Joint Transnational Call 2025

Partners

• Pless, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Fraunhofer Society (Germany)
• Taglialatela, University of Naples Federico II. (Italy)
• Villard, Aix Marseille University (France)
• Weckhuysen, University of Antwerp (Belgium)
• Wuttke, Eberhard Karls Universität Tübingen (Germany)
• Nabbout, EPICARE Hôpital Necker Enfants malades, APHP, Université de Paris, Institut Imagine (INSERM UMR 1163) (France)
• Brambilla, Dravet Italia Onlus (Italy)
• Remonato, European KCNQ2 Association (Italy)

Scientific abstract

Neuronal Kv7 (Kv7.2-5) channels encoded by the genes KCNQ2,3,5 play a critical role in modulating neuronal excitability, and mutations therein are linked to a large spectrum of epilepsy phenotypes, including severe developmental and epileptic encephalopathies (KCNQ-DEE).

KCNQ-DEEs manifest in the first months of life, characterized by treatment resistant seizures and developmental delay. Both a severe lack and excess of channel function can result in the development of KCNQ-DEE. Seizures in children with KCNQ-DEE often respond poorly to antiseizure medications (ASMs), and more importantly, therapies for the neurodevelopmental problems are currently unavailable.

Activation of neuronal Kv7 channels is a validated mechanism for epilepsy treatment, but, since the market withdrawal of the Kv7 activator retigabine in 2017 (for safety reasons unrelated to its mechanism of action) no Kv7 activator is currently available for clinical application.

In a previously funded project called TreatKCNQ, we have searched for novel Kv7 openers by screening a drug repurposing library, leading to the identification of a potent and selective candidate, JNJ-37822681, which was in advanced clinical development as an antipsychotic drug.

With the aim of developing JNJ-37822681 as a clinical candidate for KCNQ-DEE, we have established a consortium of researchers with expertise in KCNQ biology and pathobiology, drug development and clinical treatment and care.

Extending beyond KCNQ, we will aim to understand whether JNJ-37822681 could also be efficacious in related forms of DEE where there is evidence for involvement of Kv7 channels (e.g. Dravet syndrome).

We expect to provide pre-clinical evidence for JNJ-37822681´s efficacy and safety that has the potential to improve clinical outcome in KCNQ-DEE and other DEEs.

In addition, we will propose a strategy for clinical testing of JNJ-37822681, including patient´s and PAO´s perspectives.

Partners

• Prigione, Heinrich Heine University (HHU), University Clinic Düsseldorf (UKD), Department of General Pediatrics, Neonatology and Pediatric Cardiology (Germany)
• Pless, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort (Germany)
• Puighermanal, FUNDACIÓ INSTITUT D’INVESTIGACIÓ I INNOVACIÓ PARC TAULI (I3PT) (Spain)
• Del Sol, University of Luxembourg, Luxembourg Centre for Systems Biomedicine (Luxembourg)
• Cuella Martin, McGill University, McGill University, Department of Human Genetics, Victor Philip Dahdaleh Institute of Genomic Medicine (Canada)
• Riekstina, University of Latvia, Faculty of Medicine and Life Sciences, Department of Pharmaceutical Sciences (Latvia)
• Brunetti, Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta (Italy)
• Marmotta, Mitocon – Insieme per lo studio e la cura delle Malattie Mitocondriali (Italy)
• Woleben, Cure Mito Foundation (United States of America (the))
• De Bry, International Mito Patients (IMP) (Netherlands (the))

Scientific abstract

Leigh syndrome spectrum (LSS) disorders affect 1:40,000 live births causing neurodevelopmental delay, movement impairment, and early death.

Most LSS forms are currently incurable. The Consortium SynLeigh aims to identify therapeutic interventions and their potential synergy to develop a roadmap for developing clinical trials for LSS. Members of our consortium previously discovered two potential therapeutics for which they have already obtained orphan drug designation (ODD) for their use in LSS.

We will leverage these findings to assess the effectiveness and toxicity of these molecules and their possible synergy.

We will employ complementary approaches using patient-derived human models (including neurons, brain organoids, blood-brain barrier, and Organs-on-chip technologies), followed by validations and toxicology assessment in small and large animal models, and computational integrations.

We have already initiated to engage with the European Medicine Agency (EMA) and their indications will guide our experimental design to collect findings that are deemed satisfactory by the regulators.

Altogether, we aim to provide a mechanistic understanding and practical strategy for the establishment of treatments for individuals affected by currently incurable LSS disorders.

