How does cross play of DNA replication, packaging and innate immune response determine assembly efficiency of viral vectors for gene therapies?

Gene therapies are novel therapeutic approaches for rare genetic diseases. One key technology for gene therapies are engineered viral vectors, especially recombinant Adeno-associated Viruses (rAAVs). However, their manufacturing is highly inefficient, with only 1/100,000 rAAVs being fully functional. We need a better understanding of the biology and regulation underlying rAAV assembly in producer cells to optimise industrial biomanufacturing processes. We hypothesise that timing, subcellular localisation of vectors and innate immunity are critical regulators of rAAV assembly, and thus manufacturing efficiency.

You will join a highly collaborative team from the Universities of Hull and York (main supervisor Dr André Voelzmann, co-supervisors Dr Stefano Caserta and Prof Fred Antson). You will primarily be based within Biological Sciences and HYMS/Centre for Biomedicine at the University of Hull and parts of the research program will be conducted within the Department of Chemistry and the Bioscience Technology Facility at the University of York.

You will characterise the molecular dynamics and innate immune mechanisms that regulate and limit rAAV DNA replication and packaging into rAAV capsids, through the establishment of in vivo and in vitro systems. This work will lay the foundation to target these mechanisms to optimise viral vector production.

You will gain expertise in cutting-edge techniques including cell culture, super-resolution microscopy, single molecule nano-manipulations and flow cytometry at our cutting-edge facilities. You will also apply advanced cryo-electron microscopy to derive accurate 3D structures for macromolecular complexes that are key for rAAV assembly. Hence, you will become a future professional expert combining several well-sought-after technical skills with interdisciplinary knowledge.

You will be part of the first cohort of the new Yorkshire Bioscience Doctoral Training Programme (DTP) which builds on the expertise of the White Rose Mechanistic Biology DTP. You will benefit from our cohort-based training modules, masterclasses and DTP events and local career development opportunities.