ERC grants

ERC Synergy Grant 2023 - Functional cartography of intestinal host-microbiome interactions

CartoHostBug

Eduardo Villablanca, PhD - Karolinska Institute, Sweden
Stefania Giacomello, PhD - KTH Royal Institute of Technology, Sweden
Julio Saez-Rodriguez, PhD - University Hospital Heidelberg, Germany
Georg Zeller, PhD - Leiden University Center of Infectious Diseases, LUMC

• EC contribution to total project: € 10.382.670
• EC contribution to LUMC: € 2.498.875
• Start date: 01-07-2024 - End date: 30-06-2030

Abstract:

Microbiome-host crosstalk is crucial for gut homeostasis and its dysregulation is a hallmark of diseases such as colorectal cancer (CRC) and inflammatory bowel disease (IBD). Despite its key relevance for a holistic understanding of the human superorganism and its (patho-)physiology, how local host-microbiome interactions form specific niches in the gut and how these niches function at the cellular and molecular level remains unexplored, mainly due to a lack of suitable technologies.

To fill this gap, we propose to jointly reconstruct the host transcriptional and microbiome compositional landscape of the human gut across a large number of healthy individuals as well as IBD and CRC patients. For this, we will leverage a combination of novel spatial profiling technologies for unbiased transcriptome sequencing and microbiome profiling at single-cell resolution in situ. First, we will spatially delineate local niches formed of specific microbes and host cells. To dissect this complex crosstalk into specific interactions, we will secondly use in vitro and in vivo models to introduce perturbations either on the host or the microbiome side. Finally, we will integrate the resulting data to deconvolute host-microbiome circuits computationally and to predict functional niches, in particular host responses to pathogens of relevance in IBD and CRC. Interesting predictions will be tested in organoid and animal models. Developing a spatially resolved computational model of the gut ecosystem will allow us to predict early local events in disease onset; from these we will identify and validate prognostic IBD and CRC biomarkers for future clinical translation.

This work will revolutionize our understanding of intestinal host-microbiome interactions by adding a first-ever functionally resolved spatial dimension with clinical relevance for the future diagnosis and treatment of intestinal disorders.

ERC Synergy Grant 2022 – Glycans as Master Switches of B Cell Activity in Autoimmunity GlycanSwitch

Prof. Tom Huizinga, PhD – Department of Rheumatology, LUMC (corresponding PI)
Prof. Manfred Wuhrer, PhD – Center for Proteomics and Metabolomics, LUMC
Prof. Salome Pinho, PhD – University of Porto, Portugal
Prof. Gordon Lauc, PhD – GENOS, Croatia

• EC contribution for total project: €​9.975.000
• EC contribution to LUMC: €​5.000.000
• Start date: 01-01-2023 – End date: 31-12-2028

Abstract: Autoimmune diseases including rheumatoid arthritis (RA) are often life-threatening disorders with increasing disability having a negative impact on patients’ quality of life. Mechanisms leading to the breach of tolerance in development of autoimmunity are still largely unknown. Protein glycosylation is an essential regulatory mechanism in the immune system. We recently demonstrated that N-glycosylation of the variable region (Fab) of autoantibodies is a hallmark of RA development and progression. We also demonstrated that autoantibodies acquire these Fab glycosylation signatures already many years before disease onset. We herein hypothesize that Fab glycosylation at the level of the B cell receptor is a key molecular switch promoting the selection, activation and proliferation of autoreactive B cells leading to the concomitant breach of immunotolerance. Within GlycanSwitch, we will map the Fab glycome of various types of RA autoantibodies and autoreactive B cells. We will study the factors and underlying cellular mechanisms that regulate Fab glycosylation of B cell receptors and autoantibodies. We will investigate the immunological effects of Fab glycosylation and the impact in B cells signalling and activation in the context of molecular and cellular interacting partners in the immune microenvironment. Finally, we will test in relevant mouse models how Fab glycosylation of autoantibodies and autoreactive B cells contributes to the breach of tolerance. We expect that the obtained insights into the role of glycans as key checkpoint for the selection of autoreactive B cells and the rise of autoimmunity will provide leads for targeted therapeutic interventions as well as rationales for the early detection of RA and autoimmune diseases in general. We foresee that the knowledge generated will allow us to embark on a targeted prevention clinical study in patients at risk for RA to turn off the GlycanSwitch leading to chronic RA.

