Brain disorders present a staggering health-care burden, costing around 800 billion euros per year in the EU and affecting almost 180 million people. Currently, development of treatments for these disorders is very unsuccessful. Of all currently prescribed drugs, >30% target G-protein coupled receptors, that are typically activated by neuromodulators. Neuromodulators are signaling molecules secreted by most neurons, which regulate many processes in our brain and body. Dysregulation of neuromodulator secretion is firmly associated with many neuropsychiatric disorders, but no screening assay for neuromodulator secretion is currently available to test drug candidates. We have developed a human-based neuromodulator screening assay for preclinical testing of compounds for neuropsychiatric disorders. This assay, the HumanNeuronScreen, uses human neurons derived from somatic patient cells (e.g. skin), to maximally approach the situation in the patients’ CNS and thereby greatly enhancing target validation and lead optimization in preclinical research. It delivers in depth knowledge on the mechanism, potency and selectivity of drug candidates, supporting a higher success rate for clinical trials. Therefore, the value proposition of our product consists of a drastic reduction of costs in drug-development for pharmaceutical and biotech companies, and potentially impacts on 180 million patients in Europe. This proof-of-concept project aims to prove the commercial potential for the HumanNeuronScreen by measuring a reference library of compounds that establishes the resolution, reproducibility and dynamic range of the screen. An IP strategy will be developed to ensure a market position and business strategy will be created and validated. Together, this maximizes the value of the research conducted in the ERC Advanced grant DCV fusion.

The advances in medical sciences and biopharmaceutical development during the last decennia have been overwhelming. While the scientific and clinical insight in numerous diseases have significantly increased, the curative treatment to most diseases is still not in reach. The most common diseases such as cancer and chronic diseases are still challenging scientists. Therefore, during our ERC Advanced project the main goal was to develop a vaccine to cure cancer using targeted immunotherapy. We used dendritic cells (DCs) as potentiator to improve anti-tumor T cell activity. However, we discovered that many tumors display a high content of sialic acids which actively suppress DCs function and induce tolerance to tumor associated antigens. This unexpected serendipity finding that sialylation of tumor associated antigens induced tolerance to the body’s immune response opens a window of opportunity to use sialylation (modification with sialic acid) to induce tolerance in allergies, such as house dust mite allergy (HDM). In the ERC PoC project (MATCH) I will couple HDM major allergens to specific sialic acid using a linker molecule to induce immune tolerance towards effector T cells in inflammation processes during HDM allergy. The results will lead to validation of the technology developed during the ERC Advanced project and PoC that sialylation induces tolerance when used with HDM allergens. When PoC is reached, the MATCH technology will represent a new allergen immunotherapy in a vaccine technology for HDM allergy with shorter treatment protocols, better efficacy and reduced side effects can be developed. The future potential of this technology may be extended to other allergies and/or autoimmune diseases.

Pulmonary hypertension (PH) is a rare but progressive fatal disease characterized by accumulation of persistently activated cell types in the pulmonary vascular wall exhibiting abnormal expression of genes driving proliferation, inflammation, and metabolism. The currently used vasodilatory therapies have little or no impact on this activated phenotype and therefore offer no cure or even substantial survival benefit. PH has a high female predominance (3:1 to 9:1). This proposal aims to understand the mechanism behind the high female predominance to identify novel therapeutic targets to attenuate disease progression in male and female PH patients. Female predominance can be linked to sex hormones and/or incomplete X chromosome inactivation (XCI) leading to biallelic expression of immunoinflammatory and metabolic genes. To understand the impact of oestrogen and androgen signalling on abnormal vascular remodelling in PH, I will develop a unique opposite-sex lung transplantation rat model, identify oestrogen metabolites in a large set of patient serum samples and explore their biological relevance using pulmonary vascular cells from male and female PH patients in cell-based assays. Preliminary experiments suggest there is incomplete XCI in PH. I propose to combine sequencing and molecular studies to extensively characterize the impact of incomplete XCI on the physiology of male and female PAH cells and identify genes and druggable targets regulating incomplete XCI in PH. Finally, I will explore a novel pulmonary endothelium-specific drug delivery method to deliver identified promising genes/compounds to selectively inhibit the activated pulmonary vasculature thereby minimalizing side effects compared to current delivery methods. Together, this high risk-high gain study will dissect the molecular mechanisms underlying the unresolved female predominance in PH and offer novel pulmonary endothelium-specific therapies for both male and female PH patients.

Up to 40% of patients with inflammatory bowel disease (IBD) do not respond to standard of care treatment with anti-inflammatory drugs. Unfortunately, the mechanisms driving persistent inflammation are unknown, resulting in a lack of specific therapies and an important burden for patients and society. Enteric neurons are highly specialized cells that sense and respond to nutrients, microbial products and inflammatory signals and densely innervate the gut. Besides regulating gastrointestinal motility, emerging studies indicate that crosstalk between enteric neurons and immune cells regulates inflammation, tissue homeostasis and antimicrobial immunity. However, this has not been investigated in the context of IBD. I hypothesize that enteric neurons become rewired during IBD and acquire an inflammatory signature that amplifies inflammation. Recent technological advancements will allow the investigation of enteric neurons via the use of cutting-edge tools in microfluidic droplet generation, molecular biology and functional genomics. We will leverage the Xavier lab’s expertise in the field of the enteric nervous system at the Broad Institute of MIT and Harvard during the outgoing phase, the expertise of Dr. D’Haens in IBD during the return phase at the Amsterdam University Medical Center and my expertise in pre-clinical IBD models in vitro and in vivo to characterize the role of enteric neurons in IBD for the first time and find potential treatment targets.

Obesity and subsequent non-alcoholic hepatic steatosis (NAFLD-NASH) are important determinants of morbidity and mortality being imbalanced between ethnicities living in Europe. However, relatively little is known about the underlying aetiology that drives NAFLD-NASH and currently no treatment is available. We and others have mapped alterations in gut microbiota to metabolic disease, focusing on the bacterial functions. FATGAP builds on our work showing that 40% of obese humans with NAFLD-NASH are characterized by high production of the (endogenous) microbially produced metabolite ethanol derived from mixed acid fermentation of dietary sugars. Our pilot data show that catabolism of the dietary sugar fructose by (small) intestinal high ethanol producing bacterial strains relates to increased plasma levels of this metabolite. While acidic by-products of mixed acid fermentation lower intestinal pH thereby inhibiting the ethanol production, proton pump inhibitors (PPIs) increase pH. Indeed, epidemiological data have linked PPI use with NAFLD-NASH. I therefore hypothesize that gut microbial ethanol production from dietary sugar fructose is intestinal pH dependent and is driven by PPI use in humans. First, I will link gut microbial composition/function in relation to impact of endogenous (genetic) and exogenous (medication use) factors in microbial ethanol production with NAFLD-NASH in multiethnic prospective cohorts Second, we will explore how variations in intestinal pH affect kinetics by which (labelled) fructose is catabolized into ethanol and how this process is regulated by (inhibitory) strains and microbially produced metabolites. Third, we aim to culture (CRISPRcas modified) alcohol-degrading bacterial strains which can degrade intestinal ethanol at all pH levels. Finally, I will perform in vivo animal and human intervention trials with these identified (engineered) lead bacterial strains and study the effect in human NAFLD-NASH.