Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys

Abstract

Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred.

Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ‐1a Biologics

“…The SOMAscan assay version 4.1 (SomaLogic, CO) measured > 7,000 human annotated protein analytes in EDTA plasma using slow off‐rate modified DNA aptamers (or single‐stranded DNA oligonucleotides) that bind with high affinity to protein epitopes. Selective binding by a specific aptamer transforms the concentration of that protein into a defined single‐stranded DNA measurement allowing the simultaneous quantification of thousands of protein analytes by conventional DNA hybridization methods 16,17 . Of these analytes, 903 were detected more than once by a different aptamer.…”

“…Selective binding by a specific aptamer transforms the concentration of that protein into a defined single-stranded DNA measurement allowing the simultaneous quantification of thousands of protein analytes by conventional DNA hybridization methods. 16,17 Of these analytes, 903 were detected more than once by a different aptamer. For details of plasma preparation, assay testing, quality control, and analysis, see Supplementary Methods and Results (Sections S1 and S3-S6).…”

Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function

“…However, even if great progress has been made during the last two decades in different subgroups of neuromuscular disorders, there are still numerous challenges to resolve, such as the optimization of therapeutic knock-down strategies [3], targeting specific muscles and/or tissues of the nervous system [1], identifying genetic modifiers that can impair a therapeutic strategy [2], targeting common pathways being affected in different patient subgroups for a given disease [4,5], or understanding the impact of neuromuscular disorders on other tissues that could be affected but may be understudied. This Special Issue, entitled "Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function", encompasses some 15 publications from colleagues working on a diverse range of neuromuscular diseases, including Duchenne muscular dystrophy [6][7][8][9], facioscapulohumeral dystrophy [3,10,11], amyotrophic lateral sclerosis [4,5,12], spinal muscular atrophy [2], Emery-Dreifuss muscular dystrophy [13], and rheumatoid arthritis [14]. Looking across diseases, several themes are recurrent, such as the efforts to identify genotype-phenotype correlations in DMD [6,7,9] and ALS [4,5], the quest for effective biomarkers in many neuromuscular conditions [2,8,10,14], and the use of genomic and multi-omic approaches towards better ways to identify biomarkers and to understand disease [10,12,13].…”

“…Aside from therapeutic strategy development, the use of biomarkers may be critical as disease trackers for the development of effective therapeutics (for example, in FSHD [10]), but also to the personalized tailoring of existing treatments (in DMD [8], and in rheumatoid arthritis [14]), and may prove useful in a broad sense for improved stratification, diagnosis, and/or treatment (e.g., in adult SMA [2]).…”

Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function

“…This Special Issue, entitled "Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function", encompasses some 15 publications from colleagues working on a diverse range of neuromuscular diseases, including Duchenne muscular dystrophy [6][7][8][9], facioscapulohumeral dystrophy [3,10,11], amyotrophic lateral sclerosis [4,5,12], spinal muscular atrophy [2], Emery-Dreifuss muscular dystrophy [13], and rheumatoid arthritis [14]. Looking across diseases, several themes are recurrent, such as the efforts to identify genotype-phenotype correlations in DMD [6,7,9] and ALS [4,5], the quest for effective biomarkers in many neuromuscular conditions [2,8,10,14], and the use of genomic and multi-omic approaches towards better ways to identify biomarkers and to understand disease [10,12,13].…”