A mucin mRNA isoform-based biomarker assay to improve treatment response in patients with inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are very heterogenous diseases that, due to their disabling and chronic nature and the high costs associated with their disease management, entail a great burden both for patients and for society. Currently, there are no available biomarkers to help clinicians choose the most appropriate treatment for each patient, forcing them to do so empirically. One way to improve treatment, is focussing on personalized medicine where efforts must be directed towards the identification of molecular markers to assess mucosal healing as the main therapeutic endpoint. Novel markers that could fit these criteria are the mucins. These highly glycosylated proteins are the gatekeepers maintaining mucosal barrier function. However, aberrant mucin expression, as characterized by a depletion of secreted mucin expression and overexpression of transmembrane mucins, has been described in IBD and own data highlighted that increased expression of MUC1, MUC3 and MUC13 is involved in barrier dysfunction by affecting expression of junctional proteins and cell polarity. Furthermore, mucins are highly polymorphic and the presence of genetic differences in the mucin genes can result in several mRNA isoforms of which some can be implicated in disease. The mucin mRNA isoform landscape associated with IBD still remains an unexplored conundrum. We have recently performed a proof of concept study in which we identified novel and known mRNA isoforms of MUC1, MUC3A, MUC5AC, MUC12, MUC13 and MUC17 associated with IBD. We wish to further validate our mucin mRNA isoform sequencing data to unravel the mucin mRNA isoforms as biomarkers to improve follow-up and treatment in IBD. Therefore, in this project we will design a mucin mRNA isoform-based biomarker assay to improve treatment management in IBD. To do so, we will first validate and complement our PacBio proof-of-concept isoform sequencing data and unravel which of the identified mucin mRNA isoforms are aberrantly expressed in IBD, using long-read ONT nanopore sequencing and short-read Illumina sequencing, respectively. These additional sequencing technologies will allow to select the optimal set of IBD-associated mucin mRNA isoforms for further implementation in a novel multiplex RT-qPCR-based biomarker assay. This biomarker assay will then be used to unravel which of the available and novel therapeutics impacts on aberrant mucin mRNA isoform expression and subsequent barrier function/integrity (as marker for mucosal healing) using patient-derived organoid cultures and to evaluate the efficacy of the IBD-associated mucin mRNA isoforms as minimally invasive biomarkers predicting the probability of treatment success at baseline in IBD patients.

Keywords:BIOMARKERS, GASTROENTEROLOGY

Disciplines:Gastro-enterology, Biomarker evaluation