Partners

• Forlino, Fondazione IRCCS Policlinico San Matteo (Italy)
• Micha, Amsterdam UMC/Human Genetics (Netherlands (the))
• Zhytnik, Biomedical Research Instituto of Malaga and Plataform in Nanomedicine (IBIMA Plataforma BIONAND). Skeleton Biomedicine Laboratory (Spain)
• Götherström, Karolinska Institutet, Department of Clinical Science, Intervention and Technology (Sweden)
• Pedrini, IRCCS Istituto Ortopedico Rizzoli / Department of Rare Skeletal Disorders (Italy)
• Maasalu, SA TARTU ULIKOOLI KLIINIKUM/ Tartu University Hospital, Research and Development Administration (Estonia)
• Westerheim, Osteogenesis Imperfecta Federation Europe (Belgium)

Scientific abstract

Our goal is to explore if RAVICTI, a drug that is already used to treat a rare condition called urea cycle disorder (UCD), could also help people with osteogenesis imperfecta (OI), a disease that makes bones very fragile and easy to break.

Currently, there is no approved medicine for OI worldwide, except for bisphosphonates available in Italy and Japan, which help slow bone loss. Recent studies suggest that one of the main problems in OI is stress inside the cells caused by faulty collagen building up.

The active ingredient in RAVICTI, called 4-phenylbutyrate, might help fix this problem and improve collagen production. To test this, we will use both animal models of the disease and human cells grown in the lab.

Our project brings together a team of expert scientists and doctors who specialize in OI, ensuring that if we see good results, we can quickly move to testing the medicine in patients.

The company that makes RAVICTI is providing the medicine for the study, and we are working with the European Remedi4All organization that specializes in repurposing existing medicines for the treatment of several diseases, and with MetabERN that is a network dealing with UCD patients already treated with RAVICTI.

A key part of our project is the involvement of OI patient groups from the very beginning, which will ensure that our research focuses on real patient needs. By working together, we hope to find a new and timely treatment that could improve the lives of people with OI.

Partners

• Constantinos Deltas, University of Cyprus | biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus | Medical School (Cyprus)
• Olauson, Karolinska Institutet | LABMED (Sweden)
• Gilmour, Guard Therapeutics International AB | Preclinical Sciences (Sweden)
• Anders, University of Munich | Department of Medicine IV (Germany)
• Kramann, Erasmus Medical Center | Internal Medicine, Nephrology and Transplantation (Netherlands (the))
• Romagnani, Meyer Children’s Hospital IRCCS | Nephrology and Dialysis (Italy)
• Boeckhaus, University Medical Center Göttingen | Nephrology and Rheumatology (Germany)
• Finkler, Alport Selbsthilfegruppe e.V. (Germany)
• Gallego, European Kidney Patients Federation (Spain)

Scientific abstract

Alport Spectrum Disorders (ASD) are a group of rare genetic kidney diseases caused by inherited defects in the COL4A3, COL4A4, and COL4A5 genes, which produce type IV collagen (COLIV)—an important protein for kidney function.

These variants weaken the kidney filter, leading to progressive kidney disease (CKD), often resulting in kidney failure, requiring dialysis or a kidney transplant. No approved treatments currently address the disease’s root cause.

The ALP-RARE project aims to develop new therapies by identifying and testing promising drugs that help preserve kidney function. We will study three potential treatments:

• 4-PBA, a repurposed drug that we have data supporting that it improves the quality of kidney filter (improves COLIV folding) in a relevant mouse model for ASD.
• Finerenone, which reduces kidney scarring and inflammation, as tested on another mouse model.
• Alpha-1-microglobulin-based peptides, with antioxidant properties that could protect kidney cells from damage, as tested on mice with another cause of CKD.

To ensure the most reliable and effective drug testing, our project will use advanced laboratory models, including patient-derived kidney cells and kidney-filter-on-a-chip technology, as well as well-established mouse models of ASD.

We will conduct preclinical randomized controlled trials, a method designed to mimic human clinical trials, ensuring results are reproducible, reliable and clinically relevant before testing in patients. By using artificial intelligence (AI), high-quality imaging, and genetic analyses, we will identify the most effective drug combinations and ensure they are safe for human trials.

Our work will be guided by patient advocacy organizations to ensure treatments meet patient needs. The ALP-RARE project is a critical step toward personalized therapies for ASD, offering new hope for patients by accelerating the development of targeted, effective treatments that could delay kidney failure and improve quality of life.

Partners

• de Vrieze, dept. of Otorhinolaryinglogy, Radboud University Medical Center (Netherlands (the))
• Van Rompaey, Universiteit Antwerpen (University of Antwerp) Faculty of Medicine and Health Sciences, dept. of Translational Neurosciences (Belgium)
• Lehner, Department of Otorhinolaryngology, Head & Neck Surgery, Martin Luther University Halle-Wittenberg, University Medicine Halle (Saale) (Germany)
• Dueck, Cochlear Deutschland GmbH & Co. KG (Germany)
• Oldak, Institute of Physiology and Pathology of Hearing (Poland)
• Etournay, Hearing Institute – Institut Pasteur, INSERM (France)
• van Toor, Stichting de Negende van… (Netherlands (the))

Scientific abstract

Hearing loss is a growing societal problem linked to an increased risk of social isolation and unemployment. It has many causes, including mutations in over 200 different genes, leading to as many rare, inherited hearing loss disorders.

