Euro-BioImaging ERIC is the European Research Infrastructure for biological and biomedical imaging. With more than 230 imaging facilities across Europe, Euro-BioImaging provides open access to state-of-the-art imaging tools and expertise, spanning the whole spectrum of imaging from the molecular to the human scale. In addition to access to cutting-edge instruments, the Euro-BioImaging Nodes provide expertise, guidance and training on all aspects of the imaging experiment – from experimental design and sample preparation to image analysis services and data management. Many of the imaging tools made accessible through Euro-BioImaging are applicable for rare disease research, from elucidating disease mechanisms to identifying and validating potential treatments and diagnosis tools.

This presentation will introduce the services available from Euro-BioImaging, which are relevant for the rare disease research community, highlight existing collaborations and service pipelines between Euro-BioImaging and INFRAFRONTIER, and outline options for future collaborations between the communities of these two Research Infrastructures.

Rare genetic orofacial diseases pose diagnostic and therapeutic challenges due to their complexity and limited patient cohorts. Integrating model systems—animal models, organoids, and AI-driven approaches—has advanced understanding and personalized medicine. Bloch-Zupan and colleagues have identified key gene mutations linked to craniofacial anomalies, including SMOC2 (2011) for oligodontia and dentin dysplasia; LTBP3 (2015) for brachyolmia with amelogenesis imperfecta and more recently, PLXNB2 (2024) for amelogenesis imperfecta, hearing loss, and intellectual disability. Their discoveries enhance knowledge of rare disease genetics. GenoDENT, an NGS diagnostic panel, identifies genetic variants in dental and craniofacial anomalies, while PhenoDENT, a phenotypic analysis platform, refines genotype-phenotype correlations using AI-assisted imaging. AI-driven tools like D-IA-GNODENT improve diagnostic accuracy and predictive modeling. Murine (Ltbp3, Smoc2, Rogdi…) and zebrafish models validate genetic findings, replicating disease phenotypes and elucidating craniofacial development. Human-cell organoids serve as physiologically relevant models to investigate anomalies at a cellular level, enabling functional validation of novel variants of unknown significance. This multimodal strategy, supported by French and European rare disease networks, fosters translational research from bench to bedside, advancing diagnosis, treatment, and novel therapeutic interventions for rare craniofacial diseases.

María Domínguez-Ruiz, Silvia Murillo-Cuesta, Julio Contreras, Marta Cantero, Gema Garrido, Belén Martín-Bernardo, Elena Gómez-Rosas, Almudena Fernández, Francisco J. del Castillo, Lluís Montoliu, Isabel Varela-Nieto, Ignacio del Castillo.

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (<1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (>90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.

Systemic sclerosis (SSc) is a rare, complex autoimmune disorder driven by a dysregulated interplay between fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in pre-clinical SSc models, owing to their immunoregulatory, pro-angiogenic, and antifibrotic properties. MSCs have been shown to reduce fibrosis and inflammation in both skin and lung tissues of SSc-affected mice. However, the broad immunomodulatory effects of MSCs, which often result in transient and generalized immune suppression, limit their therapeutic efficacy in the context of SSc. To address these limitations and unmet clinical needs, we propose the development of a novel, precision-engineered therapeutic cell product derived from human cells. This approach will require to be evaluated in a humanized SSc mouse model, designed to assess the efficacy of selective biotherapies tailored to the disease’s unique pathophysiological mechanisms. The generation and validation of this humanized model for preclinical testing of targeted biotherapies will be discussed in this presentation, with a focus on its potential for advancing treatment strategies for SSc.

EU-OPENSCREEN is a non-for-profit European research infrastructure for chemical biology with the aim to support chemical probe and early drug discovery projects. Through its more than 30 partner institutes in nine European countries, it offers access to small molecule libraries, expertise and technology platforms for the global Life Sciences community. The network is open to collaborations with external scientists from academia and industry and offers next to high-throughput screening also tools and competence for compound optimization and mechanism of action elucidation of hit compounds. As part of our mission, we have been involved in several rare disease programs and recently, one of our partner sites performed a drug repurposing study which utilized the EU-OPENSCREEN Bioactives compound collection. In this presentation an overview of the EU-OPENSCREEN infrastructure capacities and opportunities will be presented and insights on a rare disease case study will be shared.

