Research

International Research Projects

SPMH Metabolic test in vivo for malignant hyperthermia

Call: EJP RD JTC 2022
Principal investigator: Oscar Diaz Cambronero
Role: Participant
Year: 2023

Malignant hyperthermia (MH) is a dangerous reaction to certain anesthetics, heat or exercise that can be fatal if left untreated, caused by an inherited dysregulation of calcium inside muscle cells. MH can be prevented by using alternative anesthetics in patients with suspected MH predisposition and in their relatives. At least half of the families affected by MH predisposition have no identifiable genetic marker and cannot benefit from genetic testing. To assess their risk of MH, a surgical muscle biopsy is required to evaluate their muscle response to drugs that may trigger MH by the so-called contracture tests, performed only by a few specialized centers globally. Many persons at risk refuse testing because of its invasiveness, cost, distance to the testing centre,risk of complications, and a painful convalescence.

We envisage developing a test to diagnose MH using a harmless acupuncture needle applied into muscle. Needles for this ¨chemical biopsy¨ are coated with a sorbent designed to extract specific molecules (i.e., biomarkers) by a process called solid phase microextraction. A microinjection of caffeine into the muscle would trigger a local reaction only in patients predisposed to MH but not in others, producing biomarkers that can be extracted by the modified needle and analyzed for diagnosis. Our consortium is a multidisciplinary team with the expertise to develop such a device and to test its diagnostic accuracy in a multicenter clinical trial. Developing an innocuous tool to diagnose MH predisposition would be a major breakthrough for the better of patients at risk of MH.

PREDICTOM Prediction of Alzheimer’s disease using an ai driven screening platform

Call: HORIZON-JU-IHI-2022-03-single-stage
Principal investigator: Miguel Baquero
Role: Participant
Year: 2023

Alzheimer's disease (AD) and related disorders leading to dementia are associated with staggering costs and suffering. Recently, there has been some progress in the search for effective therapeutic interventions and it is clear that any treatment is likely to be most effective if administered at the earliest stage of disease, but the health care system is not ready for this new scenario. There is an urgent need, therefore, to establish scalable, cost-efficient diagnostic markers, tools and procedures that can identify people at increased risk, at point of care for stratification into personalized interventions to prevent or delay dementia. PREDICTOM will develop an open-source, interoperable and customisable biomarker screening platform, utilizing an existing online resource to save time and money, to generate an evidence base for general population screening for AD and related disorders. We will bring diagnostics closer to the patient by examining the feasibility of using samples which can be obtained at home (e.g. finger-prick blood, saliva (for genetics and epigenetics) and stool for microbiom) for diagnostic biomarker analysis. We will also evaluate innovative technologies for disease risk identification, including digital technologies and novel MRI, EEG, eye tracking, and blood-based biomarkers. The platform will use artificial intelligence models to analyse data from all biomarkers to identify users at high risk of developing dementia and to direct them to personalized intervention to prevent further cognitive decline and development of dementia. We will seek to facilitate a change in current healthcare practice for early diagnosis of AD through development of new clinical practice guidelines based on evidence generated in the project. By improving the ease of identification of those with early signs of dementia we expect to have a significant impact on personal and financial burden of dementia in Europe and across the world.

JARDIN EU4H-2022-JA-05 Direct grants to Member States’ authorities: support ERNs integration to the national healthcare systems of Member States

Call: EU4H-2022-JA-05
Principal investigator: Maria Eugenia Gas Lopez
Role: Participant
Year: 2024

European Reference Networks (ERN) are multinational networks of highly specialized healthcare providers (HCP) across Europe in thematically coherent medical domains, addressing rare or low-prevalence complex diseases requiring exceptional concentration of expertise and resources. There are currently 24 ERN providing virtual expert consultations for patients from all member states (MS) and Norway, as well as support knowledge generation, professional training and education, and research. In this project, we aim to enhance the impact of the ERN even further by addressing all aspects of their better integration into healthcare systems in MS. This will include improving national governance of ERN-HCP, quality assurance models, patient pathways and ERN referral systems, supporting the formation of national reference networks and undiagnosed diseases programs or equivalent strategies interlinked with ERN, improving data management, aiming to finally achieve full interoperability of regional, national and European health data sources, and identifying national support options for ERN-HCP. Furthermore, we will develop strategies for systematic dissemination of information on the ERN, with a specific emphasis on patients as well as the medical community. A main focus will be to ensure the sustainability of the proposed actions and implementations, which we propose to integrate into updated national plans and strategies for rare diseases in MS.