ERC Advanced Grant 2023 – Ton Rabelink - Spatial Metabolic Regulation in Kidney Repair

SPARK

Prof. Ton Rabelink, PhD

Department of Internal Medicine

• ERC Advanced Grant 2023 – panel LS4
• EC contribution: 2.500.000 euro
• Start date: 01-01-2025 – End Date: 31-12-2029

Abstract:

Chronic kidney disease (CKD) is a global health concern, and the limited treatment options for end-stage kidney disease have remained unchanged for decades. Concurrent insults to the kidney can exacerbate disease progression, but the underlying potential to have kidney repair after such injury remains poorly understood. The tricarboxylic acid (TCA) cycle, a fundamental metabolic pathway, plays a vital role in energy production and biomolecule synthesis. Recent research by my group has revealed that failed repair and subsequent fibrosis in kidney epithelial cells are linked to anaplerotic failure in the TCA cycle, resulting in the inability to maintain sufficient levels of TCA intermediates. These metabolites regulate chromatin remodeling and cell signaling pathways, influencing cell fate decisions. SPARK aims to investigate the impact of perturbed cell metabolism and metabolic crosstalk within kidney microenvironments on cell fate decisions during injury and repair. The project will map the metabolic, proteomic, and transcriptomic interactome at an unprecedented resolution, focusing on the kidney tissue microenvironment. By integrating spatial multi-omics data, exometabolite interactome analysis, and human kidney biopsies, actionable targets will be identified. In vivo studies using reporter mice and ex vivo preserved human kidneys will validate the metabolic effects of the selected targets. This research will provide insights into how the metabolic interactome governs repair through epigenetic modulations in the kidney and establish a paradigm for studying tissue homeostasis in various contexts.

Read more: LUMC press release

ERC Advanced Grant 2021 – Maria Yazdanbakhsh - Reversing vaccine hypo-responsiveness

REVERSE

Prof. Maria Yazdanbakhsh, PhD

Department of Parasitology

• ERC Advanced Grant 2021 – panel LS6
• EC contribution: EUR 2,372,681
• Start date: 01 October 2022 – End date: 30 September 2027

Abstract

There is growing evidence that vaccine immunogenicity and efficacy present considerable variations across populations in high- and low/middle-income countries. For example, volunteers’ vaccination in Europe with attenuated malaria vaccine can result in 100 % protection, while the efficacy drops to just 29 % in Africa. Similar trends are seen with other vaccines. The EU-funded REVERSE project will understand the mechanisms underlying vaccine hypo-responsiveness across populations and find ways to reverse it. The project relies on the hypothesis that the variation in the immunological network due to exposure to microorganisms and parasites, and the cellular metabolism of populations residing in distinct environmental conditions, is responsible for vaccine hypo-responsiveness. Immunological and metabolic interventions can reverse it.

ERC Advanced Grant 2020 - Andrew Webb - Portable, accessible and sustainable magnetic resonance Andrew Webb

PASMAR

Prof. Andrew Webb, PhD

Department of Radiology

• ERC Advanced Grant 2020 – panel LS7
• EC contribution: EUR 2,493,715
• Start date: 01 September 2021 – End date: 31 August 2026

Abstract

Magnetic resonance imaging (MRI) provides high-definition diagnostic imaging. However, it’s very expensive and requires skilled maintenance and highly trained technicians. The EU-funded PASMAR project aims to provide MRI systems that will enable medical screening as part of an affordable, sustainable and accessible platform for the developing world. The objective is to design new types of low-cost low-field systems for specific clinical applications and overcome the main challenge of much lower MRI signals. These specialised systems can be used for adult/paediatric brain, orthopaedics and lung/spine scanning, taking advantage of the flexibility of permanent magnet arrays with new geometries, targeted for specific organs, and using open-source design to allow local maintenance and repair.

Andrew Webb already received an ERC Advanced Grant in 2014.

ERC Advanced Grant 2019 – Rene Toes - Targeting auto-reactive B-cells by vaccination to cure human auto-immune disease

Target to B-Cure

Prof. Rene Toes, PhD 

Department of Rheumatology

• ERC Advanced Grant 2019 - panel LS7
• EC contribution: EUR 2,500,000
• Start date: 01-01-2021 - End date: 31-12-2025

Abstract

Most incurable human autoimmune diseases are chronic conditions characterized by the presence of autoantibodies. Elimination of the autoreactive B-cells are not presently feasible due to a lack of specific markers. The EU-funded Target to B-cure project aims to develop a vaccine that will allow specific long-lasting depletion of autoreactive B-cells. Using autoimmune rheumatoid arthritis (RA) as a model, it will study the RA specific autoimmune response. Researchers will identify autoreactive B-cells and the B cell receptor (BCR) repertoire at several stages of the disease to determine the potency of the non-germline-encoded mutations in BCRs as antigens amenable to T-cell recognition and vaccination. Finally, the project will design patient-tailored vaccines and perform a phase I trial to determine the feasibility of depleting disease-causing B-cells.

