Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy

Abstract

Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids.

Serum protein biomarkers for juvenile dermatomyositis: a pilot study

“…In the first part of this pilot study, serum protein data for 12 healthy pediatric controls were from another independent study [22] and were employed as a bench mark for the initial exploratory comparison with the JDM data. In contrast, for the ELISA validation, healthy age, gender, matched controls were recruited (n = 17), and informed written consent was obtained from the parents/legally authorized representatives for those subjects aged up to 18 years, informed written assent obtained from those aged 12-17.9 years.…”

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

“…We and others have shown that circulating levels of ApN are greatly decreased in mdx mice (mouse model of DMD) [56,100], an observation confirmed in human patients [101]. Moreover, myotubes from DMD patients were unable to produce ApN for local protection [57], unlike non-dystrophic myotubes challenged by inflammation [36].…”

Duchenne Muscular Dystrophy: recent advances in protein biomarkers and the clinical application

“…In particular, the guidelines for enhanced validation of antibodies designed by the International Working Group for Antibody Validation (IWGAV), an ad-hoc formed group of leading researchers, promotes rigorous validation of such reagents and has been adopted by researchers and leading antibody producers [89][90][91]. Beside antibodies development of short single-stranded oligonucleotides as affinity reagents and the SomaLogic technology enabled researchers to analyze more than 1,000 targets in cross-sectional studies in the context of DMD [92][93][94][95][96]. The assay relies on the capture of the target in its native conformation to immobilized protein-specific Slow Off-rate Modified DNA aptamers (SOMAmers).…”

“…Beside inflammation, DMD disease progression is also associated with increasing fibrosis. Proteins like IL-6, Interleukin 10 and INF-γ and Interleukin 13 are suitable for monitoring fibrosis at different disease stages [92,94,118,121]. Biomarkers associated with muscle function, inflammation, and fibrosis may recapitulate disease progression but additional biomarkers are required for the development of therapies.…”

“…To increase the accuracy of biomarker's several studies advocate the shift from single biomarkers to biomarker 'panels' or 'signatures', a prerequisite for precision medicine [3,125]. Several studies support the use of biomarker panels to describe pathological changes as DMD is characterized by multiple processes decreasing muscle function, increasing fibrosis, and inflammation [36,94,107].…”