DFNA9 is one such disorder, relatively common in the Netherlands and Belgium (~0.6 in 10,000 individuals) but rare elsewhere in Europe. It follows a dominant inheritance pattern, meaning a mutation in just one of the two gene copies (alleles) is enough to cause hearing loss.

DFNA9 mutations are known to produce toxic proteins that disrupt inner ear function. Blocking the formation of these proteins could delay or halt disease progression. An early intervention may even prevent symptoms altogether.

We recently developed a potential treatment using antisense oligonucleotides (ASOs). This are short sequences of DNA or RNA molcules that can trigger the breakdown of the mutant COCH gene product. Our studies in cultured cells and organoid models have shown promising results. In this project, we aim to address key knowledge gaps that currently prevent us from applying ASOs to treat people with DFNA9:

1. How long do ASOs remain effective in the inner ear of mouse and guinea pig models?
2. How can we improve ASO availability with an intracochlear drug delivery device?
3. How can we identify blood biomarkers in DFNA9 patients to quickly assess treatment response?
4. How prevalent is DFNA9 across Europe? 5: How can we treat more patients by targeting additional COCH mutations?

Our multidisciplinary consortium brings together all the necessary expertise to answer these questions and take a major step toward ASO-based therapy for DFNA9.

Through our PAO partner, we will engage with the DFNA9 community and expand our outreach to DFNA9 patients across Europe.

Partners

• Gobbi, McGill University (Canada)
• Comai, University of Padua (Italy)
• De Gregorio, San Raffaele Hospital (Italy)
• Laboute, Inserm U1253 iBraiN (France)
• Millerhovf, CTC Clinical Trial Consultants AB (Sweden)
• Kelly, S.Au.S. (Soutien Autisme Soutien) (Canada)

Scientific abstract

Autism spectrum disorder (ASD) affects how people communicate, interact, and behave. Many individuals with ASD also struggle with sleep problems, anxiety, and irritability. Two genetic conditions, Fragile X Syndrome (FXS) and Phelan-McDermid Syndrome (PMS), are closely linked to ASD, but there are no approved treatments for them.

We are developing a new drug called COS01 that targets the melatonin MT2 receptor, which helps regulate sleep and brain function. COS01 has already shown a good safety profile in early tests. Now, we will study how it affects sleep, social behavior, and other ASD-like symptoms in mouse models of FXS and PMS. Our research has four main steps:

1. Studying sleep and behavior – We will examine how FXS and PMS affect sleep and social behavior in mice and see if COS01 helps improve these issues (Canada, Italy).

2. Understanding brain activity – Using advanced tools, we will study how brain circuits are affected in FXS and PMS and whether COS01 can restore normal brain function (Italy).

3. Learning how COS01 works – We will investigate how COS01 activates the MT2 receptor and changes brain cell activity (France). 4. Preparing for human trials – We will create a safe drug formula, test how to measure COS01 in human blood, and submit approval documents for clinical trials (Sweden).

Our goal is to get COS01 ready for human trials within three years, providing the first possible treatment for FXS and PMS. This could greatly improve sleep, anxiety, and overall quality of life for people with these conditions.

Partners

• Matthijs, KU Leuven (Belgium)
• Veiga-da-Cunha, de Duve Institute, UCLouvain (Belgium)
• Lefeber, STICHTING RADBOUD UNIVERSITAIR MEDISCH CENTRUM (Netherlands (the))
• Pérez, CIBER (Spain)
• Hansikova, First Faculty of Medicine, Charles University, Department of Pediatrics and Inherited Metabolic Diseases (Czechia)
• Lebredonchel, Biochemistry department, Hospital Bichat Claude-Bernard, APHP (France)
• Kornak, University Medical Center Göttingen (Germany)
• Puhe, Bundesverein CDG-Syndrom e.V. aka. GlycoKids (Germany)
• Alonso Ruiz, Asociación Española del Síndrome CDG, Defectos Congénitos de la Glicosilación (AES-CDG) (Spain)
• Boonnak, CDG UK (United Kingdom)

Scientific abstract

Congenital Disorders of Glycosylation (CDG) are a group of ≈200 rare and severe genetic diseases, notoriously difficult to treat or cure. Patients have severe neurodevelopmental symptoms, intellectual disability and dysmorphic features.

Many of them experience life-threatening seizures, bleeding problems and other complications, leading to frequent emergency hospital admittance. The RADICAL-CDG consortium is a collaboration between national hubs for diagnosis, research, and care centers across Europe, specialized in CDG.

Currently, there are very few effective therapies for CDG. This is due to a) the underlying complexity of glycosylation, related to the stepwise assembly of complex sugar chains; b) the great variety of glycoproteins in the human body, and c) the extremely rare nature of each individual CDG, with <100 affected patients for all disorders (except one, PMM2-CDG).

