Precision therapy in IBD

Facts & Details: 

Therapies targeting specific mediators of the immune system, known as “biologics”, are used in the treatment of chronic inflammatory diseases including inflammatory bowel disease (IBD). These therapies are cost-intensive, have considerably high primary and secondary non-response rates and can sometimes have adverse side effects.

Definition of clinical disease activity and deep molecular remission 
While some patients achieve a sustained quiescent state of their disease including mucosal healing, others suffer from ongoing inflammatory lesions. Local inflammatory activity is traditionally assessed using endoscopic indices. It is evident that for personalized treatment optimization, actionable, non-invasive biomarkers for clinical activity are an unmet need. 
So far, biomarker analyses related to disease activity and molecular definition of remission often only use one information layer (e.g. CRP, fecal calprotectin, single cytokines, antibody titres) and do not involve dynamic longitudinal data sets and integration into mechanistic models. We aim to develop regulatory network models of disease activity integrating several layers of information, from clinical to molecular data sets. We hypothesize that a molecular definition of deep remission and mucosal healing will become an important asset in the future management of IBD.  

Mechanism of action 
Different biologics induce various mechanisms of action (MOA), meaning each drug binds to a specific molecular target, such as a protein (TNF, IL-6, JAK-STAT) or a receptor (α4β7-integrin) of a pathway involved in chronic inflammation. When testing a potential new drug to treat IBD, the first clinical trials must assess if the anticipated target is being directly engaged. We strategically interact with the Dep. of Internal Medicine to design and utilize novel trial schemes and innovative molecular endpoints. In this systems medicine approach; we investigate dynamic changes in immune regulatory networks introduced by therapeutic interventions. We use multi-Omics analysis at early time points after therapy (hours after first administration) to detect expression changes in genes, changes in cellular heterogeneity or chromatin accessibility/transcription factor occupancy related to the respective pathways. Our goal is to scrutinize MOAs of each compound at their respective cellular targets.

Response prediction
Molecular biomarkers that can predict therapeutic response in individual patients and guide the treatment decisions in a clinical setting are still missing. Our group aims to understand the dynamic molecular changes in various biomaterials (e.g. blood, intestinal mucosa, stool) that are associated with response and non-response to different biologics (anti-TNFa, anti-IL-6, anti-JAK, anti-α4β7-integrin). We employ multi-modal clinical diagnostics and multi-omics (transcriptome, epigenome, microbiome, metabolome) analyses in longitudinal studies monitoring the disease activity in IBD patients under biologic therapy. Ultimately, we aim to identify early molecular predictors of individual disease outcome that might be applicable in future disease management of chronic inflammatory disease.

Projects:  

  • SYSCID (EU Horizon 2020)

  • FUTURE (IIT, Ferring, CAU/UKSH) 

  • sysINFLAME (eMed) / BMBF  

  • GUIDE-IBD / BMBF 

         

Main Publications

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