Yann HERAULT and the GO-DS21 CONSORTIUM

Down syndrome (DS) is a multi-organ condition characterized by physical, intellectual, and developmental features. Individuals with DS often experience cognitive impairment, developmental delays, and specific facial and physical characteristics. They also have a higher risk of obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD), a primary form of advanced metabolic liver disease marked by hepatocyte ballooning and increased fibrosis risk. In individuals with DS and obesity, MASLD is prevalent in 82%, compared to 45% in those with an average body mass index. The GO-DS21 EU-funded project used the Dp(16)1Yey DS mouse model to study MASLD. The model showed increased sensitivity to MASLD, with liver hepatocyte ballooning and lobular inflammation. Plasma analysis revealed bile acid accumulation and decreased cholesterol levels, independent of diet and sex. These changes were linked to altered gut microbiota and increased lipopolysaccharide (LPS) in plasma, triggering inflammatory responses in multiple organs. The Dp(16)1Yey model is proposed as an innovative tool for investigating MASLD. Disruptions in bile acid/cholesterol levels, driven by triplicated genes, are suggested as intrinsic contributors to MASLD in DS. Future research aims to explore the origins of liver dysfunction, regulate bile acid/cholesterol biology from birth to adulthood, and examine the genetics of MASLD in DS models. This will help identify candidate genes involved in MASLD and associated metabolic and inflammatory dysfunctions frequently observed in individuals with DS.

The Finnish disease heritage (FDH) contains almost forty monogenic, hereditary diseases that are all rare diseases. National FinnDisMice research consortium has focused on modeling a set of FDH diseases in mouse using CRISPR/Cas9 genome editing. The diseases were selected based on the lack of an existing animal model (knockout not studied or does not phenocopy the given disease), clinical relevance (patients regularly seen at hospitals) and potential for therapeutic solutions. The goal of the project is to facilitate understanding of disease pathomechanisms that are causative for selected FDH diseases. Faithful recapitulation of disease-causing mutations in mouse, their primary phenotyping and research at the organ and tissue level are essential for development of novel therapeutic strategies for these devastating, often lethal diseases. In the future, the disease models will provide valuable preclinical validation instruments for potential new therapies, thus facilitating bench-to-bedside research result transfer.

Rare diseases affect only a small proportion of the population and are often serious, life-threatening or chronic diseases requiring challenging treatment. One such condition is Urofacial (Ochoa) syndrome (UFS), an autosomal recessive inherited disorder. This syndrome is primarily characterized by urinary bladder voiding dysfunction and abnormal facial expression, but also bowel dysfunction occurs in more than 50% of the cases. The disease already manifests in childhood and is often associated with complications as chronic kidney disease or urosepsis as it progresses. Furthermore, symptoms like frequent incontinence and encopresis can have a significant psychological impact on patients. Following genetic testing, 84% of UFS cases can be attributed to mutations in the LRIG2 and HPSE2 genes. LRIG2 belongs to the LRIG family. These transmembrane proteins modulate the signaling and expression of receptor tyrosine kinases such as the ERBB receptors via positive and negative feedback loops. In this way, LRIG2 plays a role in the regulation of numerous developmental and homeostatic processes such as cell proliferation, migration and apoptosis. It is mainly expressed in the central nervous system, skin, muscle tissues and reproductive organs. LRIG2 is primarily known for its oncogenic effect in glioblastoma, cervical carcinoma or osteosarcoma, but new results also indicate a function in energy metabolism. Although LRIG2 and HPSE2 have already been shown to be involved in embryonic development of lower urinary tract innervation, further research is required to fully understand the underlying mechanisms. Therefore, we generated murine and porcine LRIG2 knockout models, to investigate the pathophysiological function of LRIG2.