Despite these challenges, decades of dedicated research have led to several promising breakthroughs:

(1) GSD1b-related neutropenia was successfully treated by repurposing a drug used for type 2 diabetes,

(2) research on TMEM165-CDG provided the rationale for treatment with the natural compounds galactose and manganese, and

(3) a replacement therapy with liposome-caged mannose-1-phosphate is currently being tested for PMM2-CDG, but we hope that more easily administrable drugs will soon become available.

By working closely with patient organizations and leveraging multidisciplinary expertise of world-class researchers, RADICAL-CDG aims to improve the lives of CDG patients by accelerating therapeutic options and ensuring access to credible, up-to-date information on preclinical and clinical advances.

We will achieve this using three key scientific strategies:

i) Repurposing existing therapies;

ii) Developing new packaging strategies for existing or novel therapeutic molecules;

iii) Synthesizing new modified molecules based on specific therapeutic targets.

Partners

• Schlotawa, Fraunhofer Institute for Translational Medicine and Pharmacology – Translational Neuroinflammation and Automated Microscopy (Germany)
• Carreras Puigvert, Phenaros Pharmaceuticals AB (Sweden)
• Giera, Leiden University Medical Center, Center for Proteomics and Metabolomics (Netherlands (the))
• Locatelli, University of Ljubljana (Slovenia)
• Porkolab, Smurfit Institute of Genetics, Trinity College Dublin (Ireland)
• Finglas, MSD Action Foundation (Ireland)

Scientific abstract

Multiple Sulfatase Deficiency (MSD) is an extremely rare, fatal, yet untreatable condition. It is caused by the inherited deficiency of an enzyme (called FGE) that activates a whole family of 17 other cellular enzymes named sulfatases. Sulfatases are indispensable for the degradation of a subset of intracellular molecules. Thus, patients with MSD and deficient sulfatases show intracellular storage of such molecules that are not degraded properly. The storage affects all organs and results in clinical symptoms like developmental delay, bone disease, and loss of motor and cognitive skills.

A putative therapy for MSD could be using drugs and drug like substances that have been developed for other diseases if they show effects on MSD in laboratory testing. We identified 56 substances that might be able to become a therapy for MSD.

In the project we propose to investigate these substances in MSD disease models including MSD mice and asses their potential to become a cure for MSD: We will create and compare the best form for application of the substance to patients, e.g. as tablets, capsules or fluids considering the specific needs of MSD patients.

We will also try to find out how effective drugs cure MSD in cells of and identify alternative drugs that could work in the same way. In addition, we will try to find out whether the compounds that may cure MSD could also be a therapy for diseases that are similar to MSD.

From the start of the project we will get help from experts in drug development, clinical experts for MSD and most important a father with a son with MSD. They will all take care that the project will reveal a successful outcome with results useful for MSD patients.

Partners

• ZAGLIA, Università degli Studi di Padova (Italy)
• Perez Pomares, Biomedical Research Institute of Malaga and Plataform in Nanomedicine (IBIMA-Plataforma BIONAND). Cardiovascular Development and Disease Research Group (H-03). (Spain)
• Remme, Amsterdam University Medical Center (Stichting Amsterdam UMC) (Netherlands (the))
• Giardini, Universitaetsklinikum Freiburg (Germany)
• LACAMPAGNE, PhyMedExp, Inserm U1046 CNRS UMR9214 (France)
• SCHWACH, Department of BioEngineering Technologies, University of Twente (Netherlands (the))
• Spadaro, GECA ONLUS, Giovani e Cuore Aritmico Onlus (Italy)
• Biller, ARVC-Selbsthilfe e.V. (Germany)
• Cecchi, AICARM APS – Associazione Italiana Cardiomiopatie (Italy)

Scientific abstract

Arrhythmogenic Cardiomyopathy (ACM) is a dramatic and deeply unsettling diagnosis—a disease with no cure that can suddenly take the lives of young, otherwise healthy individuals, including athletes.

In ACM, the heart muscle tissue is progressively lost and replaced by fibrous and fatty scar tissue, weakening the heart ability to pump blood and triggering dangerous arrhythmias, especially during stress. This condition not only impacts physical health, but also imposes a heavy emotional and psychological burden on patients and their families.

The absence of effective therapies makes ACM an orphan disease, creating an urgent clinical, ethical and societal need for new treatments. Our project introduces a fresh perspective on ACM by considering it as a disorder that affects almost every cell type in and around the heart. We identified sympathetic neurons (SN) as culprits of the disease mechanism.

SN are essential to regulate heart function and structure, at baseline and during stress, thanks to a finely regulated crosstalk with all heart cell types. Our research demonstrates that ACM-linked mutations compromise neuro-cardiac communication, and supports that interfering with abnormal SN inputs may be a strategy to prevent heart failure and life-threatening arrhythmias in patients affected by different ACM forms.

This hypothesis will be tested by the synergistic interaction of internationally renowned research scientists, who possess unique and complementary expertise. Our consortium will actively cooperate with different PAO, so that research responds to patients’ needs.