IDERHA Integration of heterogeneous Data and Evidence towards Regulatory and HTA Acceptance

Call: HORIZON-JU-IHI-2022-01-04
Principal investigator: Maria Eugenia Gas Lopez
Role: Participant
Year: 2023

Associated

IDERHA will address the key obstacles to achieving appropriate access, sharing, use and reuse of digital health care data, and thus enable enhanced regulatory and HTA decision-making for integrated health research, with the aim to improve care and better meet the needs of patients and health care professionals. The IDERHA open platform for multi-modal health data will enhance innovation in EU health care systems and is directly scalable by means of connecting additional systems, data sources and additional services and tools. It will extend and elaborate standards in semantic interpretation, data quality, ethics and transferability to ensure the harmonisation of heterogeneous data sources and wider health data reuse. Use cases positioned along the lung cancer patient pathway will be implemented using retrospective data and in a remote patient care and self-care context. These practical implementations will demonstrate the added value of multi-modal data aggregation and analysis with impacts expected on public health, patient burden, health outcomes and cost. We will perform AI/ML based lung-cancer risk profiling using patient`s EHRs, and improved CT image-based AI/ML to provide risk prediction of potential lung cancer patients, and personal prognosis of disease progression. Using patient monitoring and engagement, including digital biomarker, PROMs, and connected devices, the IDERHA platform will enable patient self-management, and provide data for joint patient-health professional decision making. Along with health care stakeholders, IDERHA will develop consensus policy recommendations for appropriate data sharing to enable multistakeholder research. Informed by Patient Advisory Groups, we will address critical obstacles and issues to heterogeneous health data primary and secondary use. Regulatory and HTA agencies will be engaged to create criteria for assessing the acceptability of heterogeneous health research results in regulatory and HTA decision-making.

JACARDI EU4H-2022-JA-03 Direct grants to Member States’ authorities: prevention of NCDs – cardiovascular diseases and diabetes

Call: EU4H-2022-JA-03
Role: Participant
Year: 2023

Affiliated entity

The Joint Action on CARdiovascular diseases and DIabetes (JACARDI) aims to reduce the burden of cardiovascular disease (CVD) and diabetes (DM) in EU countries, both at individual and societal level. JACARDI is designed to integrate validated best practices and/or (cost-)effective interventions across countries and regions through transnational pilot initiatives, complementing and reinforcing existing policies and programs. The initiative covers the entire "patient journey", from improving health literacy and awareness of CVD/DM, travelling through screening and primary prevention among high-risk populations, reaching people living with CVD/DM and their care providers, improving service pathways, self-management, and labour participation. JACARDI also addresses transversal and intersectional aspects, e.g., promoting equity in health, social, cultural, and ethnic diversity and the improvement of data availability. The activities are distributed into 11 Work Packages (WPs): 5 transversal WPs, with one innovative WP on the development of a common methodological framework and integrative approach, and 6 technical WPs. The wide coverage of JACARDI is secured by the involvement of 21 EU countries and 77 partners. The widespread implementation of 142 pilots will ensure broad coverage and geographic extension, while the adoption of a common implementation and assessment methodology will minimise the risks of failure and facilitate the analysis of success and context factors. The resulting roadmap will serve as proof-of concept case studies with the potential to extend and scale-up experiences at the national/regional level. JACARDI will enhance cross-national collaboration, maximising the exploitation of lessons learned through a clear strategy, engaging groups of interest, promoting integration and sustainability of approaches to achieve high-level impact, including the implementation of effective interaction, cooperation and co-creation between science and policy.

