Alumni from BRIDGE II

Identification of immunotherapeutic targets for restoration of immunity using acute and chronic viral infection models

This translation research project aims at investigating the restoration of immune responses that have become exhausted after prolonged exposure to viral infection with the purpose of guiding development of new immunotherapeutics. The ambition is to unravel novel mechanisms behind restoration of immune exhaustion that can be used to develop novel immunotherapeutics for individuals suffering from chronic disease. The program is based on a recent success with Immudex™, where fluorescently labelled virus-specific Dextramers were used to identify virus-specific T cells and map their genetic signature with modern genomic approaches. Using a similar approach, immune exhaustion of virus-specific immune cells will be mapped in both acute and chronic viral infections to reveal genetic signatures that can be targeted for therapeutics.

Mentors

Basic mentor: Professor Jens Bukh, Department of Immunology and Microbiology (ISIM), University of Copenhagen

Clinical mentor: Professor Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre

Industrial mentor: Dr. Liselotte Brix, Immudex™, Denmark

Clinical and functional characterization of GRIArelated disorders: functional characterization of human genetic variants and translating genetic diagnostics into personalized treatment

Some epilepsies start in childhood and may be difficult-to-treat despite medical intervention. They are often accompanied by developmental and cognitive impairment and behavioral problems. Most are presumed to be caused by innate genetic changes. Finding disease-causing genes helps us to understand how a genetic change affects gene function. This insight has taught us why genetic changes cause illness and how we can better treat the illness by using drugs that fx reverse the effect of the genetic changes. One example, is a family of genes called GRIA; they are important for normal brain function and patients with rare genetic changes in GRIA genes may develop symptoms such as learning difficulties and epilepsy. We aim to describe the type and severity of symptoms that patients with GRIA-related disorders suffer from, to understand why genetic changes cause symptoms and how to treat them. This knowledge will help physicians to avoid ineffective or even disease-aggravating treatments.

Mentors

Basic mentor: Associate Professor Anders S. Kristensen, Department of Drug Design and Pharmacology, University of Copenhagen

Clinical mentor: Professor Zeynep Tümer, Department of Genetics, Kennedy Centre, University of Copenhagen

Supplementary clinical mentor: Professor Rikke Steensbjerre Møller, Department of Epilepsy Genetics and Personalized
Medicine, Danish Epilepsy Centre, Filadelfia

Molecular phenotyping of arrhythmogenic right ventricular cardiomyopathy by single cell
proteomics

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by progressive loss of heart muscle and high propensity to life-threatening arrhythmias. A hallmark of ARVC hearts is a fibro-fatty invasion of heart tissue with fibroblasts and adipocytes. More than 40% of genetic variants linked to ARVC reside in a gene called PKP2, which encodes for the plakophilin-2 (PKP2) protein. PKP2 is part of the cell junctions which connect adjacent cardiac muscle cells and is thereby important for myocardial electrical coupling. In this project we investigate the role of PKP2 in heart muscle cells of ARVC patients. In addition, we aim to characterize the molecular profile of individual cell types at single cell resolution. Therefore we are focusing on the cell types cardiomyocytes, fibroblasts and adipocytes. These analyses will help us to understand molecular mechanisms of arrhythmia in ARCV patients and provide new targets for therapy in the future.

Mentors

Basic mentor: Professor Alicia Lundby, Department of Biomedical Sciences, University of Copenhagen

Clinical mentor: Professor Henning Bundgaard, Department of Cardiology, Rigshospitalet

Pharmacokinetics and -dynamics of a novel drug candidate for ex vivo elimination of latent cytomegalovirus in lung transplants

Where there are people, there is cytomegalovirus (CMV). This lesser-known herpesvirus has the ability to hide from our immune system and lie dormant in our bodies, awaiting the right conditions to reactivate. About half the population carries the virus, of which most are infected during early childhood without ever noticing. Despite being quite harmless to healthy people, CMV infection can have fatal consequences for the immunocompromised, e.g. organ transplant recipients. For patients requiring life-saving lung transplants, CMV reactivation is the most common viral infection with devastating impact on patient outcomes even with anti-viral treatment. This project will assess a new first-in-class drug candidate on its ability to clear dormant CMV infection in lung transplants, its stability, and, importantly, safety in the organs. If successful, this could completely change the way CMV is managed in organ transplantation settings, leading to improved survival and quality of life of the transplant recipients.