The collaboration with cardiologists, authors of some of the key discoveries in the ACM field, is fundamental for the rapid translation of our results to the clinical setting, which is also guaranteed by the use of drugs already used in the clinics, or tested in clinical trials. Our proposal really has the potential to increase longevity and life quality of ACM patients.

ID/Acronym: iSNARE

Improving SNAREopathy Perspectives

Partners

• Verhage, Amsterdam UMC & VU Amsterdam (Netherlands (the))
• Fluhr, Weizmann Institute of Science, Department of Plant and Environmental Sciences (Israel)
• Sørensen, University of Copenhagen, Department of Neuroscience (Denmark)
• Alvarez-Erviti, Fundación Rioja Salud, Department of Molecular Neurobiology (Spain)
• Alvarez-Dolado, Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC), Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) (Spain)
• Scala, IRCCS Istituto Giannina Gaslini, Medical Genetics Unit (Italy)
• Timuçin, Gebze Technical University, Faculty of Art and Sciences, Dept. of Molecular Biology and Genetics (Türkiye)
• Ben-Moshe, Rafa’s Moonshot (MERIT SPREAD FOUNDATION LTD) (Israel)
• Verhage, European STXBP1 Consortium (Netherlands (the))
• Legre, STXBP1 France (France)
• Dor, Rare Smile (the Israeli organization for STXBP1 disorders) (Israel)
• Dasilva, Fundacion Lukiss (Spain)
• Regatero, Asociación Síndrome STXBP1 (Spain)
• Rizotto, Associazione STXBP1 Italia (Italy)
• Hoffman, STXBP1 e.V. (Germany)
• Quinlan, STXBP1 Foundation (United States of America (the))
• Dellueficio, SNAP25 Foundation (United States of America (the))
• Waters, Baker-Gordon Syndrome Foundation (Syt1) (United States of America (the))

Scientific abstract

SNAREopathies are a recently identified group of rare brain disorders caused by mutations in eight genes that help brain cells communicate. The symptoms are typically severe and present from early childhood and persist into old age. Children often do not reach normal milestones of development: they may not develop speech, may not be able to walk, and they often have epileptic seizures and spasms.

In just 20 years, thanks to DNA sequencing technology, occurrence of SNAREopathies has risen from zero to one of the most common rare diseases (+/-1 in 30,000). Currently, only some symptoms can be (partially) treated, like seizure control. Hence, there is a major need for treatments.

The iSNARE consortium aims to contribute to a better future for these children by testing potential therapies using both lab-grown nerve cells, derived from patients that donated skin cells using stem cell technology, and existing mouse models of the disease.

Their approach follows three steps: (i) confirming the effects of four drugs already used in small patient groups, (ii) testing 6-10 new drug candidates, including RNA-based therapies, and (iii) designing brand-new drugs using computer models of the affected proteins.

This structured analysis process will compare the effectiveness of all available treatments and highlight the most promising ones. iSNARE includes top scientists, experts in human neurons and animal models, computer modeling specialists, and patient organizations across nine EU countries and Israel.

Their collaboration ensures that the latest scientific advances are applied to develop treatments that best meet patient needs.

Partners

• Altafaj, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (Spain)
• Carvalho, University of Coimbra (CNC-Center for Neuroscience and Cell Biology) (Portugal)
• Toonen, VU University Amsterdam/CNCR (Netherlands (the))
• Persoon, Amsterdam UMC/Human Genetics (Netherlands (the))
• Pellissier, Physiology of Reproduction and Behaviour – INRAE (France)
• Olivella, Institute for Research and Innovation in Life and Health Sciences in Central Catalonia (Spain)
• Brander, GRIN Europe (France)
• Jankowska-Płonka, STXBP1 family association (Poland)
• Verhage, The European STXBP1 Consortium (ESCO) (Netherlands (the))
• Barbosa-Guedes, Associação Phelan-McDermid Portugal – APMP (Portugal)

Scientific abstract

This project aims to develop new treatment strategies for rare neurological disorders—including certain forms of epilepsy, autism, and intellectual disability—by repurposing existing drugs. These disorders are caused by mutations in key genes (GRIN2B, SHANK3, STXBP1, and CACNG2) that disrupt communication between brain cells, particularly at the glutamatergic synapse, a critical hub for learning, memory, and behaviour. Although these conditions are genetically distinct, they share common problems in how neurons send and receive signals.

Our research will uncover these shared molecular and cellular disruptions by studying patient-derived brain cells and genetically engineered mouse models. By doing so, we aim to create a clearer picture of how these mutations affect brain function and contribute to neurological symptoms.

A key focus of the project is testing whether existing drugs can be repurposed to restore normal synaptic function. Since these drugs have established safety profiles, successfully repurposing them could significantly accelerate the development of effective treatments, reducing both time and cost compared to traditional drug development.

Our collaborative, Europe-wide consortium brings together leading experts and patient organizations, ensuring that our research is both scientifically rigorous and closely aligned with patient needs. Through cutting-edge laboratory techniques and interdisciplinary teamwork, we will generate valuable insights that could pave the way for a unified treatment strategy across multiple rare neurological disorders.