ERC Advanced Grant 2018 – Johanna Meijer - The circadian clock in day-active species: preserving our health in modern society

DiurnalHealth

Prof. Johanna Meijer, PhD

Department of Cell and Chemical Biology

• EC contribution: EUR 2,233,251
• Start date: 01 September 2019 - End date: 30 June 2026

Abstract

Due to a significant increase in the use of artificial light in our 24h economy, the biological clocks of all living organisms, including humans, are severely disrupted. Many severe health disorders are consequences of clock disruption such as diabetes, sleep/mood disorders, cardiovascular disease, and immune dysfunction. The central timekeeper in mammals is the suprachiasmatic nucleus (SCN), and the mechanisms by which light disrupts integrity of the SCN has been well investigated in nocturnal species. In contrast, mechanisms of clock disruption in humans and other diurnal (day-active) species remain poorly defined. I have evidence that the mechanisms that drive SCN function are fundamentally different between nocturnal species and diurnal species. This defines my aim to restore proper clock function in diurnal species, including humans. To test this, in Objective 1 we will identify similarities and differences between nocturnal and diurnal clocks with respect to their i) response to light, ii) neuronal synchronization, iii) output, and iv) response to physical activity. Based on these findings, in Objective 2 we will develop novel strategies to manipulate and restore clock function in diurnal species. These objectives will be achieved using novel, state-of-the-art chronobiology methods including in vivo electrophysiology and Ca2+ and bioluminescence reporters—all in freely behaving day-active animals, as well as in slice preparations containing the SCN. For studies on the human SCN we record with 7-Tesla fMRI. This proposal will help establish a new basis for chronobiology with respect to the most suitable models for studying translational applications. The results will yield immediate benefits in terms of manipulating biological clock function among vulnerable populations in modern society, particularly the elderly, patients in intensive care, and shift workers.

ERC Consolidator Grant 2022 – Gerbrand van der Heden van Noort - ADPribosylation and Ubiquitination; post-translational interplay

ADProbe

Gerbrand van der Heden – van Noort, PhD, Assistent Professor
Department of Cell and Chemical Biology

• ERC Consolidator Grant 2022 – panel LS1
• EC contribution: EUR 1.999.625
• Start date: 01-01-2024 | End date: 31-12-2028

Abstract:

ERC Consolidator Grant 2021 – Martijn Luijsterburg - Mechanisms at the interface of DNA damage repair and transcription

STOP-FIX-GO

Martijn Luijsterburg, PhD, Associate Professor

Department of Human Genetics

• ERC Consolidator Grant 2021 – panel LS1
• EC contribution: 1,999,764 euro
• Start date: 01 June 2022; End date: 31 May 2027

Abstract: 

Transcription-blocking DNA lesions can be triggered by a wide variety of DNA-damaging agents and form an obstacle to gene transcription enzymes. Transcription-coupled repair (TCR) is a specialised DNA repair pathway that selectively removes DNA lesions from actively transcribed genes, restoring transcription. The mechanisms underlying these processes are poorly understood. The EU-funded STOP-FIX-GO project will elucidate the mechanisms underlying the cellular responses to transcription-blocking damage through a combination of high-tech genomics, proteomics and mapping techniques with a focus on known and promising TCR proteins. Understanding how cells naturally overcome transcription roadblocks could point to novel therapeutics.

ERC Consolidator Grant 2021 – Daniel Pijnappels - Translational optoelectronic control of cardiac rhythm in atrial fibrillation

TransRhythm

Prof. Daniel Pijnappels, PhD

Department of Cardiology

• ERC Consolidator Grant 2021 – panel LS7
• EC contribution: 1,999,999 euro
• Start date: 01 March 2023; End date: 29 February 2028

Abstract: 

The EU-funded TransRhythm project aims to determine the translational potential of optoelectronic heart rhythm control for managing atrial fibrillation (AF) as the most prevalent cardiac arrhythmia. Immortalised human atrial cardiomyocytes expressing light-gated ion channels will be used to engineer human atrium-sized 3D models of AF. Multi-electrode-LED arrays will be integrated to control model optoelectronic rhythm via bioelectricity generation by precise illumination. Insights from the study will enable the application of this approach in AF animal models to determine the feasibility, safety, and therapeutic implications. The project objective is to establish principles of optoelectronic control of cardiac rhythm and discover novel insights into AF mechanisms and treatment.

