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.

The ISIDORe consortium, made of the capacities of European ESFRI infrastructures and coordinated networks, proposes to assemble the largest and most diverse research and service providing instrument to study infectious diseases in Europe, from structural biology to clinical trials. Giving scientists access to the whole extent of our state of the art facilities, cutting edge services, advanced equipment and expertise, in an integrated way and with a common goal, will enable or accelerate the generation of new knowledge and intervention tools to ultimately help control SARS CoV 2 in particular, and epidemic prone pathogens in general, while avoiding fragmentation and duplication among European initiatives. Such a global and interdisciplinary approach is meant to allow the implementation of user projects that are larger, more ambitious and more impactful than the EU supported transnational activities that the consortium is used to run. Our proposition is ambitious but achievable in a timely fashion due to the relevance and previous experience of the partners that we have gathered and that have complementary fields of expertise, which addresses the need for an interdisciplinary effort. Leveraging all these existing strengths to develop synergies will create an additional value and enhance Europe capacity for controlling emerging or re emerging and epidemic infectious diseases, starting with the COVID 19 pandemic. Such a global and coordinated approach is consistent with the recommendations of the One Health concept and necessary to make significant contributions to solving complex societal problems like epidemics and pandemics.