Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys

Abstract Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient–patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFβ and fibrosis pathways in muscle.

Download Full-text

Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics

Scientific Reports ◽

10.1038/srep17014 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 30

Author(s):

Anna M. L. Coenen-Stass ◽

Graham McClorey ◽

Raquel Manzano ◽

Corinne A. Betts ◽

Alison Blain ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Serum Proteins ◽

Exon Skipping ◽

Serum Levels ◽

Wild Type ◽

Protein Biomarkers ◽

Novel Therapy ◽

Serum Proteomics ◽

Dystrophin Protein

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.

Download Full-text

Instantaneous frequency as a new approach for evaluating the clinical severity of Duchenne muscular dystrophy through ultrasound imaging

Ultrasonics ◽

10.1016/j.ultras.2018.09.004 ◽

2019 ◽

Vol 94 ◽

pp. 235-241 ◽

Cited By ~ 3

Author(s):

Wen-Chin Weng ◽

Chia-Wei Lin ◽

Hui-Chung Shen ◽

Chien-Cheng Chang ◽

Po-Hsiang Tsui

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Ultrasound Imaging ◽

Instantaneous Frequency ◽

Clinical Severity ◽

New Approach

Download Full-text

HLA Polymorphism Affects Risk of de novo Mutation of dystrophin Gene and Clinical Severity of Duchenne Muscular Dystrophy in a Southern Chinese Population

Frontiers in Neurology ◽

10.3389/fneur.2018.00970 ◽

2018 ◽

Vol 9 ◽

Author(s):

Huan Li ◽

Lulu Xiao ◽

Liang Wang ◽

Jinfu Lin ◽

Min Luo ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Chinese Population ◽

De Novo ◽

Dystrophin Gene ◽

Clinical Severity ◽

De Novo Mutation ◽

Hla Polymorphism ◽

Southern Chinese

Download Full-text

Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice

PLoS ONE ◽

10.1371/journal.pone.0246507 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246507

Author(s):

Michael Ziemba ◽

Molly Barkhouse ◽

Kitipong Uaesoontrachoon ◽

Mamta Giri ◽

Yetrib Hathout ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Serum Proteins ◽

Mdx Mice ◽

Proteomic Profiling ◽

Treatment Groups ◽

Dystrophin Deficiency ◽

Repurposed Drugs ◽

Good Concordance ◽

Pharmacodynamic Biomarkers

Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.

Download Full-text

Predictors of long-term prognosis in rheumatoid arthritis-related interstitial lung disease

10.21203/rs.3.rs-707140/v2 ◽

2021 ◽

Author(s):

Juan Chen ◽

Yaqiong Chen ◽

Dehao Liu ◽

Yihua Lin ◽

Lei Zhu ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Serum Protein ◽

Serum Proteins ◽

Pulmonary Function Tests ◽

Protein Biomarkers ◽

Serum Samples ◽

Binary Logistic Regression Model ◽

Longitudinal Outcome ◽

Over Time

Abstract The aim of the study was to identify specific clinical and serum protein biomarkers that are associated with longitudinal outcome of RA-associated interstitial lung disease（RA-ILD). 60 RA patients with clinical and serological profiles were assessed by HRCT and pulmonary function tests (PFTs) at baseline (Year 0) and 5 years post enrollment (Year 5). Progression versus non-progression was defined based on changes in Quantitative Modified HRCT scores and PFTs over time. Specific serum protein biomarkers were assessed in serum samples at baseline and Year 5 by Multiplex enzyme-linked immunosorbent assays (ELISAs). At Year 5, 32% of patients demonstrated progressive RA-ILD, 35% were stable, and 33% improved. Baseline age and rheumatoid factor (RF) were significantly different between RA-ILD outcomes of progression vs. no-progression (p< 0.05). Changes in levels of CXCL11/I-TAC and MMP13 over 5 years also distinguished pulmonary outcomes (p< 0.05). A final binary logistic regression model revealed that baseline age and changes in serum MMP13 were associated with RA-ILD progression at Year 5 (p< 0.05), with an AUC of 0.7569. Collectively, these analyses demonstrated that baseline clinical variables (age, RF) and shifts in levels of selected serum proteins (CXCL11/I-TAC, MMP13) were strongly linked to RA-ILD outcome over time.