HYPIEND Understanding and preventing the impact of endocrine disruptors on the hypothalamus-pituitary axis in sensitive populations

Call: HORIZON-HLTH-2023-ENVHLTH-02
Principal investigator: Laia Tolosa
Role: Participant
Year: 2024

Exposure to multiple endocrine disrupting chemicals (EDC) is an environmental insult that interferes with the development and function of the endocrine system, governed by the hypothalamus-pituitary (HP) axis. This interaction is specially concerning in developmental stages of life, such as the perinatal period and puberty. Despite the current body of knowledge on EDC actions on the endocrine system, a comprehensive, holistic understanding of the impact on the HP axis is still lacking. HYPIEND aims to understand the effects of EDC co-exposure in the function and epigenetic programming of the HP axis to delineate interventional strategies for minimizing exposure and consequences on the neuroendocrine system during the perinatal and pre-pubertal stages. To do that, a computational toxicology methodological framework will be built leveraging public data and state of the art data analysis techniques to define EDC co-exposure patterns in target population. The resulting patterns will be evaluated in a sequential tiered approach consisting in cell-based screenings, Danio rerio models of HP axes, in vitro, in silico and in vivo models of placenta and blood brain barrier diffusion and new models of organoids-based organ-on-chip recapitulating the HP axis. EDC effects on epigenetic programming will be evaluated in preclinical models of perinatal and early childhood. Whole genome DNA methylation patterns in the different models will be explored as a source of non-invasive biomarkers of HP axis disruption by EDC. The knowledge generated in preclinical models will be applied in two multi-centre-controlled intervention studies intended to minimize exposure to EDC in children in the perinatal and pre-puberty stages. HYPIEND outcomes will be novel approach methodologies based in in vitro and in silico models, non-invasive biomarkers of HP disruption by EDC and new intervention strategies to minimize EDC exposure in sensitive population.

HAPLO-iPS Generation of human induced pluripotent stem cells from haplo-selected cord blood samples

Call: Open Call Collection OC-2021-1
Principal investigator: Laia Tolosa
Role: Participant
Year: 2022

HAPLO-iPS aims to create a collaborative network to provide a framework for hiPSC generation of hiPSC homozygous for frequent HLA haplotypes, compatible with a significant percentage of the population to be used for cell therapy clinical trials and to create a data collection system (REGISTRY) for such lines. HAPLO-iPS will establish an European-based excellence network on hiPSC-derived cell-based medicines that not only will boost the state-of-the-art of this research field if not will also contribute to Europe worldleadership through the medical, scientific, economic, and social development of Europe and strengthening Europe's competitiveness capacities. This network includes all the relevant stakeholders: hiPSC generation/banking centres, CB banks that will supply cord blood units; manufacturing centres (GMP complying), immunology experts, chemistry and manufacturing controls, regulatory bodies, National Agencies, and ethics experts. The challenge will be approached essentially by networking with all the stakeholders involved sharing knowledge, standardizing methodology and developing an educational training programme for researchers.

HAPLO-iPS is also promoting the participation of researchers from less research-intensive countries as a significant percentage of the members are from ITC countries. ITC participants will have access to research facilities, training courses, mentoring of ITC young researchers and will participate spreading excellence and widening participation programme. Furthermore, Key leadership positions in the Action Management are reserved to COST ITC.

Overall, this proposal will pioneer new approaches that will foster the progress of a haplo-selected hiPS generation of therapeutics by the development, implementation and exploitation of a registry with all the information for the benefit of patients.

PROTEMIC Integrated Spectroscopy for Protein Analysis Using Metasurfaces and Interband/Quantum Cascade Devices

Call: HORIZON-MSCA-2023-DN-01-01
Principal investigator: Julia Kuligowsky
Role: Participant
Year: 2024

Proteins are the fundamental building blocks of life and are complex biopolymers. The pharmaceutical industry and medicine have an unmet requirement for dynamic, insitu monitoring of structural changes of proteins. Proteins may incorrectly fold during the expression process, or denature in response to changes in temperature, pH amongst others. These deviations lead to loss of function, loss of therapeutic effectiveness, increased immunogenicity or reduced product shelf life. For example, growing amounts of human milk are donated to serve the needs of pre-term infants but there is a lack of quality control to monitor protein quality during pasteurisation and storage. Current analysis techniques require extracting samples from the reaction vessel, which risks contamination, or use indirect measurements of the protein structure. PROTEMIC is a Double Doctorate Training Network that brings together the disciplines of Physics, Analytical Chemistry and Biochemistry to determine the protein structure from the sample's Mid Infrared absorption spectrum without the use of labels or reagents. PROTEMIC builds on the team's experiences with the successful OPTAPHI joint doctoral network and embeds the Doctoral Candidates into multiple disciplines to gain skills that cannot be obtained from a single host, and master biochemistry and spectroscopy. The project builds and expands on breakthroughs recently made in the OPTAPHI project, for example new photonic integrated circuits and world first photothermal spectroscopy results. PROTEMIC embeds metasurface and photonic integrated circuits into the reaction vessel to provide insitu mid IR spectroscopy for the first time and map structural changes during dynamic reactions in realtime. These results will improve the efficiency of the production of protein based pharmaceuticals and through the use of metasurface microtitre plates, allow the scalable screening of proteins for the encapsulation of oral vaccines, accelerating drug discovery.

