ECCO Multi-Year Research Grant Synopsis: Marianne R. Spalinger & Raja Atreya
Marianne R. Spalinger, ECCO Grant Awardee
The PTPN2 loss-of-function variant as predictor of therapeutic response to JAK inhibitor therapy in IBD
Marianne R. Spalinger
© Marianne R. Spalinger
© Raja Atreya
Background & aim of research
JAK inhibition has emerged as a promising novel therapeutic strategy in IBD. However, only a subgroup of patients responds to JAK inhibitors and there are currently no predictive markers available that predict sustained response. Our recent work strongly indicates that loss-of-function variants in the PTPN2 gene might serve as predictive markers for therapeutic effectiveness, and the main goal of this project is to define whether PTPN2 dysfunction can serve as a predictor for efficacious JAK inhibitor therapy.
Methodology/experiments that will be used
We found that in murine colitis models, upadacitinib and filgotinib were more efficient in reducing colitis symptoms than tofacitinib. Thus, in the first part of the project we will subject mice with tissue-specific PTPN2 deletion to well-established murine colitis models to identify the molecular mechanisms behind this finding.
To translate our findings from the preclinical mouse models to the clinical setting, we will use intestinal biopsies, serum and peripheral blood mononuclear cells from patients enrolled in the Swiss IBD cohort who have previously been genotyped for the PTPN2 loss-of-function SNP rs1893217. Using these samples, we will further evaluate whether surrogate markers for PTPN2 dysfunction in the serum (i.e. cytokine profile) or mucosa (i.e. surface expression of cytokine receptors) can be used in clinical practice to predict the effectiveness of JAK inhibitor therapy.
Finally, we will prospectively collect samples from Ulcerative Colitis (UC) patients who undergo JAK inhibitor therapy, assess their PTPN2 genotype and evaluate their treatment response in order to establish whether PTPN2 – and molecular markers that correlate with PTPN2 activity – can serve as biomarkers to predict successful JAK inhibitor therapy.
Anticipated main impact
In recent decades, a number of novel therapeutic strategies for IBD have been developed, with several in clinical testing or already approved for the treatment of UC and/or Crohn’s Disease. One such therapeutic agent is the pan-JAK inhibitor tofacitinib. Unfortunately, only a proportion of IBD patients treated with tofacitinib achieve sustained remission. Since JAK inhibitor treatment is costly and can have severe side effects, definition of predictive factors for successful treatment is an important, yet unmet clinical need. The experiments proposed here aim to define easy-to-assess predictive markers for successful JAK inhibitor treatment. In this way, our experiments will provide the basis for urgently needed development of personalised medicine.
Months 1–6: Murine colitis models with PTPN2-deficient mice
Months 3–12: Validation of mechanisms in samples from IBD patients
Months 13–24: Confirmation of findings in an independent cohort of IBD patients and transfer into clinical practice