Ultimately, our goal is to transform current treatment paradigms by targeting their shared underlying mechanisms, offering hope for faster, more effective therapies that can improve the quality of life for patients and their families.

Partners

• MacParland, University Health Network (Canada)
• Erdal, Izmir Biomedicine and Genome Center (IBG) (Türkiye)
• Melum, University of Oslo Faculty of Medicine (Norway)
• Baumert, Institute of Translational Medicine and Liver Disease, Inserm U1110 (France)
• Guillot, Charité – Universitätsmedizin Berlin (Germany)
• Post, Erasmus MC (Netherlands (the))
• Vyas, PSC Partners Seeking a Cure Canada (Canada)

Scientific abstract

Challenge: Our translational and patient-partnered team studies primary sclerosing cholangitis (PSC), a rare liver disease with no approved treatments and a significant unmet medical need. Due to the limited patient population and no speedy pathway for regulatory approval, the case for for-profit investment in drug development for PSC is challenging. This proposal aims to develop new treatments for this rare disease.

Solution: To address this gap, we have developed the first transcriptomic map of the PSC liver, providing an unprecedented view of disease mechanisms at the cellular level. We have analyzed these disease mechanisms and pathways to identify known targets and their corresponding drugs. This analysis, along with expert review, identified immune modulation as an avenue to target immune-mediated fibrotic pathways within the PSC liver.

There is no completely reliable animal model of PSC for pre-clinical testing, so we will optimize mouse models and then examine the similarities between animal and human disease. We will also employ ex vivo 3D human tissue platforms using organoids and precision cut liver slices to evaluate the efficacy of small molecule interventions in human PSC liver tissue.

We will then test the ability of immune therapies to modulate fibrogenic processes in the optimized mouse models and human explanted PSC tissue in comparison to healthy human liver using spatial transcriptomics and proteomic profiling as a readout to test for normal liver function after disease condition treatment.

Expected Achievements/Impact: This work will be transformative and we will collectively make new discoveries that will translate to new options for rare liver disease patients. The patient-partnered framework is a novel approach to research that puts patients in the driver seat of the drive to new treatments for their disease.

This work will also transform the rare disease research landscape from redundant research silos to a collaborative consortium.

Partners

• Ramsey, University of Toronto (Canada)
• Rubinstein, Tel Aviv University (Israel)
• Vyklicky, Institute of Physiology CAS, Laboratory of Cellular Neurophysiology (Czechia)
• Baldassarro, IRET Foundation (Italy)
• Rondard, Institut de Genomique Fonctionelle (France)
• Brander, Tel Aviv University (Israel)

Scientific abstract

GRIN genes encode the proteins required to build the NMDA receptor, which is critically required for neuron communication and for many forms of learning and memory. GRIN-related neurodevelopmental disorder occurs with a single misspelling of one of four genes, GRIN1, GRIN2A, GRIN2B, or GRIN2D.

People with GRIN disorder experience autism, seizures, developmental delay, profound intellectual disability, speech and vision impairments, as well as eating, sleeping, and movement difficulties. Their lives are shortened by death from seizures, pneumonia, or cardiac arrest. There are no treatments for GRIN disorder, and most symptoms are completely refractory to current medications.

The GRIN-TREAT project brings together four laboratories that have expertise in GRIN disorder and have developed mouse models carrying disease-causing mutations in each of the four GRIN genes. The fifth laboratory is one that has discovered a new type of antibody-based therapy that could be effective for GRIN1, 2A, 2B, and 2D.

They have developed several nanobody therapeutics that prove effective in the Grin1 knockdown mouse model. Their novel nanobodies easily enter the brain and ameliorate symptoms by modulating metabotropic glutamate receptors, which normally function to regulate the action of NMDA receptors. Our team will test the efficacy of nanobodies to improve the symptoms of patient-variant mice.

At the same time, we will each share expertise and conduct collaborative studies to evaluate brain and blood biomarkers in the models before and after drug treatment.

We are collaborating with several patient advocacy organizations (PAOs) to achieve important goals. With PAOs we will gather caregiver input on study priorities, will support initiatives for biobanking, and will co-organize meetings to transfer knowledge bidirectionally and to the larger community of GRIN researchers.

Partners

• Melzer, Heinrich Heine University Düsseldorf (Germany)
• Colciaghi, Foundation IRCCS Neurological Institute Carlo Besta (FINCB) (Italy)
• Carcak, Istanbul University (Türkiye)
• Greene, Royal College of Surgeons in Ireland, Department of Physiology & Medical Physics (Ireland)
• Strüber, Goethe University Frankfurt, Center of Neurology and Neurosurgery, Epilepsy Center Frankfurt Rhine-Main (Germany)
• Egervari, University of Geneva, Department of Pathology and Immunology (Switzerland)
• Bieler, Selbsthilfegruppe Autoimmunenzephalitis (Germany)
• Stempfle, Deutsche Epilepsievereinigung e.V. (Germany)

Scientific abstract

Autoimmune limbic encephalitis and Rasmussen’s encephalitis are considered rare to ultra-rare forms of autoimmune brain inflammation in children and adults presenting with seizures as well as behavioral (cognitive/motor) decline.