Mentors

Basic mentor: Professor Mette Rosenkilde, Department of Biomedical Sciences, University of Copenhagen

Clinical mentor: Clinical Associate Professor Michael Perch, consultant, Department of Cardiology, Section for Lung Transplantation, Heart Centre, Rigshospitalet

Industry mentor: Dr. Thomas Kledal, CEO at Synklino

A deeper understanding of the gut microbiome and its influence on disease in patients undergoing stem cell transplantation 

Stem cell transplantation (SCT) is a potentially curative treatment for patients suffering from blood cancers or other blood-related diseases, though it can lead to life-threatening complications. The risk of developing these complications is not fully explained but research suggests that gut bacteria may play an important role. In this project we will combine in-depth clinical, bioinformatic and machine learning expertise from three respective mentor groups to analyse high-quality clinical information with novel approaches to study gut bacteria. Findings from these analyses will allow for the identification of different bacterial groups and/or characteristics that support a pro-inflammatory versus a less-inflammatory gut environment. The future goal is to develop ways of changing gut bacteria towards a less-inflammatory environment, thereby potentially reducing patients’ risk of complications after SCT and also testing these environments in other patients with impaired immunity.

Mentors

Basic mentor: Associate Professor Mani Arumugam, Arumugam Group, Center for Basic Metabolic Research (CBMR)

Clinical mentor: Professor Jens D. Lundgren, CHIP/PERSIMUNE, Department of Infectious Diseases, Heart Centre, Rigshospitalet
and University of Copenhagen

Industrial mentor: Dr. Henrik Bjørn Nielsen, Chief Scientific Officer, Clinical Microbiomics, Copenhagen

Demonstrating the impact of impaired neuronal and glial crosstalk by deconstructing the Huntington’s disease brain

Huntington’s disease (HD) is a genetic condition that causes physical and intellectual disabilities in adulthood with no available cure. Mutant huntingtin, resulting from the HD mutation, leads to specific brain region shrinkage years before symptoms occur, but the mechanism behind selective neuronal impairment is unclear. Though neurons are most studied in HD, our work in HD models and patient samples show that glial dysfunction greatly contributes to neuronal death, emphasizing importance in revealing their roles in HD and health. State-of-the-art mass spectrometry will be used to study regional neuronal and glial communication over time to provide significant knowledge of their natural and disease causing interactions. Parallel analysis of patient-derived cells and plasma will aid in validating preclinical findings. Results from this work will identify novel biomarkers and drug targets in order to improve clinical outcomes for sufferers of HD or other neurodegenerative disorders.

Mentors

Basic mentor: Dr. Niels H. Skotte, NNF Center for Protein Research (NNF CPR) and Department of Drug Design and Pharmacology (ILF), University of Copenhagen

Clinical mentor: Dr. Jørgen E. Nielsen, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet

Cerebrospinal fluid peptides involved in migraine pathophysiology: Identification, evaluation, and
therapeutic targets potential

Migraine is a complex neurovascular brain disorder that affects 15% of the global adult population in their most productive years of life, with a health and economic burden of billions of dollars globally. The origin of migraine and its associated pain remains elusive. Though the recent development of new migraine drugs targeting calcitonin gene-related peptide (CGRP) has shown efficacy in responsive patients, many remain refractory to effective treatment. This project will use state-of-the-art cerebrospinal fluid peptidomics, mass spectroscopy, and animal models to decode migraine pain and identify novel biomarkers for the diagnosis, assess disease progress, monitor treatment and provide a rationale for the development of new treatments.

Mentors

Basic mentor: Professor Maiken Nedergaard, Center for Translational Neuromedicine, University of Copenhagen

Clinical mentor: Professor Messoud Ashina, Danish Headache Center, Rigshospitalet Glostrup

Environment, epigenomics and genomics in monozygotic twins discordant for migraine

How can identical twins get different diseases? We want to figure out why one identical twin develop migraine when the other twin does not, in the hope that it can help us prevent, diagnose and treat migraine. Migraine is a chronic headache disorder and it causes great disability, especially among young women, with large consequences for both the individual, the family and for society. Still, we do not know why migraine develops. Identical twins inherit the same genes from their parents and they usually also share environment growing up. Despite this, more than half of the time only one identical twin develops migraine. We will examine the twins through questionnaires on their environment and take blood samples to examine their genes. Identical twins have the same genes but small changes in the genes can occur. We will also examine epigenomic changes in the twins. Epigenomic changes is one way the environment can affect when genes are active. All this could explain migraine development.

