Serum miRNAs Are Pharmacodynamic Biomarkers Associated With Therapeutic Response in Pediatric Inflammatory Bowel Disease

Abstract

Background We sought to identify microRNAs (miRNAs) associated with response to anti-TNF-α or glucocorticoids in children with inflammatory bowel disease (IBD) to generate candidate pharmacodynamic and monitoring biomarkers. Methods Clinical response was assessed by Pediatric Crohn’s Disease Activity Index and Pediatric Ulcerative Colitis Activity Index. Quantitative real-time polymerase chain reaction via Taqman Low-Density Array cards were used to identify miRNAs in a discovery cohort of responders (n = 11) and nonresponders (n = 8). Seven serum miRNAs associated with clinical response to treatment, along with 4 previously identified (miR-146a, miR-146b, miR-320a, miR-486), were selected for further study. Candidates were assessed in a validation cohort of serum samples from IBD patients pre- and post-treatment and from healthy controls. Expression of miRNA was also analyzed in inflamed mucosal biopsies from IBD patients and non-IBD controls. Results Discovery cohort analysis identified 7 miRNAs associated with therapeutic response: 5 that decreased (miR-126, miR-454, miR-26b, miR-26a, let-7c) and 2 that increased (miR-636, miR-193b). In the validation cohort, 7 of 11 candidate miRNAs changed in the same direction with response to anti-TNF-α therapies, glucocorticoids, or both. In mucosal biopsies, 7 out of 11 miRNAs were significantly increased in IBD vs healthy controls. Conclusions Five candidate miRNAs associated with clinical response and mucosal inflammation in pediatric IBD patients were identified (miR-126, let-7c, miR-146a, miR-146b, and miR-320a). These miRNAs may be further developed as pharmacodynamic and response monitoring biomarkers for use in clinical care and trials.

Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy

“…Plasma miR-454 has been identified as a biomarker of myotonic dystrophy [ 72 , 73 ]. Serum miR-146b is a pharmacodynamic biomarker in inflammatory bowel disease (IBD) [ 34 , 35 ]. Intriguingly, miR-146b is also known to down-regulate dystrophin in multiple muscle diseases, is increased in dystrophinopathies and in myositis, and is also drug-responsive in the mdx mouse model of DMD [ 30 , 31 ].…”

“…RNA was isolated and quantified from the discovery cohort of patients as described previously [ 34 ]. Briefly, RNA was isolated from 150 µL of plasma using Trizol liquid sample (LS) reagent (ThermoFisher, Waltham, MA, USA), then converted to cDNA using the High Capacity Reverse Transcription Kit with multiplexed reverse transcription (RT) primers (ThermoFisher).…”

“…In addition to myomiRs, inflammatory miRNAs such as miR-146a, miR-146b, miR-221 and miR-155 have been found to be dysregulated in multiple forms of muscular dystrophies [ 29 , 30 , 31 ]. These two classes of miRNA show potential as pharmacodynamic biomarkers, with myomiRs proposed for muscle-stabilizing treatments such as gene therapy [ 32 , 33 ], and inflammatory microRNAs proposed for current steroids [ 34 , 35 ] as well as newly emerging dissociative anti-inflammatory drugs such as vamorolone [ 36 , 37 , 38 ] or edasalonexent [ 39 , 40 ]. In parallel to development of miRNA monitoring biomarkers, new advances in whole exome sequencing are enabling clinicians to diagnose novel mutations in over 60 genes known to be responsible for muscular dystrophies such as FSHD and limb-girdle muscular dystrophy (LGMD) [ 41 , 42 , 43 , 44 ].…”

The Osteoporosis/Microbiota Linkage: The Role of miRNA

“…Corresponding to the quantity of complementary mRNA, miRNA connections can provoke mRNA translational degradation, repression, or both [ 48 ]. miRNAs can interfere in the onset of numerous pathologies, such as asthma, cancer, and inflammatory bowel disease [ 49 , 50 , 51 ].…”

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers

“…For example, Batra et al. validated that the expression of seven miRNAs showed in remarkable changes after treatment in responders but not in non-responders in a small cohort of paediatric IBD with diverse treatments including anti-TNF mAbs [52] . However, a Greek group evaluated the association of miRNA polymorphisms with anti-TNF treatment response [53] did not detect any correlations between studied miRNA (miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172) polymorphisms and patients’ response to anti-TNF mAbs in 107 CDs.…”