Daniel Pijnappels already received an ERC Starting Grant in 2016.

ERC Consolidator Grant 2020 – Milena Bellin - Human mini hearts: looking for culprits and victims in cardiac disease

Mini-HEART

Milena Bellin, PhD, Associate Professor

Department of Anatomy & Embryology

• ERC Consolidator Grant 2020 – panel LS4
• EC contribution: 2,000,000 euro
• Start date: 01 September 2021; End date: 31 August 2026
• We are hosting this research together with the University of Padua

Abstract

Cardiac disease causes morbidity and mortality as frequently as cancer. Predicting cardiac arrhythmia and cardiac failure, understanding multicellular (patho)physiological mechanisms, and devising new treatments represent unmet needs in the field. Human induced pluripotent stem cells (hiPSC) could revolutionise the way we study human disease but unfortunately, they still fall short in recapitulating variable phenotypes and complex cardiovascular diseases. This is partly due to functional immaturity of hiPSC-derived cardiac tissues, shortage of methods for accurate functional analysis and inability to identify cell-type specific contributions to disease pathology. I will address these challenges in Mini-HEART. We recently assembled novel three-dimensional multi-cellular cardiac microtissues as an important step towards full maturation and used these to demonstrate that cardiac disease mutations might directly affect non-myocyte cardiac cells. However, application of hiPSC microtissues to precision medicine remains to emerge. Using a multidisciplinary approach, I will combine isogenic hiPSC, their differentiation into distinct cell types of the heart, multifaceted biophysical assays, and tissue engineering to prove cell-type causality of disease and identify new molecules targeting the culprit cells to rescue the disease phenotype. I plan to use our unique complex hiPSC-cardiac microtissue to

1. identify and synthetically enhance maturation mechanisms;
2. reveal late arrhythmic and fibrotic phenotypes;
3. dissect cell-type specific contributions to complex cardiac diseases, including the role of macrophages and sympathetic nerves;
4. test two therapeutic strategies based on drug-tailoring and gene editing, to modulate the disease phenotype.

Together, Mini-HEART will create new opportunities for designing novel biomedical tools to
i) capture phenotypic changes,
ii) reveal (patho)physiological mechanisms and ii) develop new therapeutic approaches for heart disease.

ERC Consolidator Grant 2017 – Jenny van der Steen - Attempts to control the end of life in people with dementia: two-level approach to examine controversies

CONT-END

Jenny van der Steen, PhD, Associate Professor

Department of Public Health and Primary Care

• ERC Consolidator Grant 2017 - panel SH3
• EC contribution: EUR 1,988,972
• Start date: 01 December 2018 - End date: 31 May 2025​

Abstract

In dementia at the end of life, cognitive and physical decline imply that control is typically lost. CONT-END will examine control in the context of three emerging interventions which contain a controversial element of striving for control in the process of dying with dementia: advance care planning of the end of life, use of new technology to monitor symptoms when unable to self-report, and euthanasia. To perform outstanding research, the proposed research examines control at the level of clinical practice, but also at the level of end-of-life research practice. The latter provides ample opportunities for researchers to control the research process. That is, research designs are often flexible and we will study how flexibility impacts research in an emotionally charged area.

I will take an empirical mixed-methods approach to study the two practices in parallel. The work is organised in three related Work Packages around three research questions.

1. In a 6-country study, I will examine if and when people with dementia, family caregivers and physicians (900 respondents) find the interventions, shown on video, acceptable.
2. A cluster-randomised 3-armed controlled trial in 279 patients and their family caregivers assesses effects of two types of advance care planning differing in level of control (detailed advance treatment orders versus goal setting and coping based) on outcomes ranging from favourable to less favourable, and whether effects differ in subgroups. cases in which the technology is preferred or applied are observed.
3. Ethnographic fieldwork in two different end-of-life research practices and a Delphi study to synthesize CONT-END’s findings assess how researchers shape findings. This greatly improves the quality of CONT-END and provides the input to develop new methodology for improving research quality and integrity.