Mentors

Basic mentor: Professor Eva R. Hoffman, Department of Cellular and Molecular Medicine, University of Copenhagen

Clinical mentor: Clinical Professor Jes Olesen, Leader of Migraine Basic Research Group, The Danish Headache Center, Rigshospitalet

Supplementary clinical mentor: Associate Professor Thomas Folkmann Hansen, Leader of the NeuroGenomics Group, Department of Neurology, Rigshospitalet

Developing ovarian organoids for drug screening and personalized medicine

Reproductive aging impacts women’s lives world-wide. Socioeconomic changes that have led to women delaying childbirth, early menopause increasingly affects women and their reproductive choices. One major challenge to our understanding why some women are 30 and others 60 years when they experience menopause is the lack of scientific tools to study the effect of genetics as well as drugs in experimental settings prior to testing them clinically. Therefore, I propose to develop an artificial ovary (ovarian organoid) that can be used for studying how our genes regulate ovarian function and whether certain drugs might improve it. This tool will help clinicians provide diagnosis to patients – 20% of women in fertility treatment do not respond to the fertility drugs. Furthermore, working with industry, I will also provide the first evaluation of whether this artificial ovary can be used for drug screening. This would allow pharma companies to test and develop new drugs for fertility treatment.

Mentors

Basic mentor: Professor Eva R. Hoffmann, Department of Cellular and Molecular Medicine, University of Copenhagen

Clinical mentor: Professor Anja Pinborg, Fertility Clinic, The Juliane Marie Centre for Women, Children and Reproduction, Rigshospitalet

Supplementary clinical mentor: Dr. Bernadette Mannaerts, Senior Medical Research Director Reproductive Medicine & Maternal Health, Ferring Pharmaceuticals, Copenhagen, Denmark

Trained innate immunity: The missing link between early life infections and later development of cardiovascular disease

Children across the world are exposed to infections as a natural part of life. However, when children become too much exposed by multiple infections, it can have serious consequences. It is well-known that if children when in mother’s womb, or in the first few years of life have many infections, they also have increased risk of developing heart diseases later in their life. We think this is due to the immune cells changing into a more aggressive and “inflammatory” form that damages the blood vessels and heart already in childhood. We want to identify how the cells are changed into this more inflammatory state and to pinpoint exactly where and when these changes of the cells are making too much damage. This will be accomplished by studying a large group of children from a rural area in Tanzania, who we have followed ever since their mother become pregnant. We aim to provide answers that can be used to identify this “missing link” and ultimately to prevent these children from getting heart diseases.

Mentors

Basic mentor: Professor Romain Barrès, Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen

Clinical mentor: Clinical Professor Peter Damm, Department of Obstetrics, Copenhagen University Hospital

Supplementary clinical mentor: Dr. David Burgner, Pediatric Infectious Diseases Physician, Murdoch Children’s Research Institute, Melbourne, Australia

Impact of the gut microbiota on innate immune activation in children with acute leukaemia

Chemotherapy is a mainstay in the treatment of most cancer patients but comes with severe acute side effects initiated due to disruption of the barrier in the gut. The gut microbiota is important for the barrier homeostasis, but anti-cancer treatment including high doses of chemotherapy and broad-spectrum antibiotics may cause severe alteration in the gut microbiota leaving the patients in risk of uncontrolled systemic inflammation and fatal invasive infections. In the present study we will explore how changes in the gut microbiota are related to activation and recovery of the immune system after chemotherapy in patients with acute lymphoblastic leukaemia (ALL).

This study may lead to identification of biomarkers, which are highly needed to guide clinical decisions for an optimized use of antibiotics in patients undergoing chemotherapy. Furthermore, such understanding may lead to new preventive strategies targeting the intestinal microbiota as well as paving the way for development of gut microbiota-sparring antibiotics or probiotics supporting recovery of the immune system following treatment of ALL.

Mentors

Basic mentor: Associate Professor Hannelouise Kissow, Department of Biomedical Sciences, University of Copenhagen 

Clinical mentor:  Professor Klaus Müller, Department of Paediatrics and Adolescent Medicine, Rigshospitalet

Industry mentor: Professor Filip K. Knop, Steno Diabetes Center, Copenhagen

Personalized assessment of kidney function for optimized medication prescribing (OptiMED-GFR)

Dosing recommendations for nearly half of all medications depend on kidney function. Clinicians and drug developers typically estimate kidney function based on levels of an endogenous marker in the blood, but this method can be highly inaccurate in certain patient populations. Alternatively, kidney function can be directly measured by injecting an exogenous substance into the blood and measuring how long it takes for that substance to leave. However, this method is expensive and cumbersome, which limits its clinical applicability. The objectives of the OptiMED-GFR program are to evaluate alternative methods for estimating or measuring kidney function. Our central hypothesis is that a technique known as dried blood spot testing (DBS) could revolutionize the direct measurement of kidney function by reducing costs, improving patient comfort, and shortening the total procedure time. The ultimate goal of OptiMED-GFR is to develop a platform for personalized assessment of kidney function.