While in vivo animal models continue to be extremely relevant to study genes and pathways controlling the differentiation and function of the immune system, a number of caveats must be taken into consideration before knowledge can be translated from animals to humans. iPSC-derived human organoids can circumvent some of these hurdles of translation. We have recently developed a novel platform to differentiate bone fide human bone marrow organoids that consist of vascular, stromal and hematopoietic cells. This model can be used to study both inborn errors of immunity and acquired diseases such as leukemias. 

Facioscapulohumeral muscular dystrophy (FSHD) is a complex neuromuscular disorder characterized by progressive weakness and atrophy of specific muscle groups. The disease arises from genetic and epigenetic alterations in the D4Z4 repeat array at the subtelomeric 4q35 locus. Additionally, mutations in SMCHD1, a chromatin-associated factor, contribute to disease onset and progression by modulating the epigenetic regulation of the 4q35 region. Despite significant research advancements, the precise pathophysiological mechanisms underlying FSHD remain highly complex and incompletely understood. One of the major challenges in FSHD research is the absence of relevant animal models. Mice entirely lack the D4Z4 repeat region, and no syntenic genomic counterpart exists in their genome. This fundamental difference makes it difficult to generate genetically accurate mouse models that faithfully replicate FSHD pathology, necessitating alternative approaches to study the disease.

To address these challenges, we have developed an integrated and interdisciplinary strategy that begins with clinical data and genotype characterization, providing a foundation for unraveling the molecular intricacies of FSHD. To complement genotype-based studies, we have recently established a human-induced pluripotent stem cell (iPSC)-derived model, combined with tissue bioengineering approaches, to recapitulate the FSHD phenotype in vitro. By considering the diversity of patient genotypes, this interdisciplinary approach provides a comprehensive framework to dissect FSHD pathophysiology at both the molecular and cellular levels, ultimately paving the way for the identification of key disease-driving pathways and the development of targeted therapeutic strategies.

Genodermatoses are a group of rare inherited skin disorders caused by genetic mutations affecting the structure and function of the skin and its appendages. These conditions often manifest at birth or in early childhood and can vary in severity, ranging from mild cosmetic concerns to life-threatening complications. Pathogenic mutations in connexin-encoding genes associated with genodermatoses, such as keratitis-ichthyosis-deafness syndrome and Clouston syndrome, also known as hidrotic ectodermal dysplasia, lead to increased hemichannel activity. Biophysical studies on these mutant connexins provide mechanistic evidence supporting the idea that reducing this aberrant hemichannel activity could help mitigate epidermal abnormalities. Research using pharmacological inhibitors and engineered monoclonal antibodies in mouse models of keratitis-ichthyosis-deafness syndrome and Clouston syndrome, has validated hemichannel inhibition as a promising therapeutic strategy for these conditions. These findings may also be relevant for other genetic diseases linked to aberrant connexin hemichannels, such as X-linked Charcot-Marie-Tooth type 1 disease, a disabling peripheral neuropathy.

Sara Marcó, Gemma Elias, Miquel Garcia, Xavier Sánchez, Carles Roca, Albert Ribera, Víctor Sánchez, Joan Bertolin, Jennifer Pérez, Maria Molas, Estefania Casaña, Claudia Jambrina, Víctor Sacristan, Xavier León, and Fatima Bosch.

