Clinical utility of serum biomarkers in Duchenne muscular dystrophy

Hathout, Yetrib; Seol, Haeri; Han, Meng; Zhang, Aiping; Brown, Kristy J.; Hoffman, Eric P.

doi:10.1186/s12014-016-9109-x

Cited by 63 publications

(61 citation statements)

References 57 publications

(62 reference statements)

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“…The extent of disruption of distinct components of the cytoskeleton/sarcomere may be unequal, as suggested by our finding that the expression of titin was disrupted by lengthening contractions whereas that of desmin, nebulin, and α-actinin was unperturbed. Our data are consistent with two other reports describing abnormal titin staining and reduced passive tension in WT muscle after lengthening contractions (31,34), as well as with the fact that titin fragmentation is detected in serum and urine, in dystrophindeficient mice as well as Duchenne muscular dystrophy patients (54)(55)(56). Disruption of the DGC is accompanied by compromised lateral force transmission (31,34).…”

Section: Discussionsupporting

confidence: 81%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contractioninduced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contractioninduced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions. muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan

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Section: Discussionsupporting

confidence: 81%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent study has shown that circulating miRNAs are found to be elevated in serum of patients with Duchenne and Becker muscular dystrophies. The level of the identified miRNAs decreased after exon skipping therapy and restoration of dystrophin protein [16]. …”

Section: Genomics and Transcriptomicsmentioning

confidence: 99%

Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine

et al. 2016

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There are more than 8000 rare diseases (RDs) that affect >5 % of the world’s population. Many of the RDs have no effective treatment and lack of knowledge creates delayed diagnosis making management difficult. The emerging concept of the personalized medicine allows for early screening, diagnosis, and individualized treatment of human diseases. In this context, the discovery of biomarkers in RDs will be of prime importance to enable timely prevention and effective treatment. Since 80 % of RDs are of genetic origin, identification of new genes and causative mutations become valuable biomarkers. Furthermore, dynamic markers such as expressed genes, metabolites, and proteins are also very important to follow prognosis and response the therapy. Recent advances in omics technologies and their use in combination can define pathophysiological pathways that can be drug targets. Biomarker discovery and their use in diagnosis in RDs is a major pillar in RD research.

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“…Blood fluid samples are simple to obtain and provide insight into the circulating protein in the entire body in normal as pathological conditions 49 . Initially, serological level of creatine kinase (CK) was used to screen for DMD in newborns 50,51 .…”

mentioning

confidence: 99%

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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Clinical utility of serum biomarkers in Duchenne muscular dystrophy

Cited by 63 publications

References 57 publications

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine

Identification of serum protein biomarkers for utrophin based DMD therapy

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