PIs: Professor Imre Berger, Dr Francesco Aulicino, Professor Gavin Welsh, and Professor Moin Saleem
Next-generation therapeutic genome engineering intervention (Gene Therapy 2.0), critically depends on highly efficient delivery of large synthetic multifunctional DNA circuitry and their efficient and sustainably realisation in the target cell. The Berger lab at the Max Planck Bristol Centre engineered next-generation synthetic virus-derived nanosystems (SVNs) derived from a non-human circular dsDNA viral vector (AcMNPV) characterised by unprecedented DNA cargo capacity (exceeding 100 kb). Our SVNs can faithfully deliver genetically encoded complex multigene CRISPR/Cas9 based editing DNA including multiplexed prime editing modalities, demonstrated by successful genetic repair of a key protein in steroid-resistant nephrotic syndrome (SRNS) in patient derived kidney cells.
Our ambition is to expand our successful proof-of-concept to bona fide gene therapeutic intervention in animal models and, ultimately, humans. A prerequisite is precise control of the intracellular immune response mediated by the cGAS/STING DNA-sensing pathway, that can inactivate multifunctional DNA circuitry as an antiviral defence mechanism. You will engineer powerful protein-based cGAS/STING inhibition modalities (STING-SHIELD) to overcome transgene inactivation and integrate these modules into our SVNs. This will provide us with potentially game-changing 2nd generation SVNs, comprising STING-SHIELD, to enable rapid and reversible cGAS/STING inactivation until the genomic repair of interest is completed, to transform gene therapy.