Sandhoff and Tay-Sachs diseases are rare autosomal recessive lysosomal storage disorders caused by deficiency in β-hexosaminidase A (HEXA), a αβ heterodimer enzyme responsible for GM2 ganglioside degradation. Mutations in either HEXA or HEXB genes, coding for α and β subunits, results in Tay-Sachs or Sandhoff diseases, respectively. Clinically, both conditions present severe, progressive neurodegeneration including developmental regression, neurological deterioration, motor deficits (hypotonia, spasticity and ataxia), seizures and vision loss, leading to a premature death. To date, there is no effective treatment. Here, we developed a novel gene therapy approach based on a single AAV9 vector encoding both HexA and HexB genes fused with a short flexible linker (AAV9-HexA-L-HexB) that resulted in the production of a covalently linked HEXA protein in Sandhoff and Tay-Sachs mice. Intra-cerebrospinal fluid (CSF) AAV-mediated gene transfer in Sandhoff mice led to widespread CNS HEXA activity resulting in correction of primary GM2 and secondary cholesterol storage, along with reversion of CNS lysosomal pathology, demyelinization, impaired autophagic flux, and neuroinflammation. Additionally, hepatic and circulating engineered HEXA protein corrected peripheral storage pathology. Treatment with AAV9-HexA-L-HexB reverted behavioral deficits, including locomotor alteration, coordination, and mobility, and significantly extended lifespan (about 2 years) in affected mice. Altogether, our pre-clinical results demonstrated that a single intra-CSF administration of AAV9-HexA-L-HexB vectors led to whole-body correction of disease pathology, providing strong evidence for clinical translation of this approach to treat Tay-Sachs and Sandhoff patients.

In recent years, large-scale sequencing efforts have helped to uncover a growing number of new rare diseases. Among them is the neurodevelopmental disorder PURA syndrome. First described in 2014, it is caused by sporadic, heterozygous mutations in the PURA gene (5q31.3) resulting in haploinsufficiency of the DNA and RNA binding protein PURA. Patients with PURA syndrome suffer from intellectual disability, hypotonia, epilepsy, scoliosis, and a range of other, variable symptoms. There is currently no established treatment strategy. Together with colleagues and with the support of patient advocacy groups, we have established a research network to understand the disease etiology of the PURA Syndrome and to develop strategies for therapeutic intervention. My group contributes to these efforts by using different approaches, ranging from structural biology, biochemical studies to multi-omics analyses. For the latter, we use human iPSC-derived 2D and 3D cultures from patient cells and CRISPR-generated PURA KO together with their isogenic controls. This work is complemented by patient-related efforts, such as co-founding and supporting the German patient advocacy group, PURA Syndrome Deutschland e.V., and establishing a PURA biobank at Helmholtz Munich.

Rare diseases are pathologies defined by their low prevalence (1/2000 in Europe), and present significant challenges in diagnosis, treatment, and research. The complexity of these conditions, coupled with limited patient populations, makes it difficult to gather sufficient clinical data and to develop effective therapies. In this context, computational and experimental models have emerged as powerful tools in advancing our understanding of rare diseases. These models, ranging from machine learning systems to cell-based systems and animal models, enable to study disease progression, explore genetic and molecular mechanisms, and identify potential therapeutic targets in a way that would otherwise be difficult to reach. This talk will emphasize the critical role of animal models in rare disease research, highlighting their ability to replicate disease progression, provide insights into pathophysiology, and facilitate preclinical testing of new treatments. By overcoming the challenges posed by scarce human data, animal models help bridge the gap between laboratory findings and clinical applications, offering a unique potential in the fight against rare diseases, opening new avenues for innovative treatments and improved patient outcomes.

Michele Pitaro, Barbara La Ferla, Lorenzo Taglietti, Giuseppe Bonapace, Giuseppe Felice Mangiatordi, Rosanna Rizzi, Maria Giovanna Eva Papadopoulos, Daniela Concolino