ERC Starting Grant 2024 – Maartje Huijbers - Understanding and targeting pathogenic IgG4 responses

Acronym: IgG4-START

Maartje Huijbers, Associate Professor
Department of Human Genetics

• ERC Starting Grant 2024 – panel LS6
• EC contribution: EUR 1.493.090
• Start date: TBC – End date: TBC

Abstract

Will follow soon

ERC Starting Grant 2022 – Simon Jochems – Understanding respiratory tract infections through minimally-invasive, daily nasal sampling in children

DailySAM

Simon Jochems, PhD, Assistant Professor
Department of Parasitology

• ERC Starting Grant 2022 – panel LS7
• EC contribution: EUR 1.677.858
• Start date: 01 July 2023 – End date: 30 June 2028

Abstract

Pneumonia is the number one infectious cause of death in children worldwide. Many of the viruses and bacteria that cause pneumonia regularly infect, or colonize, the upper respiratory tract (URT) without causing disease. This drives community transmission but is also an important source of immunity. The processes and key host immune and microbiota factors that determine the infection kinetics, transmission and development of immunity during such infections need elucidation.

I have recently optimized minimally-invasive nasal sampling analysis methods using Synthetic Absorptive Matrix (SAM) strips that now allow me to address these knowledge gaps. Through the daily collection of such well-tolerated nasal samples in children, I will study non-pathological, naturally-acquired URT infections, but also controlled infections in an ethical and safe manner using the live attenuated influenza vaccine. In addition, I will perform high frequency nasal sampling in groups of schoolchildren to precisely measure transmission events over time and even infer exposure. Incoming bacteria, viruses and the resident URT microbiome as well as mucosal host innate and adaptive immune responses will be quantified in parallel throughout infections using existing and new high-throughput assays, including an antigen array and microfluidic qPCR for 32 pathogens. Multi-omics integrative time-series analyses and mathematical modelling will be used to identify parameters that are central and predictive for pathogen acquisition, replication and clearance; as well as for transmission and immune boosting. Key novel markers and concepts will be validated using state-of-the-art in vitro mucosal models.

The comprehensive and detailed understanding of URT infections obtained in this project can lead to better diagnostics, mucosal targeted therapies and vaccines, and provide a basis for the improved predictions of pathogen spread and public health effects of interventions at the population level.

ERC Starting Grant 2022 - Meta Roestenberg - Dissecting early Skin-based immune responses to PARasites in ControLled human infection studies to design novel vaccines

SPARCL

Meta Roestenberg, PhD, Professor
Department of Parasitology

• ERC Starting Grant 2022 – panel LS6
• EC contribution: EUR 1.499.894
• Start date: 01 May 2023 – End date: 30 April 2028

Abstract

Parasitic diseases cause considerable morbidity and mortality in poverty-stricken areas, affecting hundreds of millions of lives globally. Vaccines are urgently needed to alleviate disease and lift the economic consequences. Plasmodium falciparum malaria, Schistosoma mansoni and Necator americanus hookworms are together responsible for the greatest burden of disease. Vaccination with attenuated parasites is an efficacious strategy in inducing immunity to parasites in animal models. Recently, we have translated attenuated parasite vaccination to humans in proof-of-concept clinical trials in which we protected subsets of individuals from challenge. This unique preliminary data indicates a role for the skin as a prime immunological organ. Based on these findings, I propose to create a next generation highly immunogenic, adjuvanted whole parasite vaccines, ready for pre-clinical testing. We will build on our previous experience with chemical tools to load whole parasites with adjuvants. To measure the potency of the new vaccines, we aim to measure early skin-based humoral and cellular immune markers which correlate with protection in our samples from prior and novel controlled human infection models. We will assess the functionality of antibodies by adapting our current molecular imaging tools to quantitatively analyze movement kinematics of parasites in representative 3D environments resembling the human skin. Cellular correlates of protection in skin will be mapped using imaging mass cytometry on freshly obtained skin biopsies from experimentally infected volunteers. Through combined, parallel analysis of circulating immune markers by high-dimensional flow cytometry, we aim to take a comprehensive approach including local and circulating markers to identify protective immune responses. This high-risk high-gain proposal is aimed to break the impasse in the field of parasite vaccine development and open a novel out-of-the-box avenue to fill the vaccine pipeline.

