Heart attacks are common and can leave survivors suffering cardiogenic shock (CGS), with its extremely high risk of early death (42% versus 4% for non-CGS) and high incidence of chronic heart failure, with its associated socio-economic disease burden (ill-health, recurrent heart failure admissions, no return to full time activities, need for expensive therapeutic devices and life-long drugs). Outcomes from CGS are even worse in, females, the elderly (mortality>70%) and high risk sub-groups. The incidence of CGS in Europe alone is >50 000 patients pa. This unacceptably high mortality/morbidity rate represents a true unmet clinical need. No clear strategy exists to improve outcomes, with ad hoc therapies given too late in a spiralling, irrecoverable process. EURO SHOCK aims to improve outcomes for CGS patients. At its core is a robust phase3 randomised trial comparing a novel strategy of very early use of ECMO (Extracorporeal Membrane Oxygenation) to current standard of care. Evidence suggests very early ECMO will halt the spiral of decline and so significantly reduce 12 month death rate and need for heart failure re-admissions. Since both costs of CGS, and ECMO are high a health-economic cost efficacy analysis will be core. A cardiac magnetic resonance imaging sub-study will test novel protocols in sick patients and provide mechanistic data. We will test transfer networks for CGS patients and analyse ECG data to determine which patients benefit most from early transfer. Our multidisciplinary consortium comprises renowned physician-scientists, statisticians, health economists and technology providers, including specialised ECMO SME. EURO SHOCK will impact on heart attack survivors, healthcare providers and Europe`s medical technology sector by 1) reducing healthcare costs associated with CGS 2) provide novel cost effective framework for cardiac interventions 3) delivering innovative healthcare technologies and 4) informing guidelines for effective CGS intervention.

Obtaining functional information on living organs non-invasively across different size scales is a tremendous challenge in medical imaging research, as diseases start locally at the cellular level deep into organs before expressing large-scale and observable symptoms. The unique complexity of the human brain adds another level of difficulty for neuroimaging. The cerebrovascular system consists of a multiscale network of blood vessels. Interaction between neurons and this vascular system, the so-called neurovascular coupling, is a major foundation of brain function leading to constant adaptation of the local cerebral blood flow to local metabolic demand. Its alteration is intimately linked to cerebral dysfunction. Current brain imaging modalities are essential for evaluating cerebrovascular diseases in patients but are restricted to millimetric resolution and fail to capture most of blood flow dynamics. Here, we propose to revolutionize the field of neuroimaging by introducing a groundbreaking technology called functional Ultrasound Localization Microscopy (fULM) capable of monitoring transcranially the whole human brain vasculature and function down to microscopic resolution. Beyond opening a complete paradigm shift in brain angiography (at least two orders of magnitude increase in spatial resolution), fULM will also be able to map the functional brain response during task-evoked and spontaneous activity at microscopic levels. We will address major technical challenges of ultrasound imaging, develop advanced neurocomputational analysis methods, validate our methods in preclinical models of cerebrovascular diseases and perform a First-In-Human study. Fundamental understanding of brain hemodynamics and neurovascular coupling as well as early clinical diagnosis of neurovascular abnormalities and evaluation of drug efficacy would tremendously benefit from such capabilities revealing both the brain vasculature and neurofunctional activity down to microscopic resolutions.

Crigler-Najjar syndrome (CN) is a rare recessive disorder caused by mutations in the uridine diphosphate glucuronosyltransferase 1A1(UGT1A1) gene. CN is a life-threatening disease with no cure which constitutes a severe burden for the patients, their families, and the society. CureCN has the objective of developing a curative gene therapy for CN syndrome based on liver gene transfer with and adeno-associated virus (AAV) vector expressing the UGT1A1 transgene. Additional goals of CureCN are to develop strategies to allow for vector re-administration and to address the issue of pre-existing anti-AAV neutralizing antibodies (NAbs), which prevent large proportion of seropositive patients from receiving AAV mediated gene therapy. Proof-of-concept studies of AAV8-UGT1A1 gene transfer provide a strong rationale for the safety and efficacy of gene therapy for CN. CureCN proposes to carry out an open-label, multicenter clinical trial of AAV8-UGT1A1 gene transfer to prove the safety and efficacy of the therapy in severe CN patients, and file for marketing authorization in Europe at the end of the study. CureCN will also produce enabling data for the clinical translation of a groundbreaking immunomodulatory strategy to allow for vector administration. Additionally, a technology for the selective removal of anti-AAV NAbs from the bloodstream of seropositive patients will be developed. The goal of these studies is to ultimately allow all CN patients to access AAV8-UGT1A1 gene therapy. CureCN is a patient-driven initiative that gathers top clinicians and scientists; it also includes small medium enterprises in its partners, to foster economic growth and valorization of intellectual property. CureCN sets itself in the ambitious goal set by the IRDiRC by 2020 by developing a curative treatment for CN syndrome. Importantly, it validates technologies that will broaden the scope of gene therapy, thus will have an impact on the development of treatments for several other rare diseases.

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system. Since there is no cure available yet for MS, the primary therapeutic goal for MS patients is to slow down disability progression and to reduce relapses at early stages of the disease. Despite 19 available disease modifying treatments (DMTs), the large heterogeneity of the disease, further complicated by the high prevalance of comorbidities and multipharmacy, and the limited understanding of the working mechanisms DMT thereon results in a poor and variable treatment response in a real-world setting. The CLAIMS project is a public-private partnership aiming to address this and make precision medicine for MS patients a reality through data-driven prognosis and treatment advice, in order to better slow down disease progression and eventually conversion to progressive MS. We will develop, validate and submit for regulatory approval a companion diagnostic platform, which offers the MS care team a holistic view of the patient through the visualization of the clinical and subclinical biomarkers and the prediction of the expected disease trajectory under different treatments. For biomarker extraction and treatment prediction, state-of-the-art technologies that allow a reliable and scalable implementation across the world will be used. We believe this platform will initiate the paradigm shift from a trial-and-error, experienced-based treatment of MS patients to a first-time-right, value-based holistic treatment management, and will, hence, improve patient outcomes at a lower total cost of care, enhance patient experience and improve the well-being of the care team.