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by pathogenic IDUA variants, leading to α-L-iduronidase deficiency and glycosaminoglycan (GAG) accumulation. MPS I manifests as severe (Hurler syndrome) or attenuated (Hurler-Scheie and Scheie syndromes) forms, with attenuated cases retaining partial enzymatic activity and exhibiting slower disease progression. Current mouse models focus on severe MPS I, characterized by complete enzyme deficiency or truncated protein production, but do not replicate the molecular defects of attenuated forms. Among these, the L490P and P533R mutations account for 13.3% and 10.8% of attenuated cases, respectively. Existing treatments, including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), reduce systemic GAG accumulation but fail to prevent progressive central nervous system (CNS) damage, as ERT does not cross the blood-brain barrier (BBB) and HSCT provides limited neuroprotection. Our research group is focused on the development of pharmacological chaperones as a novel therapeutic approach for attenuated MPS I. These molecules stabilize mutant α-L-iduronidase, enhancing residual activity and potentially crossing the BBB to address neurological manifestations. However, the lack of preclinical models expressing L490P and P533R mutations hinders their preclinical validation. We propose generating transgenic mouse models with these IDUA variants to enable in vivo assessment of chaperone-based therapies. These models will facilitate pharmacokinetic and pharmacodynamic studies, assess biodistribution, and provide critical insights into treatment efficacy.

Research funded by the European Union – Next Generation EU, under the National Recovery and Resilience Plan (PNRR), Mission 4, Component 1, Project CUP 2022S2M7E5.

Friedreich Ataxia (FA) is an inherited neurodegenerative disease caused by reduced levels of frataxin (FXN), a nuclear encoded mitochondrial protein. FXN is an essential protein involved in the biosynthesis of Fe-S clusters, required for the function of a myriad of proteins involved in key cellular processes such as respiration, central metabolism, protein translation and DNA replication/maintenance. FA is characterized by a progressive sensory and spinocerebellar ataxia associating cardiomyopathy and increase incidence of diabetes. The disease is characterized by severe loss of primary proprioceptive neurons of the dorsal root ganglia (DRG). Both developmental deficits and progressive degeneration are believed to contribute to proprioceptive neuron pathology. Using different mouse and cell models of the disease, we aim at investigating the full pathophysiological consequences of FXN deficiency. Recent advances in the field will be discussed and how they have contributed to developing novel therapeutic approaches.

Neil A Roberts, Filipa Lopes, Ben Jarvis, Sara Al Mahdy, Simon Waddington, Adrian Woolf

Urofacial syndrome is a devastating autosomal recessive condition caused by mutations in HPSE2. Affected individuals have life-long bladder dysfunction, causing urinary incontinence and leading to life-threatening kidney failure. There are no cures, and current interventions can exacerbate the urinary dysfunction. Our work in mutant mouse models revealed an autonomic neuronal aetiology, indicating a potential therapeutic tissue target for advanced therapeutics. We adopted an adeno-associated virus (AAV9) gene delivery strategy to target human HPSE2 to mouse bladder neurons in vivo. Newborn Hpse2 mutant mice were treated initially, followed by progressively older animals. Therapeutic efficacy was investigated by whole tissue physiology using a myograph platform. Systemic delivery of AAV9/HPSE2 vector safely targeted the transgene to bladder neurons in vivo and resulted production of the coded for protein, heparanase 2. Treatment of newborn Hpse2 mutant mice completely restored neuromuscular function in bladder tissues as assed by ex vivo physiology. Delivery of the therapeutic vector to older mice indicated the therapeutic window may extend past the newborn period.
Conclusion: Gene therapy using an AAV vector can efficiently and safely deliver therapeutic transgenes to bladder neurons and rescue the specific neuro-muscular pathophysiology associated with urofacial syndrome. These findings indicate a route to clinical use of gene therapy for urofacial syndrome, and a strategy for treating other genetic conditions affecting the urinary tract.