Mentors

Basic mentor: Associate Professor Trine Meldgaard Lund, Translational Pharmacology, Department of Drug Design and Pharmacology, University of Copenhagen

Clinical mentor: Clinical Associate Research Professor Mads Hornum, Department of Nephrology, Copenhagen University Hospital Rigshospitalet

Supplementary clinical mentor: Clinical Professor Ove Andersen, Department of Clinical Research, Copenhagen University Hospital Hvidovre

Validation of Novel Invasive Cardiovascular Catheter System for Diagnosing and Quantifying Coronary
Microvascular Disease

Coronary microvascular dysfunction (CMD) is increasingly recognized as having an integral role in various conditions involving the hearts circulation. Existing methods for evaluation and quantifying CMD are cumbersome, operator-dependent and only provide surrogate measures of the desired metric (blood flow) while making numerous assumptions. We have invented an invasive cardiovascular catheter system capable of measuring blood flow to the heart muscle directly in a faster, simpler and less operator-dependent way compared with existing methods. The aim of the project is to validate the technology in vivo in a porcine model. This simple and reliable tool for measuring coronary artery blood flow has the potential to revolutionize cardiac muscle blood flow diagnostics and personalized treatment of cardiac diseases, such as small vessel disease of the heart.

Mentors

Basic mentor: Professor Thomas Jespersen, Department of Biomedical Sciences, University of Copenhagen

Clinical mentor: Professor Thomas Engstrøm, Consultant cardiologist, The Heart Center, Rigshospitalet, Copenhagen University Hospital and Department of Clinical Medicine, University of Copenhagen, Denmark

Targeting the tumor microenvironment in mycosis fungoides: Implications for disease progression and
treatment strategies

Mycosis fungoides (MF) is usually a slowly progressing primary skin lymphoma. However, one third of the patients experiences an increasingly aggressive disease with a lethal outcome. Unfortunately, we do not know why only some patients develop an aggressive disease course, but we know that the composition of cells in the tumor changes over time. In early-stage disease, the lymphoma cells are outnumbered by reactive immune cells that keep the malignant cells under control. When the disease progresses, the cell composition changes, and the malignant cells undergoes immune escape to benefit their own survival. What causes the shift in cell composition during disease progression is unknown. We here aim to elucidate the role of B-cells in disease progression, as we believe that these cells play a major role in maintaining the unfortunate balance in the microenvironment. By targeting B-cells, with a well-established anti-CD20 treatment (Rituximab), we hypothesize that a more balanced microenvironment can be restored and thereby reverse disease progression.

Mentors

Basic mentor: Professor Niels Ødum, LEO Foundation Skin Immunology Research Center & Department of Immunology and Microbiology, University of Copenhagen

Clinical mentor: Clinical Associate Research Professor Lise Mette Rahbek Gjerdrum, Department of Pathology, Zealand University Hospital & Department of Clinical Medicine,
University of Copenhagen

First supplementary basic mentor: Professor Thomas Litman, Department of Immunology and Microbiology, University of Copenhagen

Second supplementary basic mentor: Professor MSO Anders Woetmann, LEO Foundation Skin Immunology Research Center & Department of Immunology and Microbiology, University of Copenhagen

Personalized and early determination of Hidradenitis Suppurativa disease trajectories – a translational study

Hidradenitis suppurativa is a chronic inflammatory, recurrent, painful, scarring and suppurating skin disease. It has an estimated prevalence of ~1% in western cultures and has a large negative impact on patient mortality, morbidity and life course. Patients typically go 7-10 years before being diagnosed, and when diagnosed have no way of knowing if their disease will progress in severity or have a mild course. The aim of this project is therefore to develop and validate a predictive algorithm that will enable medical professionals to gauge which patients are likely to develop a severe and protracted disease course, so that they can receive optimum treatment at an early stage. To do this we will evaluate genetic and morphological characteristics of patients with the disease. We will look for potential biomarkers of disease progression. Based on that we will construct an algorithm that will subsequently be tested in a large cohort of blood donors.

Mentors

Basic mentor: Professor Liv Eidsmo, Professor, Skin Immunology Research Centre, Department of Immunology and Microbiology, University of Copenhagen

Clinical mentor: Associate Professor Ditte Marie Saunte, Department of Clinical Medicine, University of Copenhagen and Department of Dermatology, Zealand University Hospital, Roskilde

Supplementary clinical mentor: Associate Professor Ole Birger Vesterager Pedersen, Department of Clinical Medicine, University of Copenhagen and Department of Clinical Immunology, Zealand University Hospital, Køge