ERC Starting Grant 2021 – Anna Alemany – Deciphering signalling pathway dynamics during cell-fate commitment in stem cells

i-SignalTrace

Anna Alemany, PhD, Assistant Professor

Department of Anatomy & Embryology

• ERC Starting Grant 2021 – panel LS2
• EC contribution: EUR 1.500.000
• Start date: 01 March 2023 – End date: 29 February 2028

Abstract

Understanding the identity and intensity of the specific extracellular signals that a cell experiences at different times during its differentiation is essential to develop advanced cellular therapies. However, uncovering the sequence of these signaling events, their intensities, timing, and relevance in development and disease is proving to be very challenging.

Here, I propose to build i-SignalTrace: a CRISPR/Cas9-based molecular recorder with the capacity to store both lineage information and signalling pathway activity for multiple signals over time in single cells. By performing kinetic experiments and mathematical modeling, I will use i-SignalTrace to extract the probability of signalling pathways to be activated in stem cells when subject to different extracellular signals and reconstruct the lineage tree of pathway activities during differentiation with single-cell resolution. In combination with single-cell RNA sequencing, i-SignalTrace will make it possible to characterize transition and intermediate states along differentiation trajectories, and quantify the integration between extracellular signals and autonomous programs of gene expression. These results will allow predicting the differentiation trajectories that stem cells follow when subject to external perturbations, and deciphering the role of heterogeneity in signalling pathway activity during cell-fate commitment.

Using i-SignalTrace, I will identify missing or redundant signalling pathways induced during in vitro differentiation protocols. Therefore, I expect that exploitation of i-SignalTrace will allow establishing new criteria to design protocols to differentiate stem cells on demand. As a proof-of-concept, I propose a framework to improve the functionality of monolayer-derived cardiomyocytes. Taken together, i- SignalTrace will find applications in both fundamental developmental biology and translational regenerative medicine, which will benefit a much wider scientific community.

ERC Starting Grant 2020 – Baoxu Pang - The darker side of the genome: systemically studying the biology of repressive elements - silencers - in the human genome

Silencer

Baoxu Pang, PhD, Assistant Professor 
Department of Cell and Chemical Biology

• ERC Starting Grant 2020 - panel LS2
• EC contribution: EUR 1,750,000
• Start date: 01 February 2021 - End date: 31 January 2026

Abstract

Less than 1.5% of the human genome contains protein coding information of the estimated 25,000 genes. The rest of the non-coding genome includes many regulatory elements that control the spatial and temporal transcription of genes. With the help of the non-coding regulatory elements, the diverse cell types and tissues of a complex human body could be derived from the combinational expression of a limited number of genes from the same copy of the genome. Most regulatory elements (REs) have been characterized extensively, e.g. promoters, enhancers and insulators. These REs have been implicated to play very important roles in cell physiology, tissue development and disease onsets. Surprisingly, one class of REs—silencers—which repress the transcription of genes, have not been systematically characterized and studied. I have developed a lentiviral system to systematically identify functional silencer elements. In the small-scale proof-of-principle experiments, by focusing on the transcriptional factor (TF) accessible DNA sequences, I showed that this system is robust to identify novel and bona fide silencers, which could be validated using complementary functional assays such as luciferase and CRISPR knockout assays. In this proposed research plan, I aim to identify silencers in an unbiased way, rather than focusing on TF accessible regions, to have a more general understanding of the biology of silencers. Based on the unbiased identification of silencers, I aim to identify a general pattern of epigenetic modifications of silencers, unique combination of sequence motifs, responsible regulatory TFs, biological pathways that are regulated by silencers, diseases that might be related to mutations in silencers, and finally better manipulation strategies of silencers.

ERC Starting Grant 2019 – Noel de Miranda - RAtional design of canceR ImmunoTherapY: one size does not fit all

RARITY

Noel de Miranda, PhD
Department of Pathology

• ERC Starting Grant 2019 - panel LS7
• EC contribution: EUR 1,499,795
• Start date: 01 December 2019 - End date: 30 November 2024