Download Full-text

Genetic analysis of 62 Chinese families with Duchenne muscular dystrophy and strategies of prenatal diagnosis in a single center

BMC Medical Genetics ◽

10.1186/s12881-019-0912-x ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Jingjing Zhang ◽

Dingyuan Ma ◽

Gang Liu ◽

Yuguo Wang ◽

An Liu ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

De Novo ◽

Clinical Symptoms ◽

Perinatal Care ◽

Genetic Diagnosis ◽

Point Mutations ◽

Inherited Disease ◽

Positive Results

Abstract Background Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder. Patients with DMD usually have severe and fatal symptoms, including progressive irreversible muscle weakness and atrophy complicated with gastrocnemius muscle pseudohypertrophy. DMD is caused by mutations in the dystrophin-encoding DMD gene, including large rearrangements and point mutations. This retrospective study was aimed at supplying information on our 4-year clinical experience of DMD genetic and prenatal diagnosis at the Department of Prenatal Diagnosis in Women’s Hospital of Nanjing Medical University. Methods Multiplex ligation-dependent probe amplification (MLPA) was used to detect the exon deletions or duplications. And Ion AmpliSeq™ panel for inherited disease was used as the next-generation sequencing (NGS) method to identify the point mutations in exons of DMD gene, but the introns were not sequenced. Results In this study, the large deletions and duplications of DMD gene were detected in 32 (51.6%) of the 62 families, while point mutations were detected in 20 families (32.3%). The remaining 10 families with a negative genetic diagnosis need to be reevaluated for clinical symptoms or be detected by other molecular methods. Notably, six novel mutations were identified, including c.412A > T(p.Lys138*), c.2962delT(p.Ser988Leufs*16), c.6850dupA (p.Ser2284Lysfs*7), c.5139dupA (p.Glu 1714Argfs*5), c.6201_6203delGCCins CCCA(p.Val2069Cysfs*14) and c.10705A > T (p.Lys3569*). In 52 families with positive results, 45 mothers (86.5%) showed positive results during carrier testing and de novo mutations arose in 7 probands. The prenatal diagnosis was offered to 34 fetuses whether the pregnant mother was a carrier or not. As a result, eight male fetuses were affected, three female fetuses were carriers, and the remaining fetuses had no pathogenic mutation. Conclusions This study reported that MLPA and NGS could be used for screening the DMD gene mutations. Furthermore, the stepwise procedure of prenatal diagnosis of DMD gene was shown in our study, which is important for assessing the mutation type of fetuses and providing perinatal care in DMD high-risk families.

Download Full-text

A clinical case of severe Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene in a girl

L.O. Badalyan Neurological Journal ◽

10.46563/2686-8997-2021-2-4-227-232 ◽

2021 ◽

Vol 2 (4) ◽

pp. 227-232

Author(s):

Tatyana V. Podkletnova ◽

Olga B. Kondakova ◽

Eugeniya V. Uvakina ◽

Dariya A. Fisenko ◽

Anastasiya A. Lyalina ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

X Chromosome ◽

Clinical Symptoms ◽

Chromosomal Rearrangements ◽

Clinical Manifestations ◽

Severe Form ◽

Rapid Progression ◽

Compound Heterozygous ◽

Dmd Gene

Duchenne muscular dystrophy (DMD) is a hereditary progressive muscular dystrophy, mainly manifested in boys, is characterized by the onset at an early age, gradual symmetrical atrophy of the striated musculature of the limbs, trunk, as well as damage to the heart muscle. As a rule, girls and women inheriting a pathological mutation are classified only as its carriers and do not have clinical manifestations of the disease. Rare cases when women or girls show clinical manifestations of DMD may be due to chromosomal rearrangements involving the region of the short arm of the X chromosome (Xp21.2), deletions of this region, complete loss of the X chromosome (Shereshevsky-Turner syndrome), homogenous X chromosome dysomnia, compound heterozygous state for two pathogenic mutations in the DMD gene, nonequilibrium inactivation of the X chromosome. When female mutation carriers have DMD clinical symptoms, they usually manifest much milder than boys and young males. Descriptions of patients with the severe course and rapid progression of the disease, comparable in the rate of progression with boys, are rare. In this article, the authors share their experience of observing a girl patient who suffered from a severe form of DMD.

Download Full-text

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1507719112 ◽

2015 ◽

Vol 112 (23) ◽

pp. 7153-7158 ◽

Cited By ~ 136

Author(s):

Yetrib Hathout ◽

Edward Brody ◽

Paula R. Clemens ◽

Linda Cripe ◽

Robert Kirk DeLisle ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Healthy Volunteers ◽

Large Scale ◽

Biomarker Discovery ◽

Medical Center ◽

Drug Effects ◽

Serum Samples ◽

Normal Volunteers ◽

Surrogate Outcome

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.

Download Full-text