., H.G.-D., E.H., A.L., and J.K.M. performed research; Y.H., E.B., R.K.D., Y.M.K., B.M., S.N., M.N., B.S., F.S., D.S., H.L.S., S.W., and L.G. analyzed data; and Y.H., E.B., R.K.D., Y.M.K., S.N., F.S., D.S., H.L.S., and L.G. wrote the paper.

  • Reviewers included: A.J., University of Massachusetts Medical School.

  • Conflict of interest statement: L.G. is the founder and a stakeholder in SomaLogic, Inc; E.B., R.K.D., B.M., M.N., B.S., F.S., D.S., and S.W. are employees and stakeholders in SomaLogic, Inc.; Y.M.K. has been affiliated with the Eli Lilly and Co. since October 2012.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1507719112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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