Baculovirus is a highly efficient delivery system for recombinant genes into eukaryotic cells, with great impact on the production of eukaryotic proteins, including high-value drug targets for pharmaceutical development. Vaccines against cervicular cancer and others are produced by this method. More recently, baculovirus has emerged as a versatile tool for gene therapy. We contributed to the field the award-winning MultiBac technology for multiprotein complex research.
These applications, at the forefront of modern biology, rely on a large baculovirus genome (130 kb) derived from wild-type AcMNPV. This genome has been intensively researched, mainly by entymologists. Genes essential for propagation in nature and in cell culture were delineated, as well as non-essential genes, and genes which impede applications in the laboratory. Several genetic alterations of the wild-type viral genome have been performed, by classical knock-out technologies, to improve gene insertion, delivery and protein production properties. Such alterations require an excessive effort by specialists. Therefore, it is currently not possible to fully exploit the vast potential of the baculovirus system.
In the present project, we boldly propose to fully reverse the current approach. We will design in silico and construct in vitro new, fully synthetic customized baculovirus genomes which will be, for the first time, in an optimized, streamlined, highly versatile format for the transfr of designer multigene DNA circuitry for next-generation drug discovery and gene therapy. We will apply state-of-the-art genome editing tools, notably CRISPR-Cas9, to inform our approach by systematically disrupting and eliminating genes and non-coding DNA elements including gene regulatory regions. We also aim to address the so-called “scale-up problem” which currently impedes pharma-scale biologics production. As proof-of-concept, we already created a partly synthetic hybrid genome by replacing a large part (20 kb) of wild-type with reconfigured synthetic DNA. Rigorous validation of this prototype genome compellingly underpins our approach.
The PhD student will be working in the team of Prof Imre Berger at the Max Planck Bristol Centre at the University of Bristol, and benefit from a network of international expert collaborators, in academia and industry.