Abstract

Checkpoint blockade immunotherapies have revolutionized cancer treatment. However, this immunotherapy only benefits a minority of patients (< 15%), mainly those diagnosed with cancers having many mutations. Furthermore, checkpoint blockade therapy does not selectively activate cancer-reactive T cells. RARITY responds to these shortcomings, aiming to provide innovative solutions for the development of effective immunotherapies for patients who do not benefit from current treatments. The ground-breaking preliminary data included in this application demonstrates that cancer-reactive T cells can be naturally present in so-called non-immunogenic cancers and that they acquire distinctive phenotypes. RARITY will apply state-of-the-art technologies to fingerprint these phenotypes. This will allow the isolation of cancer-reactive T cells from tumour tissues and their employment as highly-effective therapies. Therapeutic vaccination with cancer antigens can also be used to induce T cell responses in patients where natural activation of cancer-specific T cells is not detectable. However, the applicability of vaccination is compromised by the lack of specific targets, particularly in malignancies with few mutations. RARITY will address this problem by deploying a novel class of cancer antigens. An unprecedented screening of non-exomic genomic regions will be done to detect unannotated proteins that arise from de novo transcription and translation events. These proteins can then be targeted by personalized immunotherapies. Finally, thought-provoking findings included in RARITY suggest that immune cell subsets other than T cells play a major role in anti-tumour immune responses. These subsets need to be fully inventoried and categorised so that complementary strategies to T cell immunotherapies can be developed. RARITY will do so by conducting multidimensional analysis of cancer microenvironments using imaging mass cytometry and ex vivo modulation of immune responses.

ERC Proof-of-Concept Grant 2024 – Susana Chuva de Sousa Lopes – Developing a human-based stem cell model for reproductive toxicity

Susana Chuva de Sousa Lopes – Developing a human-based stem cell model for reproductive toxicity

Project acronym: ReproTox

PI: Susana Chuva de Sousa Lopes, PhD
Department of Anatomy and Embryology

• EC contribution: EUR 150.000
• Start date: 01-08-2024 – End date: 31-01-2026

Abstract:

Environmental factors and chemicals are thought to be one cause of declining male fertility. Reproductive toxicity is becoming a major public health problem. Currently, new pharmacological or chemical compounds are tested in animals for their effects on reproduction before entering the market. This risk assessment is essential but time-consuming, expensive and is not always predictive in humans since animals have different reproductive characteristics and physiology. A validated and qualified human system to assess reproductive toxicity would be invaluable in addressing this conundrum between regulatory requirements and true relevance.

Through my ERC-CoG, I have built a large repository of knowledge and developed robust technology on human in vitro gametogenesis, more specifically on how to generate male gamete progenitors from human pluripotent stem cells. This, together with my bioinformatics knowhow, makes me exceptionally well-placed to optimise a human-based high-throughput screening assay for male reproductive toxicity for use by the private sector in filing reproductive safety data to the regulatory authorities. This ReproTox assay will be further optimised (increase throughput, standardise measurements) and integrated with a software innovation (machine learning algorithm to automate quantification and webtool), before we carry out a pilot screen using FDA-approved spermatotoxic compounds and market research to define the commercialisation route.

Reducing the number of compounds that show male reproductive toxicity at very early stages of drug development will contribute to an effective first-tier toxicity screening, not only providing standard protocols for quantitative, rapid, cost-effective, high-throughput, scalable and reproducible toxicity testing, but also reducing, perhaps eventually replacing animal use. ReproTox will ultimately lead to economic, societal, environmental, health and ethical benefits.

Read more: LUMC press release

ERC Proof-of-Concept Grant 2023 - Baoxu Pang - Targeting the dark side of the human genome — non-coding regulatory elements — to treat diseases

Baoxu Pang - Targeting the dark side of the human genome — non-coding regulatory elements — to treat diseases

Project acronym: TargetNCREs

PI: Baoxu Pang, PhD
Department of Cell and Chemical Biology

• EC contribution: EUR 150.000
• Start date: 01 May 2024 – End date: 31 October 2025

Abstract:

The 98% of the human genome, sometimes referred to as the dark side of the human genome, contains many non-coding regulatory elements (NCREs), which control the combinational expression of the limited number of genes (only 2% of the genome) to form diverse cell types and tissues of a complex human body, all from the identical copy of the genome. Most genetic variants and mutations also lie in NCREs. However, the number of NCREs as potential therapeutic targets remains very limited. In TargetNCREs, two novel and unique high-throughput screening systems further developed within the ECR starting grant (Silencer) will be exploited for their innovation and commercial potential to harness the therapeutic values of NCREs. We aim to test and validate previously identified top hits in vivo, carry out pilot research to show the technologies to be effective and appropriate for commercial applications, clarify the IPR protection strategy, engage partners and stakeholders to focus on potential pipelines, and perform a market search for future business development.