Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy

Hathout, Yetrib; Brody, Edward N.; Clemens, Paula R.; Cripe, Linda H.; DeLisle, Robert Kirk; Furlong, Pat; Gordish‐Dressman, Heather; Hache, Lauren P.; Henricson, E.; Hoffman, Eric P.; Kobayashi, Yvonne M.; Lorts, Angela; Mah, Jean K.; McDonald, Craig M.; Mehler, Bob; Nelson, Sally K.; Nikrad, Malti; Singer, Britta Swebilius; Steele, Fintan R.; Sterling, David; Sweeney, H. Lee; Williams, Stephen; Gold, Larry

doi:10.1073/pnas.1507719112

Cited by 247 publications

(259 citation statements)

References 44 publications

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“…RELT/ TNFRSF19 was previously described as significantly decreased in DMD patient 56 highlighting importance of this group of cytokine receptors primarily involved in pleatoric activities as inflammation, apoptosis, proliferation, survival and differentiation. Another intriguing protein that emerged from our study is the neural immunoglobulin family adhesion molecule Contactin-1, significantly reduced in abundance in mdx sera.…”

Section: Discussionmentioning

confidence: 92%

Identification of serum protein biomarkers for utrophin based DMD therapy

Guiraud

Edwards

Squire

et al. 2017

Neuromuscular Disorders

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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.Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene 1 . This disorder affects 1 in 5000 boys 2 and is characterized by a progressive muscle wasting leading to loss of ambulation by 8-12 years of age 3 and death by early adulthood due to cardiorespiratory failure 4 . Dystrophin, an essential link between the dystrophin associated protein complex (DAPC) at the sarcolemma and the cytoskeleton, maintains the strength, flexibility and stability in skeletal muscles 5 . In the absence of dystrophin, the myofibres are more susceptible to contraction-induced injury which results in muscle wasting and premature death 6 . There is currently no effective treatment for the disease. Glucocorticoid treatment is the current standard of care which delays the loss of ambulation by 3-4 years 7,8 but shows no long treatment benefit and is often associated with debilitating side effects [9][10][11] . The urgency to seek a therapy for DMD has resulted in parallel efforts to develop exon skipping 12,13 , termination codon read through 14 , dystrophin gene replacement or editing therapies 15,16 and non-dystrophin strategies [17][18][19] such as utrophin modulation 20,21 . However, despite the recent accelerated approval of Exondys 51 (eteplirsen) in US, disappointing clinical trials results 22 and failure of approval from the FDA for Ataluren 23 and Kyndrisa 24 drugs rekindle discussions about clinical trials designs and endpoints. We have focused on utrophin modulation because it is applicable to all DMD patients irrespective of their dystrophin mutation. Utrophin is found at the sarcolemma in utero and is progressive...

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Section: Discussionmentioning

confidence: 92%

Identification of serum protein biomarkers for utrophin based DMD therapy

Guiraud

Edwards

Squire

et al. 2017

Neuromuscular Disorders

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“…mice performed using Somalogics SomaMERs 151 , in combination with Western blotting using a monoclonal antibody from abcam, which, at the time, was reported to be specific for GDF11. Subsequent reports from our group 104 and others 87, 143, 152 revealed that the SomaMER and mAb used in these initial studies cross-react with MSTN, and so, while these studies are consistent with a reduction in the circulating pool of GDF11 and MSTN in aged animals, these data cannot discriminate the relative impact of aging on systemic levels of GDF11 specifically. A report from Egerman and colleagues argued that circulating levels of GDF11 might actually increase with age, based on the results of Western blot, RNA expression, and GDF11-specific immunoassay 87 .…”

Section: Current Controversiesmentioning

confidence: 86%

Biochemistry and Biology of GDF11 and Myostatin

Walker

Poggioli

Katsimpardi³

et al. 2016

Circulation Research

167

106

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Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging. (Circ Res.

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“…Another study demonstrated that WFIKKN2 is more expressed in a chicken line that has been selected for 60 years for rapid growth of the skeletal muscle tissue (Ross 708 broiler bird) than in a legacy chicken line (Illinois bird) [46]. The concentration of WFIKKN1 in the serum also decreased with age in a Duchenne muscular dystrophy patient while it increased with age in controls [47]. Further, WFIKKN2 is one of the 32 most highly enriched proteins in human embryonic stem cells-conditioned medium [48] known to enhance the proliferation of mouse and human muscle progenitors.…”

Section: Wfikkn Expression In Musculoskeletal Systemmentioning

confidence: 99%