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.

Patients with cardiovascular risk factors, e.g. hypertension and obesity are at risk of developing heart failure with preserved ejection fraction (HFpEF), a highly prevalent disease in the elderly, mostly women population. There is currently no specific, defined treatment for HFpEF, beyond control of risk factors. Activation of cardiac and vascular Beta3-adrenergic receptors (B3AR) represents a new concept and a novel target for structural cardiac disease. B3AR expression and coupling were demonstrated in human myocardium and vasculature. In pre-clinical models with expression of the human receptor, its activation attenuates myocardial remodelling, i.e. decreases hypertrophy and fibrosis in response to neurohormonal or hemodynamic stress. Mirabegron is a new agonist of B3AR available for human use, that was recently introduced for a non-cardiovascular indication (overactive bladder disease). The primary objective of the project is to design and implement a multi-centric, prospective, randomized, placebo-controlled clinical trial testing the additional beneficial effect of mirabegron, versus placebo over 12 months on top of standard treatment of patients carrying structural cardiac disease without overt heart failure (stage B of AHA classification); the co-primary end-point will be the quantitative change in myocardial hypertrophy measured by cardiac MRI; and in diastolic ventricular function, measured by Doppler echocardiography (E/E’); in addition, exercise tolerance (peak VO2) will be measured as well as circulating biomarkers reflecting both myocardial remodeling and function. In addition, we will test the effect of mirabegron on beige/brown fat activation and metabolism. Our proposal therefore combines a major conceptual advance and repurposing of an original drug to validate pre-clinical discoveries in the context of a major health problem.

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.