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.

In order to be fully effective as an oncolytic virus or vaccine, achieving of precise and specific traits are pivotal. However, current technologies are limited to the confines of a virus’s existing biological make-up. They are left with manipulation of genes within the virus e.g. deleting and adding proteins, inability to manipulate silent codes etc. where achievement of such precision is simply not possible from such naturally-rooted manipulation. The SynVaccine solution taps into 3 billion years of viral evolutionary data which is continually updated, ensuring the highest degree of accuracy on rules that govern all viruses found today. Through this, it becomes the only solution to govern the rules of viruses on a cellular level, giving the important ability to precisely dictate the traits and behaviour of the newly designed, bottom-up, created viruses. As a result, only the most effective oncolytic viruses and vaccines are ever produced, ensuring the highest levels of treatment and immunity. We have invested over €3.1 million into the development and testing of our solution to ensure its robustness and efficiency, and thus move into the next stage of specific drug development. Our management and scientific leadership capacity involves 10 multi-disciplinary experts in the fields of; entrepreneurship, virology, synthetic biology, computational biology, engineering and automation. The proposed work in Phase 1 of the SME instrument fits into our overall plan to reach the market by contributing the financial resources needed to plan a fast sound wider deployment of our SynVaccine derived solutions, and their market uptake.