ERC FUNDED PROJECTS

In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial. The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.

2 495 200 €

Start date: 2014-04-01, End date: 2019-03-31

Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.

1 883 750 €

Start date: 2017-04-01, End date: 2022-03-31

The fundamental limitation in our ability to dissect human diseases is the scarce availability of human tissues at relevant disease stages, which is particularly salient for neural disorders. Somatic cell reprogramming is overcoming this limitation through the derivation of patient-specific induced pluripotent stem cells (iPSC) that can be differentiated into disease-relevant cell-types. Despite these tantalizing possibilities, there are critical issues to be addressed in order to secure iPSC-modeling as a robust platform for the interrogation of disease aetiology and the development of new therapies. These concern the taming of human genetic variation, the identification of differentiation stages in which to uncover and validate phenotypes, and finally their translational into drug discovery assays. This project confronts these challenges focusing on the paradigmatic case of two rare but uniquely informative disorders caused by symmetric gene dosage imbalances at 7q11.23: Williams Beuren Syndrome and the subset of autism spectrum disorders associated to 7q11.23 microduplication. The hallmark of WBS is a unique behavioral-cognitive profile characterized by hypersociability and intellectual disability in the face of comparatively well-preserved language abilities. Hence, the striking symmetry in genotype and phenotype between WBS and 7dupASD points to the 7q11.23 cluster as a surprisingly small subset of dosage-sensitive genes affecting social behaviour and cognition. We build on a large panel of iPSC lines that we already reprogrammed from a unique cohort of WBS and 7dupASD patients and whose characterization points to specific derangements at the level of transcriptional/epigenetic control, protein synthesis and synaptic dysfunction. Through the integration of transcriptomic and epigenomic profiling with targeted mass spectrometry and gene network prediction we propose an innovative drug discovery pipeline for the identification of new therapeutic leads.

1 997 804 €

Start date: 2014-09-01, End date: 2019-08-31

Most biotechnological therapeutics used in the clinic today and under current development, are of protein nature. Eukaryotic expression systems (such as yeasts and mammalian cells) for these therapeutic proteins add carbohydrate moieties (glycans) to the proteins, and these glycans strongly modulate the protein's in vivo biodistribution and therapeutic efficacy. Until recently, no adequate tools were available to accurately control glycosylation structure in these expression systems, but bio-engineering research in our lab and elsewhere has now largely overcome this problem. In the GlycoTarget ERC Consolidator grant project, we aim at exploring the relation between the structure of the glycans on therapeutic proteins and the in vivo targeting properties of these modified proteins to different tissues/cells/subcellular organelles. As highly medically relevant test cases for this exploration, we have selected three diseases with strong unmet therapeutic need, that could potentially be treated with glyco-targeted biopharmaceuticals through three different routes of protein delivery: progressive liver disease (intravenous), allergic asthma (subcutaneous immunization) and active tuberculosis (intrapulmonary delivery).

1 994 760 €

Start date: 2014-03-01, End date: 2019-02-28