Current evidence suggests that both diseases often develop into irreversible circumscribed brain atrophy and scarring with devastating treatment-refractory focal epilepsy. This process is mainly driven by neuron- and potentially also astrocyte-directed T cell responses. Currently, there is no approved tailored treatment option for T cell responses prevailing in both disease and no approved immunotherapy at all.

Members of the T-CARE consortium have recently established and published mouse and rat models of autoimmune limbic encephalitis and Rasmussen’s encephalitis all involving T cell-driven focal immune responses in the brain.

The T-CARE consortium will establish strong collaborations between epileptologists and immunologists including model transfer for validation/reproduction of the experimental findings to obtain strong reliable data from two independent labs for each model regarding the role of T cells. It will independently test the application of specialized anti-CD3 monoclonal antibodies that have been shown to dampen autoimmune T cell responses on the clinical and paraclinical disease manifestations in a preventive and therapeutic setting.

With this large data-set in 3 relevant experimental models, we will aim at further development of the approach in tight collaboration with Sanofi, the provider of Teplizumab, a recombinant monoclonal anti-CD3 antibody already approved for children and adults with T cell-mediated type 1 diabetes (T1D) and conduct proof-of-concept clinical trials in autoimmune limbic encephalitis and Rasmussen’s encephalitis.

Partners

• van Montfrans, UMC Utrecht (Netherlands (the))
• Grimbacher, UNIVERSITÄTSKLINIKUM FREIBURG Institut für Immundefizienz (Germany)
• Meyts, University Hospitals Leuven, KU leuven, Belgium (Belgium)
• Fellay, Ecole Polytechnique Fédérale de Lausanne (Switzerland)
• Bastard, Imagine Institute (France)
• Bariş, Marmara University, Faculty of Medicine, Department of Pediatric Allergy and Immunology (Türkiye)
• Prevot, IPOPI (Belgium)

Scientific abstract

Physicians have clear treatment guidelines for common immune diseases like inflammatory bowel disease and rheumatoid arthritis. However, for a class of immune diseases called Primary Immune Dysregulatory Diseases, which are rare and complex immune disorders where the immune system attacks multiple organs, treatment is largely trial-and-error due to the high variability of these diseases and the lack of predictive tools.

Advances in genetic- and epigenetic technologies have identified many disease-causing mutations, but this has not translated into better treatment strategies. Primary Immune Dysregulatory Diseases present with overlapping symptoms and unpredictable responses to existing immunosuppressive drugs, making it difficult for physicians to select the most effective therapy.

Unlike cancer treatment, where AI helps match patients to therapies, immune diseases lack predictive models, leaving doctors without evidence-based guidance. IMMUNE-AI will revolutionize treatment selection by combining multi-omics data integration, AI-driven predictive modeling, and in vitro drug testing.

AI models will analyze patient data to identify immune patterns (endotypes) linked to treatment responses, ensuring a shift from empirical approaches to precision medicine. These AI-driven therapy predictions will then be validated in laboratory models using patient-derived immune cells before clinical application.

Led by experts in rare immune diseases from ERN-RITA, a European network for rare immune disorders, IMMUNE-AI ensures that its AI-driven predictions are both scientifically rigorous and clinically practical for real-world use. By implementing a structured, biomarker-driven approach, IMMUNE-AI will help physicians select effective therapies faster, minimize side effects, and reduce healthcare costs.

This work lays the foundation for AI-powered precision medicine in rare immune diseases, offering new hope for patients who currently lack targeted treatment options.

Partners

• Delprat, MMDN, Inserm U1198 (France)
• Kaasik, University of Tartu, Department of Pharmacology (Estonia)
• Bultynck, Laboratory of Molecular and Cellular Signaling (Belgium)
• Abate, Università degli Studi di Bari, Dipartimento di Farmacia-Scienze del Farmaco (Italy)
• Sprenger, Max Planck Institute for Biology of Ageing, Department Sprenger (Germany)
• Maurice, Sitera Pharmaceuticals (France)
• Le Floch, Association Syndrome de Wolfram (France)

Scientific abstract

Cells execute their specialized functions through specific compartments, so-called organelles. These organelles do not function independently of each other, but are closely connected through membrane contact sites. The contact sites between two of the organelles, endoplasmic reticulum and mitochondria, named MAMs serve as hubs for signaling.

It has become increasingly clear that such contact sites play a key role in cellular health and cell function. Therefore, the time is ready to translate these findings and understand how MAMs are dysregulated in rare diseases, how MAM dysregulation contributes to disease progression and whether restoring MAMs integrity and functionality can improve disease outcomes.

Our project will focus on a group of rare diseases for which a deficit in MAM functioning is a determining physiopathological event.