We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the rare neurometabolic disease phenylketonuria (PKU), introducing the prevalent intronic splice PAH variant c.1066-11G>A. This variant creates a novel 3’ splice site leading to a mutant transcript coding for a protein with an internal three amino acids insertion. Homozygous Pah c.1066-11A mice accurately recapitulate the splicing defect and present almost undetectable hepatic phenylalanine hydroxylase (PAH) activity, elevated blood and brain L-Phe levels, decreased L-Tyr, L-Trp and monoamine neurotransmitter levels, lower brain and body weight and hypopigmentation. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Immunohistochemistry analyses confirmed altered microglia and astrocyte morphology, increased GFAP and Iba1 staining signals and decreased myelinization. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of DNAJC12 and HSP70 chaperones and increased LAMP1 and LC3BII autophagy markers, suggesting possible coaggregation of mutant protein with chaperones and subsequent autophagy processing. This novel PKU mouse model with a prevalent human variant representative of the most severe phenotype is ideal for pathophysiology research and for development of RNA or pharmacological therapies targeting the splicing variant or the mutant protein defects.

Marta Agnes Somorai, Clara Lettl, Volker Mall

Precision therapy approaches for monogenic neurodevelopmental disorders (mgNDDs) are an emerging topic. First precision therapies have already received a marketing authorization. In other cases, targeted therapies are available through admission in an interventional clinical trial or as off-label treatment options. At the Center of Rare Developmental Disorders, kbo-Kinderzentrum, Munich a structured online data-base search using 14 databases is carried out for every genetic diagnosis. In this retrospective observational study, we analyze the precision therapies found, offered and carried out in pediatric patients with mgNDDs presenting 01/06/2021–31/12/2024. Data-base searches were carried out for 221 NDD genes (376 patients). CNS-directed precision therapy approaches could be identified for 57/221 mgNDDs genes (26%), non-CNS-directed targeted therapies for 17/221 mgNDDs genes (7.7%). 54/376 patients received a precision therapy (14%): an approved targeted therapy in 2/375 patients (0.5%), an investigational product within an interventional clinical trial in 4/375 patients (1%), and an off-label targeted therapy in 50/375 patients (13%, 6 externally initiated, 44 in-center, from those 17 in progress for evaluation at data-cut). From 27 evaluable in-center off-label therapies 15 showed positive effects, prompting a long-term therapy (12) or in developmental/gait analyses (3). Therapy acceptance was high (90%). data-cut on 30/01/2025.
Conclusion: Approved precision therapy approaches and enrollments in interventional clinical trials were significantly less common (<1%), than drug-repurposing (13%) in our cohort of pediatric patients with mgNDDs. Drug-repurposing, although certainly not able to heal all symptoms, seems to be an available and potentially beneficial therapeutic option in this cohort.

Lore Becker, Patricia Da Silva-Buttkus, GMC Consortium, Claudia Seisenberger, Susan Marschall, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis and Nadine Spielmann

Congenital cardiomyopathy with hearing loss is rare disease condition for which only a few genetic models are available. ZFP280D, a member of the ZNF280 family, is thought to function as a transcription factor involved in developmental processes. Although no direct genetic disorder in humans has been clearly attributed to ZFP280D, its role in cardiac and auditory function remains unexplored. Knockout mouse models have successfully contributed to the understanding of human monogenic heart disease. To this end, we generated a Zfp280D knockout (KO) mouse that underwent systemic phenotyping at the German Mouse Clinic. Zfp280D-KO mice showed significantly reduced ejection fraction (27.8 % vs. 82.7 % in wild type), progressive left ventricular dilatation and complete hearing loss. Histopathological evaluation showed myocardial fibrosis and structural remodeling. These results make Zfp280D-KO mice a promising model for congenital cardiomyopathy with hearing loss, offering insights into disease mechanisms and potential therapeutic interventions.