NANOEAR New DX243-conjugated nanoparticles as a neuroprotective drug for hearing disorders

Call: (EuroNanoMed III) Joint Transnational Call for Proposals (2021) for “European Innovative Research & Technological Development Projects in Nanomedicine”
Principal investigator: Jose María Millán Salvador
Role: Participant
Year: 2022

Because of their high prevalence, 5% of the population worldwide, an untreated decline of hearing impairments, has a profound negative impact on the affected individuals' quality of life, impeding communication, and leading to social isolation, depression, reduced physical and cognitive functions. Impaired synaptic transmission, degeneration of auditory neuron neurites, and neuronal loss characterize most of these disorders. Despite progress on hearing loss mechanisms, treatment options are mostly missing, and the economic and societal burden on healthcare systems worldwide keeps increasing. To date, the cochlear implant, which bypasses the damaged HCs by providing direct electrical stimulation of the primary auditory SGNs, is used to restore functional hearing in profoundly deaf patients. However, their beneficial outcomes vary significantly among patients, often impacted by the number and functional state of surviving auditory SGNs. A therapeutic approach that would prevent or delay degenerative processes is thus urgently needed. We previously identified a new drug that exhibits excellent potential to prolong neuronal survival. The efficacy of this drug in the inner ear and drug' stability after delivery is yet to be established. Here, we take advantage of two deaf mouse models, each displaying hearing loss and varying degree of neuronal degeneration. Using these mice as model systems for neuronal degeneration (early-onset, slow progression for clarin-1, and late-onset, rapid progression for clarin-2), the objective of NANOEAR is to develop a novel nanoparticle-based pharmacologic strategy to prevent and/or correct deafness-mediated neuronal degeneration.

CHIP-AML22 Improved diagnostics and survival for all children with Acute Myeloid Leukemia treated within the NOPHO-DB-SHIP consortium; a cross-European collaboration

Call: EU4H-2021-PJ-02
Principal investigator: Jose Maria Fernandez Navarro
Role: Participant
Year: 2022

We hereby apply for funding for the practical implementation of front-line genetic diagnostics and targeted treatment for children with acute myeloid leukemia (AML) within our consortium. AML is a severe form of blood cancer and despite intensive chemotherapy, treatment results are dissatisfactory. Through recent advances in risk-adapted treatment, based on 1) the cytogenetic basis of the disease and 2) treatment response as measured by MRD (minimal residual disease), survival rates are typically around 70%.

AML in children is rare and necessitates international collaborations to improve outcome. NOPHO countries (Nordic Society Pediatric Oncology Hematology) Sweden, Denmark, Finland, Norway, Iceland, Estonia, Lithuania, Latvia, together with the Netherlands, Belgium and Hong Kong, started the AML12 treatment protocol year 2012. Since 2012, Spain, Israel and Portugal have joined and currently our consortium is named NOPHO-DB-SHIP. Central in AML12 was cytogenetic risk-group allocation and advanced MRDbased treatment adaptation, resulting in an unprecedented survival of 80% for patients with access to the full diagnostic workup. Herein, we present the successor of AML12; the CHildhood International Protocol - Acute Myeloid Leukemia 2022 (CHIP-AML22). CHIP-AML22 aims to consolidate cytogenetic and flow MRD risk-adaptation and make this available across all participating countries.

In addition, based on the lessons learned from AML12, more advanced cytogenetic profiling of disease will be implemented with the aim to improved risk-stratification. Further, we aim that next generation sequencing (NGS) will be used to guide novel tailored and targeted treatment for a subset of patients, as well as to further optimize MRD-analysis. In many participating countries NGS techniques are not performed as standard of care. We aim for a cross-consortium implementation of these techniques and treatments to allow equal access to optimal care for all disease children with AML.