The Wolfram syndrome (WS) and Charcot-Marie-Tooth type 2A disease (CMT2A) affect children and severely impact their quality of life. Worse, WS patients die around 35 years old. Unfortunately, no treatment is available to stop the progression of the pathologies.

Interestingly, sigma-1 receptor, a protein involved in the regulation of MAMs function, was efficient in restoring cellular deficits and behavioral impairment in preclinical models of the pathologies when activated. Indeed, sigma-1 receptor may be targeted by small molecules, such as agonist, to activate its function.

These promising data prompt us to develop novel sigma-1 receptor agonist that may be translated into a medicine. We generated different chemicals series with agonistic function and identified a lead compound, SIT3060 whose preliminary physicochemical and pharmacological characterization was very encouraging. Our project aims at validating its effect in relevant preclinical in vitro and in vivo models, in better understanding of its role on mitochondria, in clarifying its target engagement and in finalizing its characterization to initiate clinical trials.

Partners

• Flygare, Lunds universitet (Sweden)
• Rognan, Université de Strasbourg/CNRS – Faculté de Pharmacie, Laboratoire d’Innovation Thérapeutique (France)
• Ditadi, Fondazione Telethon ETS (Italy)
• Oudelaar, Max Planck Institute for Multidisciplinary Sciences (Germany)
• Pospíšilová, Univerzita Palackého v Olomouci (Czechia)
• Karaca, Izmir Biomedicine and Genome Center / Computational Structural Biology Lab. (Türkiye)
• Hibert, Association Francophone de la Maladie de Blackfan Diamond (AFMBD) (France)
• Reijnen, The Stichting Zeldzame Bloedziekten (Netherlands (the))
• Fenselau, Diamond – Blackfan — Anämie Selbsthilfe e.V. (Germany)

Scientific abstract

Diamond-Blackfan Anemia (DBA) is a rare and serious blood disorder that affects about 5-7 people per million births worldwide. It prevents the body from making enough red blood cells, which are vital for carrying oxygen throughout the body.

Current treatments, such as regular blood transfusions, corticosteroids, or stem cell transplants, often come with severe side effects, lower quality of life, and reduced life expectancy. The CDKure-DBA project aims to develop a groundbreaking new treatment: a simple oral drug that targets two specific proteins, CDK8 and CDK19.

These sibling proteins play a role in regulating gene activity and have been independently discovered by two partners in this consortium to mediate blockage of red blood cell production in DBA. Using computer simulations to understand how drugs interact with these proteins at the molecular level, we hope to design molecules that can turn off the function of these proteins and restore the body’s ability to produce healthy red blood cells in patients with DBA.

This project brings together leading experts in diverse fields including hematology, computational molecular modeling and pharmaceutical chemistry.

The team is using innovative methods to develop and test the new treatment, including studying its effects in human cells and animal models to ensure it works well and is safe.

The project also examines how the treatment impacts the blood system at the molecular level and engages closely with DBA patients and their families to ensure the treatment addresses their needs. This teamwork is essential for successfully bringing our new treatment to patients.

Partners

• Fähndrich, Medical Center – University of Freiburg, Department of Pneumology (Germany)
• Winterberg, Fraunhofer Institute for Toxicology and Experimental Medicine (Germany)
• Biasin, Department of Physiology and Pathophysiology (Austria)
• Kuipers-Skarsfeldt, Nordic Bioscience – Translational Research (Denmark)
• Liepins, Latvian Institute of Organic Synthesis (LIOS)/Laboratory of Pharmaceutical Pharmacology (Latvia)
• Huss, Lungenfibrose e.V. (Germany)

Scientific abstract

Idiopathic pulmonary fibrosis (IPF) is a rare but serious lung disease that causes scarring (fibrosis) of the lungs, making it increasingly difficult for patients to breathe. Currently, there are only two approved treatments, and they don’t work well for all patients and can cause significant side effects.

Our research focuses on developing a new treatment called aloxistatin that patients can inhale directly into their lungs. When taken as a pill, aloxistatin loses its effectiveness because the body breaks it down too quickly. However, by delivering it directly to the lungs through inhalation, we believe we can make it work much better.

Early tests have shown that inhaled aloxistatin is safe and may help reduce both inflammation and scarring in the lungs. In this project, we will conduct detailed laboratory studies to understand exactly how inhaled aloxistatin works and determine the best dose to use in patients.

We’ll test it in various models that mimic lung scarring, from individual cells to tissue samples and animal studies. We’re also developing new ways to measure whether the treatment is working using special imaging techniques. Importantly, we’re working closely with patient organizations throughout this project to ensure our research meets real patient needs.

Our team includes scientists and doctors from five different European institutions, each bringing unique expertise to solve this complex challenge. If successful, this research will provide the evidence needed to begin testing inhaled aloxistatin in patients with IPF, potentially offering a new, more effective treatment option for this serious disease.

Our work could also lead to better ways of identifying which patients are most likely to benefit from the treatment and how to adjust doses for the best results.