The Neuronal Ceroid Lipofuscinoses (NCL) are a group of diseases that share some remarkable histopathological as well as clinical features. Today, 13 NCL genes causing different subtypes of Batten disease have been identified. The most common forms include CLN3, CLN2, and CLN1. Despite sharing histopathological and clinical features, the gene defects underlying NCLs are very diverse. Commonalities in terms of molecular pathways they might share remained largely obscure until recent developments in technologies allowing rapid isolation of intact lysosomes (lysoIP). The latter allows studying lysosomal function and lysosomal metabolism in cell and animal models, as well as in freshly isolated PBMCs from patients. Accordingly, it has been shown that CLN3 defects result in a massive intra-lysosomal accumulation of glycerophosphodiesters (GPDs), the ultimate breakdown products of glycerophospholipids. Also, several NCL genes, including CLN3, CLN5, CLN8, share common pathway defects related to homeostasis of the endo-lysosome-specific lipid bis(monacylglycero)phosphate (BMP). Lysosomal BMP is key to sustain the activity and stability of lysosomal hydrolases. These and other breakthroughs in understanding the fundamentals of NCL gene function may result in designing novel therapies beyond those that are being explored today. The NCL Foundation fosters and funds worldwide activities to understand the fundamentals of CLN3 disease, to identify and help translate disease-transforming therapies to the clinic.

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked DMD gene, resulting in the absence of dystrophin, progressive muscle degeneration, and heart failure. Animal models have played key roles in dissecting disease mechanisms of DMD and in developing and testing new diagnostic procedures and therapeutic concepts. The mdx mouse model as well as genetically engineered mouse strains resembling human DMD mutations are most widely used, but have limitations in the resemblance of the human DMD phenotype. Moreover, the small size of rodent models limits the translatability of positively tested therapeutic approaches to human patients. Therefore, large animal models are essential for bridging the gap to clinical studies. We have developed a porcine DMD model lacking DMD exon 52 (DMD52), which resembles a frequent human DMD mutation and reveals molecular, clinical and pathological hallmarks of the human disease. Compared to DMD patients, the disease progression in DMD pigs is markedly accelerated, which allows safety and efficacy readouts for new treatment strategies in a reasonable period of time. DMD pigs have been used for studying disease mechanisms by omics-profiling of skeletal muscle and heart samples and for validating multispectral optoacoustic tomography (MSOT) as a tool for non-invasive monitoring of muscle fibrosis. Moreover, DMD pigs have been used to evaluate therapeutic concepts, such as gene editing to reframe a disrupted DMD reading frame or artificial chromosome vectors carrying the complete DMD gene, thus bridging the gap between proof-of-concept studies in rodent models and clinical studies in patients.

Andrea Wutte, Manuela Pausan, Saba Abdulghani, Eleanor Shember, Jana Pavlic-Zupanc, Johanna Kostenzer, Petr Holub, Heimo Müller, and Jens K. Habermann

BBMRI-ERIC is the European research infrastructure for biobanking and biomolecular resources in health and life sciences. BBMRI-ERIC encompasses 24 Members and Observer countries and IARC/WHO; comprising 25 National Nodes, 473 biobanks and affiliated partners. BBMRI-ERIC enables the development of innovative technology and processes as transnational European infrastructure that facilitates responsible access to high quality samples, data and biomolecular resources. BBMRI-ERIC engages its community and partners in more than 23 active EU projects, including various projects for advancing cancer research that are strongly aligned with Cancer Mission and the EU Cancer beating plan namely, canSERV, EOSC4Cancer, EUCAIM, and the newly granted UNCAN projects. Our federated access and analysis platform has become a strong asset and reference point for major EU initiatives. (e.g., EHDS, 1+Mio, GDI). For over a decade, BBMRI-ERIC has actively contributed to the field of rare diseases, by developing sustainable access to biobank resources of population groups affected by these conditions through numerous projects. As part of the European Rare Disease Research Alliance (ERDERA), BBMRI-ERIC is contributing to the “RD Virtual Platform”, which focuses on discovering and accessing the data ecosystem of biobanking resources, for human rare disease populations. Within “Rare Disease Moonshot” the collaboration within RI’s aims to scaling up public-private partnerships to accelerate rare disease research. Conclusion: We will showcase how to access and make use of the richness of BBMRI-ERIC’s resources and how to collaborate with our wider community on different topics through in-house or EU funding – locally, nationally or EU wide, to foster biomedical research.