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-minute 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, with proximal strength associated with growth and remodeling pathways, and muscle endurance centered on TGFβ and fibrosis pathways in muscle.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study

“…Clinical evaluators were trained according to standard operating procedures that were harmonized between the CINRG vamorolone, CINRG DNHS, and CINRG prednisone studies. Reliability of these outcomes (percent coefficient of variation) has been reported for the VBP15-002/VBP15-003 studies [ 19 ]. Assessments were done at baseline (VBP15-002 entry), 24 weeks (VBP15-003 last visit), and 18 months (VBP15-LTE midpoint assessment at 12 months).…”

A Blood Biomarker for Duchenne Muscular Dystrophy Shows That Oxidation State of Albumin Correlates with Protein Oxidation and Damage in Mdx Muscle

“…There is increasing interest in identifying and using blood biomarkers to monitor disease progression in mdx mice and DMD boys [ 62 , 63 , 64 ]. Therefore, in this study we examined the relationship between levels of protein thiol oxidation in muscles, to albumin thiol oxidation in plasma, of dystrophic mdx and control wild type C57Bl10scsn (C57) mice at various ages across their life-span (at 23 days, 6 and 12 weeks and 18 months).…”

Development of outcome measures according to dystrophic phenotypes in canine X-linked muscular dystrophy in Japan

“…Serum OPN is also expected to be applicable as an outcome measure in clinical trials with muscle regeneration-inducing agents [112,113]. [80,[114][115][116]. The 6MWT, which measures the distance walked in 6 minutes, is a primary outcome measure of motor function in DMD [117,118], but this test is not sufficiently sensitive to measure disease progression in younger DMD boys [119].…”

“…The levels of various cytokines and growth factors in the blood have also been found to be elevated in association with dystrophic pathology, including tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-13, interferon-γ, transforming growth factor-β, and basic fibroblast growth factor [ 70 , 75 , 76 , 77 , 78 , 79 ]. Serum levels of several proteins are correlated with the clinical severity in ambulatory and nonambulatory patients with DMD [ 71 , 76 , 80 ].…”