In the EU alone, according to the Orphanet DB (https://pubmed.ncbi.nlm.nih.gov/31527858/), 30 million persons, 3,5-6% of the general population, are affected by one of the 6,172 different rare diseases (RDs) of which 72% are genetic and 70% affect children. The path to diagnosis for people suffering from a RD is burdensome, often severely delayed by a diagnostic odyssey. Lack of timely diagnosis affects disease management, family planning, identification of potential beneficial treatments and / or clinical trials. This unacceptable situation does not meet the concept of equity for EU citizens, and requires rapid, structured, and cost-effective corrective actions. The Screen4Care (S4C) consortium will leverage the genomic and digital advent to develop and pilot genetic NBS and AI-guided symptom recognition algorithms, while accounting for all relevant legal, regulatory and ethical considerations. S4C aims to harmonize the results of existing efforts in a horizon scan, by looking at the totality of the available data resources, diagnostic algorithms, and other initiatives with similar ultimate goals. The genetic NBS will interrogate 1) currently treatable RDs (TREAT-map gene panel), 2) actionable RDs (ACT-map gene panel) in 18.000 new-borns in 3 EU countries (D, It, and Cz). Further, S4C will offer whole genome sequencing (WGS) to early symptomatic babies, tested negatively during panel-based NBS to identify known NBS-escaped RDs and novel genes/phenotypes. S4C will also provide two digital diagnosis support systems for RD on the basis of features and symptom complexes: 1) federated ML- and literature-evidence-based algorithm for continuous and automated screening of EHR and 2) meta symptom checker with virtual clinics for patients and HCP offering the possibility of increased accuracy of diagnosis and ongoing supports. Our ambitious goal is to evaluate the validity of our multi-pronged approach to shorten the time to diagnosis for all patients affect by RDs, improve value-based healthcare resource utilization, and hopefully reduce the suffering of millions of European citizens.

Progress in the life sciences and related technologies offer great potential for therapeutic benefits to patients in need. However, major adaptations to current paradigms of bringing medicines to patients are required in order to realize that potential and to address important challenges in the healthcare ecosystem. Against this background, several initiatives are exploring new pathways to market, collectively referred to as Medicines Adaptive Pathways to Patients (MAPPs). The ADAPT-SMART consortium is aligning a limited number of major stakeholders eager to progress towards MAPPs implementation. It will act as a neutral collaborative platform that will engage industry, SMEs, regulators, Health Technology Assessment bodies (HTAs), payers, governments, clinicians and patients. The ADAPT-SMART consortium will contribute to align understanding of the impact of MAPPs, to share learnings between all stakeholders, and to allow the field to actively work towards MAPPs implementation. The impact of the ADAPT-SMART CSA will be a result of the delivery of • actionable advice/recommendations to IMI on how to best leverage results from past/current projects; • concrete proposals for future (IMI) projects; • actionable advice/recommendations and information to other actors in the healthcare environment; • synthesis of learnings from pilot projects and case studies with relevance to MAPPs; • communication of CSA outcomes by way of publications and conference presentations. This CSA will increase the probability of successful implementation of MAPPs and accelerate access to crucial therapies, thus improving the position of both the patients in need of novel treatments and the research-based pharmaceutical industry.

Major current hurdles for wide clinical use of AAV vectors are attributable primarily to: (i) host elimination by both immune and non-immune sequestering mechanisms – such neutralization by host antibody responses critically limits the possibility of repeated AAV delivery; (ii) AAVs are prevalent in the environment and hence a large proportion of the population carry AAV antibodies (up to 80%)– this pre-existing immunity renders AAV unable to infect target cells forcing substantial patient cohorts to be excluded from clinical trials. The current proposal is founded on compelling track record in the field and brings together a ‘best-with-best’ multidisciplinary team of international leading academic and EFPIA partners with complimentary expertise in gene therapy, immunology, chemistry, engineering, biotechnology, drug safety, viral vector production, regulatory and clinical trials. The overall goal is to analyse the currently available clinical data and then design preclinical and clinical studies to fill the knowledge gaps in advanced therapies development. Our main aims are to: 1) Develop improved model systems for predicting product immunogenicity in humans. This will be achieved by generating human and NHP 3D hepatic models; 2) Enhance our understanding of gene/cell therapy drug metabolism inside a host of cell types. The plan is to define metabolism of the therapeutic vector genome in different cell types to understand whether rates of degradation, episomal maintenance, or integration, and metabolic stress induced by AAV vector transgene expression vary from cell to cell. We will then adopt strategies to mitigate the loss of vector genomes and improve persistence; 3) Use diverse clinical expertise to establish the clinical factors around pre-existing immunity limiting patient access to advanced therapies therapy; 4) Engage regulators to ensure that the concepts and the data generated through this IMI programme will fill the gaps and support furture trials.